KR20210125457A - Composition And Kit For Diagnosing Prognosis Of Bladder Cancer According To Recurrence - Google Patents

Abstract

The present invention provides a composition for prognostic diagnosis according to whether bladder cancer recurs, a kit for prognosis diagnosis of bladder cancer, and a method for providing information necessary for prognosis diagnosis of bladder cancer using the same. It is possible to help establish a treatment strategy for the bladder cancer patients by diagnosing and predicting the prognosis such as the possibility of survival or recurrence after treatment depending on the recurrence of the bladder cancer using the composition and kit for prognostic diagnosis of the bladder cancer of the present invention.

Description

Composition And Kit For Diagnosing Prognosis Of Bladder Cancer According To Recurrence}

The present invention relates to a composition for diagnosing the prognosis of bladder cancer according to the recurrence of bladder cancer, a kit for diagnosing the prognosis of bladder cancer, and a method for providing information necessary for prognostic diagnosis of a bladder cancer patient using the same.

Bladder cancer (BC) is the most frequently occurring cancer in the urinary system. As such, the incidence rate is lower than in the West, but the incidence rate is increasing every year, and it is known as the cancer with the highest incidence among cancers of the urinary system in Korea (Lee C, et al., 1992).

Bladder cancer is largely divided into non-muscle invasive bladder cancer (NMIBC) and invasive (muscle invasive bladder cancer, MIBC) bladder cancer according to the degree of invasiveness. Noninvasive bladder cancer is a lesion in which the cancer is confined to the mucous membrane without invasion of the muscle layer. recurrence and progression to invasive cancer are problematic.

On the other hand, invasive bladder cancer refers to a state in which the cancer has penetrated to the muscle layer, and for its treatment, it is necessary to perform complex urinary diversion along with radical cystectomy, and it may lead to fatal results for the patient. Therefore, it is very important to predict, early detection and prevention of recurrence and progression after primary treatment.

For this reason, early diagnosis of bladder cancer and development of markers that can check the remaining lifespan after cancer onset is required. Patent Document 1 discloses a series of genetic markers that can be used for detection or diagnosis of human bladder cancer.

Although markers for diagnosing bladder cancer and other cancers have been developed, research has not yet been made on the relationship between the recurrence of bladder cancer patients or the survival rate of patients with recurrent bladder cancer and mutations in specific genes.

In order to diagnose bladder cancer or to discover a therapeutic agent for bladder cancer and determine a treatment strategy, the present inventors focused on the need to develop a marker capable of diagnosing the prognosis of a bladder cancer patient, The relationship with recurrence was studied.

Korean Patent Publication No. 2014-0092905 (2014.07.24)

In order to apply a therapeutic strategy suitable for bladder cancer patients, it is necessary to develop a marker that can predict the prognosis of bladder cancer patients and provide information to determine a treatment strategy. An object of the present invention is to provide a marker that helps to diagnose a bladder cancer patient's prognosis and determine a treatment strategy for a bladder cancer patient based on the recurrence of bladder cancer.

One aspect of the present invention is BTBD10 gene mutation, GRIA2 gene mutation, GUCY1A2 gene mutation, ITGA3 gene mutation, MED1 gene mutation, MTUS2 gene mutation, PIK3C2A gene mutation, QARS gene mutation, SALL1 gene mutation , SIN3A gene mutation and SLC45A1 gene mutation provides a composition for prognostic diagnosis of bladder cancer comprising a reagent capable of detecting a recurrence-specific marker of a bladder cancer patient comprising at least one selected from the group consisting of mutations.

Another aspect of the present invention is BTBD10 gene mutation, GRIA2 gene mutation, GUCY1A2 gene mutation, ITGA3 gene mutation, MED1 gene mutation, MTUS2 gene mutation, PIK3C2A gene mutation, QARS gene mutation, SALL1 gene mutation , SIN3A gene mutation and SLC45A1 gene mutation provides a kit for prognostic diagnosis of bladder cancer comprising a reagent capable of detecting a recurrence-specific marker of a bladder cancer patient comprising at least one selected from the group consisting of mutations.

Another aspect of the present invention comprises the steps of preparing a sample DNA from a sample of a bladder cancer patient; and confirming the presence or absence of a recurrence-specific marker using the composition for prognosis diagnosis of bladder cancer or the kit for prognosis diagnosis of bladder cancer with respect to the sample DNA; a method of providing information necessary for prognostic diagnosis of bladder cancer patients, including to provide.

Using the composition for prognostic diagnosis of bladder cancer of the present invention and a kit for prognostic diagnosis of bladder cancer comprising the same, prognosis such as viability or recurrence possibility after treatment can be diagnosed and predicted based on whether bladder cancer recurs. This can help establish a treatment strategy for bladder cancer patients.

1 shows the Kaplan Meier survival curve and log rank test results showing the total survival period when the event is determined as death for 11 genes of the candidate gene group 1 & 2 group as an embodiment of the present invention. .
2 shows the Kaplan Meier survival curve and log-rank test results showing the disease-free survival period when the event is determined as recurrence for 11 genes of the candidate gene group 1 & 2 as an embodiment of the present invention. .

In this specification, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In general, the nomenclature used herein and the experimental methods described below are those well known and commonly used in the art.

In the present invention, the term 'gene' and its variants include DNA fragments involved in polypeptide chain generation; It includes regions before and after the coding region, eg promoters and 3'-untranslated regions, respectively, as well as intervening sequences (introns) between individual coding fragments (exons).

As used herein, the term 'cancer' includes any member of a class of diseases characterized by the uncontrolled growth of abnormal cells. The term includes all known cancers and neoplastic conditions, whether characterized as malignant, benign, soft tissue or solid, and cancers of all stages and grades, including cancers before and after metastasis.

In the present invention, the term 'prognosis' refers to the progress and cure of neoplastic diseases such as cancer, such as the possibility of cancer-caused death or progression, including recurrence, metastatic spread, and drug resistance, for example. For the purpose of the present invention, it may be to predict the prognosis of bladder cancer, preferably to predict the disease-free survival rate or survival rate of bladder cancer patients.

In the present invention, the term 'diagnosis' refers to confirming the presence or characteristics of a pathological condition, and for the purpose of the present invention, not only confirming whether or not cancer occurs, but also recurrence, metastasis, drug reactivity, resistance of the subject after treatment of cancer It means judging whether or not Preferably, when using the mutation of the gene of the present invention, it is possible to predict whether or not the subject will develop cancer, as well as whether the prognosis of the subject will be good in the future by checking whether the mutation is present from the subject's sample.

In the present invention, the term 'relapse-specific marker' may refer to a mutation in a gene or mutations in a gene that can be an indicator for predicting the prognosis of bladder cancer in a subject after treatment based on whether bladder cancer recurs. Also, in the present invention, the 'marker gene' may be used to refer to each gene mutation included in the recurrence-specific marker.

1. Composition and kit for prognostic diagnosis of bladder cancer

One aspect of the present invention provides a composition for prognostic diagnosis of bladder cancer comprising a reagent capable of detecting a recurrence-specific marker of a bladder cancer patient. The recurrence-specific marker of the composition for prognosis diagnosis of bladder cancer of the present invention may be an index predicting the prognosis of bladder cancer in a subject after treatment, depending on whether bladder cancer recurs.

For example, if the recurrence-specific marker is identified and bladder cancer recurrence is confirmed in a bladder cancer patient, if applicable, the survival rate of the individual is higher or the recurrence rate is lower than that of a person for which the recurrence-specific marker is not identified. .

Or, conversely, when the recurrence-specific marker is identified and bladder cancer recurrence is confirmed in a bladder cancer patient, the survival rate of the subject is lower or the recurrence rate is higher than that of a person for which the recurrence-specific marker is not identified. can judge

Specifically, the relapse-specific marker is a mutation of the BTBD10 gene (Gene bank accession number: NM_032320.6), a mutation of the GRIA2 gene (Gene bank accession number: NM_001083619.1), and the GUCY1A2 gene (Gene bank accession number: NM_000855.3) ) mutation, ITGA3 gene (Gene bank accession number: NM_002204.4) mutation, MED1 gene (Gene bank accession number: NM_004774.4) mutation, MTUS2 gene (Gene bank accession number: NM_001033602.3) mutation, PIK3C2A Mutation of gene (Gene bank accession number: NM_002645.4), QARS gene (Gene bank accession number: NM_005051.3) mutation, SALL1 gene (Gene bank accession number: NM_002968.2) mutation, SIN3A gene (Gene bank accession) number: NM_001145357.2) mutation, SLC45A1 gene (Gene bank accession number: NM_001080397.2) may include at least one selected from the group consisting of mutations.

In addition, the recurrence-specific marker is a mutation of the ABCC4 gene (Gene bank accession number: NM_005845.4), a mutation of the CNTN2 gene (Gene bank accession number: NM_005076.5), and the EPAS1 gene (Gene bank accession number: NM_001430.5) mutation, HPD gene (Gene bank accession number: NM_002150.3) mutation, IGDCC4 gene (Gene bank accession number: NM_020962.3) mutation, KBTBD3 gene (Gene bank accession number: NM_152433.3) mutation, MAATS1 gene (Gene bank accession number: NM_033364.4) mutation, RBP2 gene (Gene bank accession number: NM_004164.3) mutation, SULT2A1 gene (Gene bank accession number: NM_003167.4) mutation, TMPRSS9 gene (Gene bank accession number) : NM_182973.2) mutation and TXK gene (Gene bank accession number: NM_003328.3) may further include at least one selected from the group consisting of mutations.

The full names of the abbreviations of the genes are ABCC4 (ATP binding cassette subfamily C member 4), BTBD10 (BTB domain containing 10), CNTN2 (contactin 2), EPAS1 (endothelial PAS domain protein 1), GRIA2 (glutamate ionotropic receptor AMPA type), respectively. subunit 2), GUCY1A2 (guanylate cyclase 1 soluble subunit alpha 2), HPD (4-hydroxyphenylpyruvate dioxygenase), IGDCC4 (immunoglobulin superfamily DCC subclass member 4), ITGA3 (integrin subunit alpha 3), KBTBD3 (kelch repeat and BTB domain containing 3) ), MAATS1 (MYCBP associated and testis expressed 1), MED1 (mediator complex subunit 1), MTUS2 (microtubule associated scaffold protein 2), PIK3C2A (phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 alpha), QARS (glutaminyl- tRNA synthetase 1), retinol binding protein 2 (RBP2), spalt like transcription factor 1 (SALL1), SIN3 transcription regulator family member A (SIN3A), solute carrier family 45 member 1 (SLC45A1), sulfotransferase family 2A member 1 (SULT2A1) , TMPRSS9 (transmembrane serine protease 9), TXK (TXK tyrosine kinase) can

In the present invention, the reagent capable of detecting the recurrence-specific marker may include one or more selected from the group consisting of a primer, a probe, an antibody, and an aptamer for the recurrence-specific marker. The primer, probe, antibody or aptamer can be manufactured using a known technique, and a primer, probe, antibody or aptamer capable of detecting a mutation of a gene of the present invention is included in the scope of the present invention.

In the present invention, the term 'primer' is a nucleic acid sequence having a short free 3' hydroxyl group, which can form a base pair with a complementary template and is a starting point for template strand copying. It refers to a short nucleic acid sequence that functions as The primers are capable of initiating DNA synthesis in the presence of reagents for the polymerization reaction (ie, DNA polymerase or reverse transcriptase) and the four different nucleoside triphosphates in appropriate buffer solutions and temperatures. In the present invention, PCR amplification is performed using the forward and reverse primers of the mutant gene to determine the presence or absence of a corresponding gene marker through the generation of a desired product, and it can be used for diagnosis. For example, in the case of a forward primer, a primer corresponding to a mutant in which deletion, substitution, or insertion has occurred is designed, and a reverse primer is designed and PCR corresponding to a position where mutation does not occur, mutation of the gene of the present invention In the case of a chain, an amplification product will be generated by PCR, but if it is not a mutant of the gene of the present invention, no amplification product will be generated. PCR conditions, forward and reverse primer lengths can be modified based on those known in the art.

In the present invention, the term 'probe' refers to a nucleic acid fragment such as RNA or DNA capable of forming a specific binding with DNA, and consists of several bases to several hundred bases as long as possible. Since the probe is labeled, the presence or absence of a specific DNA can be confirmed. The probe may be manufactured in the form of an oligonucleotide probe, a single stranded DNA probe, a double stranded DNA probe, an RNA probe, or the like. In the present invention, by performing hybridization using a probe complementary to a mutation in a gene, it is possible to diagnose whether bladder cancer recurs based on whether or not hybridization occurs. For example, when a probe corresponding to a mutant having a deletion, substitution or insertion is synthesized and the probe is hybridized with the genomic DNA of a bladder cancer patient, hybridization will occur in the case of a mutant of the gene of the present invention, but If the gene is not a mutant, hybridization will not occur. Selection of suitable probes and hybridization conditions can be modified based on those known in the art.

In the present invention, the term 'antibody' is a term known in the art and refers to a specific protein molecule directed against an antigenic site. In the present invention, the antibody may refer to an antibody that specifically binds to each marker gene. Such an antibody can be prepared by cloning each marker gene into an expression vector according to a conventional method to obtain a protein encoded by the marker gene, and from the obtained protein by a conventional method. This also includes a partial peptide that can be made from the protein, and the partial peptide of the present invention contains at least 7 amino acids, preferably 9 amino acids, more preferably 12 or more amino acids. The form of the antibody of the present invention is not particularly limited, and a part thereof is included in the antibody of the present invention as long as it has polyclonal antibody, monoclonal antibody, or antigen-binding property, and all immunoglobulin antibodies are included. Furthermore, the antibody of the present invention includes a special antibody such as a humanized antibody. Antibodies used for the detection of marker genes of the present invention include functional fragments of antibody molecules as well as complete forms having two full-length light chains and two full-length heavy chains. A functional fragment of an antibody molecule refers to a fragment having at least an antigen-binding function, and includes Fab, F(ab'), F(ab') ₂ and Fv.

As used herein, the term 'aptamer' refers to a single-stranded nucleic acid (DNA, RNA, or modified nucleic acid) that has a stable tertiary structure by itself and can bind to a target molecule with high affinity and specificity. Aptamers can be synthesized by known chemical methods, for example, by a method called SELEX (Systematic Evolution of Ligands of Exponential enrichment) for various target substances (proteins, sugars, dyes, DNA, metal ions, cells, etc.) You can develop aptamers.

The mutation of the gene may include any one or more mutations, for example, a truncating mutation, a missense mutation (or a missense mutation), a nonsense mutation, a frame shift. ) mutation, in-frame mutation (or in-frame mutation), splice mutation, and splice_region mutation may have at least one mutation selected from the group consisting of mutations. The frameshift mutation may be at least one of a frame shift insert (FS ins) mutation and a frame shift delete mutation (FS del). The in-frame mutation may be at least one of an in-frame insertion (IF ins) mutation and an in-frame delete (IF del) mutation.

The term "X#Y" with respect to a mutation in a polypeptide sequence is self-recognized in the art, where "#" indicates the mutation site with respect to the amino acid number of the polypeptide, and "X" is that of the wild-type amino acid sequence. indicates the amino acid found at that position, and "Y" indicates the mutant amino acid at that position. For example, the designation “Q302H” with respect to a BTBD10 polypeptide indicates that glutamine is present at amino acid number 302 of the wild-type BTBD10 sequence and that glutamine has been replaced with histidine in the mutant BTBD10 sequence. Mutations in these genes are as follows:

The mutation of the BTBD10 gene is, in the amino acid sequence of SEQ ID NO: 1, a missense mutation that is Q302H, a missense mutation that is S404Y, a missense mutation that is R27C, a missense mutation that is M292I, a missense mutation that is R388L, a missense mutation that is E260Q, It may be a missense mutation that is R64T or a missense mutation that is R352T.

The mutation of the GRIA2 gene is, in the amino acid sequence of SEQ ID NO: 2, a missense mutation that is R45Q, a missense mutation that is E412Q, a missense mutation that is I819V, a missense mutation that is K716T, a missense mutation that is L139F, a missense mutation that is K850N, It may be a missense mutation that is S585T, a missense mutation that is E190K, or a missense mutation that is N482D.

The mutation of the GUCY1A2 gene is, in the amino acid sequence of SEQ ID NO: 3, a missense mutation that is H183Y, a missense mutation that is E669Q, a missense mutation that is S525L, a missense mutation that is S101L, a missense mutation that is L710V, Splice_Region mutation that is L162 = ( c.486C>T), missense mutation with S101W, missense mutation with G343V, missense mutation with Q462H, missense mutation with L594F, missense mutation with R172T, frameshift deletion mutation with Q217Hfs*32 or in-frame with R655del It may be a deletion mutation. The notation method for frameshift mutations is amino acid type (amino acid position) amino acid type fs* (number of nucleotides from the amino acid position to the stop codon in the downstream direction) explanation is omitted). In the notation method of in-frame deletion mutations, del indicates that the corresponding amino acid is deleted at the corresponding amino acid sequence position (the description is omitted below).

The mutation of the ITGA3 gene is, in the amino acid sequence of SEQ ID NO: 4, a missense mutation that is P845H, a missense mutation that is E63K, a missense mutation that is H356Y, a Splice_Site mutation that is X714_splice (c.2140-1G>A), and a missense that is F543L. mutation, a missense mutation that is W220C or a missense mutation that is S202G.

The mutation of the MED1 gene is, in the amino acid sequence of SEQ ID NO: 5, a missense mutation that is H1526D, a missense mutation that is S387T, a missense mutation that is S1227L, a missense mutation that is S1379L, a missense mutation that is S1218C, a missense mutation that is K202N, Missense mutation that is L69I, missense mutation that is K283T, missense mutation that is S1375C, missense mutation that is P1208A, nonsense mutation that is S256*, missense mutation that is S682L, nonsense mutation that is S1363*, missense mutation that is S1439F, S1558* It may be a nonsense mutation that is P381A, a missense mutation that is S1368F, a missense mutation that is E8K, a missense mutation that is S1111L, a missense mutation that is S349L or a missense mutation that is M1172I. In the nonsense mutation, * indicates that the amino acid synthesis at the corresponding amino acid position is terminated (the description is omitted below).

The mutation of the MTUS2 gene is, in the amino acid sequence of SEQ ID NO: 6, a missense mutation that is K741T, a missense mutation that is D444N, an in-frame deletion mutation that is K1330del, a missense mutation that is L935I, a nonsense mutation that is E163*, and a missense mutation that is E180K. , can be a missense mutation that is D417H, a missense mutation that is R29K, a missense mutation that is G223E, a missense mutation that is R109T, a missense mutation that is R160S, a missense mutation that is E268D, a missense mutation that is E398K or a missense mutation that is L688F. have.

The mutation of the PIK3C2A gene is, in the amino acid sequence of SEQ ID NO: 7, a missense mutation that is L1652V, a missense mutation that is D839N, a missense mutation that is A1501G, a missense mutation that is I1475V, a missense mutation that is Q1349E, a missense mutation that is L1034V, nonsense mutation that is R1570*, nonsense mutation that is Q434*, nonsense mutation that is R1259*, missense mutation that is D870N, nonsense mutation that is S702*, missense mutation that is D25Y, missense mutation that is S1457L, missense mutation that is Q770K, missense mutation that is S259F a missense mutation, a missense mutation that is D846H, a missense mutation that is E865K, or a missense mutation that is S128L.

The mutation of the QARS gene may be a missense mutation that is E399K, a missense mutation that is E84K, a missense mutation that is R464C, a missense mutation that is K25N, or a missense mutation that is C687Y in the amino acid sequence of SEQ ID NO: 8.

The mutation of the SALL1 gene is, in the amino acid sequence of SEQ ID NO: 9, a missense mutation of P675A, a missense mutation of E599K, a missense mutation of E51Q, a missense mutation of R276Q, a missense mutation of E1251K, a missense mutation of D263Y, L762H, missense mutation, I981M, missense mutation, R757G, missense mutation, Q107E, missense mutation, V433A, missense mutation, R1128S, missense mutation, S961F, missense mutation, A387P, missense mutation, D819H missense mutation, missense mutation in A646P, missense mutation in P1069A, missense mutation in L72F, missense mutation in A214V, missense mutation in A672T, missense mutation in T636A, missense mutation in P635T, missense mutation in E515Q mutation or a missense mutation that is S1302N.

The mutation of the SIN3A gene is, in the amino acid sequence of SEQ ID NO: 10, a missense mutation that is R471Q, a missense mutation that is F1169L, a missense mutation that is I1133V, a missense mutation that is T1049K, a missense mutation that is Q100H, a missense mutation that is E540K, It may be a missense mutation that is K1148N, a missense mutation that is E513Q, a missense mutation that is Q805E, a missense mutation that is H333R, a missense mutation that is D1090Y, a missense mutation that is N423K, a missense mutation that is Q1208E or a missense mutation that is R428C. .

The mutation of the SLC45A1 gene is, in the amino acid sequence of SEQ ID NO: 11, a missense mutation that is D220N, a nonsense mutation that is Q657*, a missense mutation that is A687S, a missense mutation that is P295L, a missense mutation that is L690V, a missense mutation that is E98Q, a missense mutation that is A274E, a missense mutation that is A587V, a missense mutation that is G619R, a missense mutation that is Q81H or a missense mutation that is S499F.

The mutation of the ABCC4 gene is, in the amino acid sequence of SEQ ID NO: 12, X936_splice Splice_Site mutation (c.2807-1G>A), E424K missense mutation, V776I missense mutation, I1197M missense mutation, L1198F missense mutation, L261=Splice_Region mutation (c.783G>A), Q699* nonsense mutation, S736* nonsense mutation, V569D missense mutation, P1094A missense mutation, I33S missense mutation, E378Q missense mutation or E920K missense mutation.

The mutation of the CNTN2 gene is, in the amino acid sequence of SEQ ID NO: 13, D339N missense mutation, G319D missense mutation, T676N missense mutation, D954N missense mutation, D389N missense mutation, E809K missense mutation, R432G missense mutation, D618N a missense mutation, a D618V missense mutation or a W852C missense mutation.

The mutation of the EPAS1 gene may be an R690Q missense mutation, a D107N missense mutation, a K7R missense mutation or a G792R missense mutation in the amino acid sequence of SEQ ID NO: 14.

The mutation of the HPD gene may be an S293F missense mutation, a P189T missense mutation, a G53S missense mutation or a Q341R missense mutation in the amino acid sequence of SEQ ID NO: 15.

The mutation of the IGDCC4 gene is, in the amino acid sequence of SEQ ID NO: 16, F934L missense mutation, S235F missense mutation, G510E missense mutation, X846_splice Splice_Site mutation (c.2536+1G>A), G510A missense mutation, R1086W missense mutation mutation, D1111N missense mutation or W731* nonsense mutation.

The mutation of the KBTBD3 gene is, in the amino acid sequence of SEQ ID NO: 17, W531S missense mutation, E464Q missense mutation, R14Q missense mutation, E23Q missense mutation, R413T missense mutation, X78_splice Splice_Site mutation (c.234-2A>G ) or V218I missense mutation.

The mutation of the MAATS1 gene is, in the amino acid sequence of SEQ ID NO: 18, E758K missense mutation, D452H missense mutation, K349N missense mutation, K454N missense mutation, E130Q missense mutation, E666K missense mutation, P464Lfs*21 frameshift deletion mutation or S185* nonsense mutation.

The mutation of the RBP2 gene may be an I26T missense mutation, a Q5H missense mutation, a Q5H missense mutation, an E119Q missense mutation, an E112K missense mutation or a D25Y missense mutation in the amino acid sequence of SEQ ID NO: 19.

The mutation of the SULT2A1 gene may be a W284R missense mutation, a R193K missense mutation, a P278S missense mutation or a K224E missense mutation in the amino acid sequence of SEQ ID NO: 20.

The mutation of the TMPRSS9 gene is, in the amino acid sequence of SEQ ID NO: 21, P469S missense mutation, R221Q missense mutation, R1021W missense mutation, A286V missense mutation, G689V missense mutation, D292H missense mutation, S365L missense mutation or L596V It may be a missense mutation.

The mutation of the TXK gene is, in the amino acid sequence of SEQ ID NO: 22, S407* nonsense mutation, S400L missense mutation, H323L missense mutation, X149_splice Splice_Site mutation (c.447-2A>G), L163V missense mutation, E481K missense mutation mutation, G463V missense mutation, D267Y missense mutation, E217K missense mutation, Q204* nonsense mutation or D408G missense mutation.

Next generation sequencing (NGS), RT-PCR, direct nucleic acid sequencing method, and microarray can be used as an analysis method for diagnosing the prognosis of bladder cancer using the mutation of the gene, and the gene of the present invention Any method that can confirm the presence of a mutation using a mutation of In one embodiment, the presence of a mutation is determined using an anti-(mutant of each gene) antibody or nucleic acid probe that hybridizes under stringent conditions to the polynucleotide of the mutant of each gene. In another embodiment, the antibody or nucleic acid probe is detectably labeled. In another embodiment, the label is selected from the group consisting of an immunofluorescent label, a chemiluminescent label, a phosphorescent label, an enzymatic label, a radioactive label, avidin/biotin, colloidal gold particles, colored particles, and magnetic particles. In another embodiment, the presence of the mutation is determined by radioimmunoassay, western blot assay, immunofluorescence assay, enzymatic immunoassay, immunoprecipitation assay, chemiluminescence assay, immunohistochemical assay, dot blot assay, slot blot assay or flow cytometry. determined by the assay. In another embodiment, the presence of the mutation is determined by RT-PCR. In another embodiment, the presence of a mutation is determined by nucleic acid sequencing.

As used herein, the term 'polynucleotide' generally refers to any polyribonucleotide or polydeoxyribonucleotide, which may be unmodified RNA or DNA or modified RNA or DNA. Thus, for example, polynucleotides as defined herein include, but are not limited to, single- and double-stranded DNA, DNA comprising single- and double-stranded regions, single- and double-stranded RNA, and single- and double-stranded DNA. - RNA comprising a region, single-stranded or more typically double-stranded, or hybrid molecule comprising DNA and RNA, which may comprise single- and double-stranded regions. Thus, DNA or RNA having a backbone that has been modified for stability or other reasons is a 'polynucleotide' as the term is intended herein. Also included in the term 'polynucleotide' as defined herein is DNA or RNA comprising an unconventional base such as inosine or a modified base such as a tritiated base. In general, the term 'polynucleotide' includes all chemically, enzymatically and/or metabolically modified forms of unmodified polynucleotides. Polynucleotides can be prepared by a variety of methods, including in vitro recombinant DNA-mediated techniques, and by expression of DNA in cells and organisms.

Another aspect of the present invention is BTBD10 gene mutation, GRIA2 gene mutation, GUCY1A2 gene mutation, ITGA3 gene mutation, MED1 gene mutation, MTUS2 gene mutation, PIK3C2A gene mutation, QARS gene mutation, SALL1 gene mutation , SIN3A gene mutation and SLC45A1 gene mutation provides a kit for prognostic diagnosis of bladder cancer comprising a reagent capable of detecting a recurrence-specific marker of a bladder cancer patient comprising at least one selected from the group consisting of mutations.

In addition, the relapse-specific markers include a mutation in the ABCC4 gene, mutation in the CNTN2 gene, mutation in the EPAS1 gene, mutation in the HPD gene, mutation in the IGDCC4 gene, mutation in the KBTBD3 gene, mutation in the MAATS1 gene, mutation in the RBP2 gene, SULT2A1 gene It may further include at least one selected from the group consisting of a mutation of the TMPRSS9 gene and a mutation of the TXK gene.

For example, when the recurrence-specific marker is identified, it may be determined that the survival rate is higher or the recurrence rate is lower than that of a person in which the recurrence-specific marker is not identified. Or vice versa.

The reagent capable of detecting the recurrence-specific marker may include one or more selected from the group consisting of primers, probes, antibodies, and aptamers, and detailed descriptions thereof are omitted since they are the same as described above.

The kit of the present invention may be an RT-PCR kit, a DNA chip kit or a protein chip kit. As an example, the RT-PCR kit for measuring the mRNA expression level of the marker gene of the present invention may be a kit including essential elements necessary for performing RT-PCR. The RT-PCR kit contains, in addition to each primer pair specific for the marker gene, a test tube or other suitable container, reaction buffer (with varying pH and magnesium concentration), deoxynucleotides (dNTPs), Taq-polymerase and enzymes such as reverse transcriptase, DNase, RNAse inhibitors, DEPC-water, sterile water, and the like. In addition, a pair of primers specific to a gene used as a quantitative control may be included.

As another example, the DNA chip kit of the present invention may include essential elements necessary for performing a DNA chip analysis method. The DNA chip kit may include a substrate to which cDNA corresponding to a marker gene or a fragment thereof is attached as a probe, and reagents, agents, enzymes, and the like for producing a fluorescently labeled probe. In addition, the substrate may include cDNA corresponding to a quantitative control gene or a fragment thereof.

As another example, the kit of the present invention is a protein chip kit for measuring the level of a protein expressed from the marker gene, and the kit is not particularly limited thereto, but includes a substrate, an appropriate buffer, It may include a chromogenic enzyme or a secondary antibody labeled with a fluorescent substance, a chromogenic substrate, and the like. The substrate is not particularly limited thereto, but a nitrocellulose membrane, a 96-well plate synthesized from a polyvinyl resin, a 96-well plate synthesized from a polystyrene resin, a glass slide glass, etc. may be used, and the chromogenic enzyme is not particularly limited thereto. However, peroxidase and alkaline phosphatase may be used, and the fluorescent material may be FITC, RITC, etc., but is not particularly limited thereto, and the color development substrate solution is not particularly limited thereto, but ABTS (2, 2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)) or OPD (o-phenylenediamine), TMB (tetramethyl benzidine).

In addition, the kit of the present invention may further include a buffer, an indicator, or a combination thereof as a reagent.

The kit for prognostic diagnosis of bladder cancer of the present invention is very economical because it saves time and money compared to the existing general gene mutation detection method. Using existing gene mutation detection methods such as Single Strand Conformational Polymorphism (SSCP), Protein Truncation Test (PTT), cloning, and direct sequencing, it takes several days on average to test all one gene. It takes several months. In addition, gene mutations can be precisely tested quickly and simply through next generation sequencing (NGS). When mutations are tested by conventional analysis methods such as SSCP, cloning, direct sequencing, and Restriction Fragment Length Polymorphism (RFLP), it takes about a month to complete the test, whereas using the kit of the present invention, sample DNA is prepared If it is done, results can be obtained within about 10 to 11 hours, and since a primer set capable of detecting mutations is integrated on one chip, not only time but also cost can be reduced compared to the conventional method. Compared to the conventional method, the average cost of reagents is less than half per experiment, so even greater cost savings can be expected when the researcher's labor costs are taken into account.

2. A method of providing necessary information for prognostic diagnosis of bladder cancer

Another aspect of the present invention comprises the steps of preparing a sample DNA from a sample of a bladder cancer patient; It provides a method for providing information necessary for prognostic diagnosis of bladder cancer patients, comprising: confirming the presence or absence of a recurrence-specific marker using the sample DNA for prognosis diagnosis of bladder cancer.

The method may further include amplifying the sample DNA prepared from the bladder cancer patient's sample using the composition or kit for prognostic diagnosis of bladder cancer.

The description of the ' composition and kit for prognostic diagnosis of bladder cancer' is the same as that described in '1. Composition and kit for prognostic diagnosis of bladder cancer ', so a detailed description will be omitted.

The term 'patient' usually includes humans as well as other animals, such as other primates, rodents, dogs, cats, horses, sheep, pigs, and the like.

The term 'sample' refers to a sample of an individual or tissue in which cancer or tumor has already occurred or is expected to occur, and a target sample for diagnosing its prognosis. Specifically, it may refer to a tumor lysate or extract prepared from frozen tissue obtained from a patient with bladder cancer.

The term 'subject' includes a subject diagnosed with or suspected of having bladder cancer.

The method can predict the overall survival or disease-free survival of bladder cancer patients.

In the present invention, the term 'overall survival (OS)' includes a clinical endpoint that describes a patient who is alive for a limited time after being diagnosed with or treated for a disease, such as cancer, and is related to whether or not the cancer recurs. the possibility of surviving without it.

In the present invention, the term 'disease-free survival (DFS)' includes a period in which a patient survives without cancer recurrence after treatment for a specific disease (eg, cancer).

According to the present invention, by confirming the presence of a mutation in the gene of the present invention in a sample of a bladder cancer patient, it is possible to predict what prognosis an individual having the target sample has for cancer. In addition, this method can be achieved by comparing the p-value of total survival or disease-free survival with an individual in a control group that does not have a mutation known to have a good prognosis. In the present invention, an individual known to have a good prognosis means an individual without a history of metastasis, recurrence, death, etc. after cancer has developed.

The relapse-specific marker is a mutation in the BTBD10 gene, mutation in the GRIA2 gene, mutation in the GUCY1A2 gene, mutation in the ITGA3 gene, mutation in the MED1 gene, mutation in the MTUS2 gene, mutation in the PIK3C2A gene, mutation in the QARS gene, mutation in the SALL1 gene. , may include at least one selected from the group consisting of a mutation of the SIN3A gene and a mutation of the SLC45A1 gene.

In addition, the recurrence-specific marker is mutation in the ABCC4 gene, mutation in the CNTN2 gene, mutation in the EPAS1 gene, mutation in the HPD gene, mutation in the IGDCC4 gene, mutation in the KBTBD3 gene, mutation in the MAATS1 gene, mutation in the RBP2 gene, mutation in the SULT2A1 gene, mutation in the TMPRSS9 gene and It may further include at least one selected from the group consisting of a mutation of the TXK gene.

The method of providing information necessary for prognostic diagnosis of the bladder cancer patient may predict the total survival rate or disease-free survival rate of the bladder cancer patient. For example, in the method, when the recurrence-specific marker is identified and bladder cancer recurrence is confirmed in a bladder cancer patient, determining that the survival rate is higher or the recurrence rate of bladder cancer is lower than that of a person in which the recurrence-specific marker is not identified ; may be included.

In addition, the method includes the steps of, when the recurrence-specific marker is identified and bladder cancer recurrence is confirmed in a bladder cancer patient, determining that the survival rate is lower or the recurrence rate of bladder cancer is higher than that of a person for which the recurrence-specific marker is not identified; may include

As such, bladder cancer recurrence using mutations in at least one gene selected from the gene group consisting of BTBD10, GRIA2, GUCY1A2, ITGA3, MED1, MTUS2, PIK3C2A, QARS, SALL1, SIN3A and SLC45A1, which are mutations of the genes of the present invention It has not yet been revealed whether the prognosis, such as the viability of bladder cancer or the possibility of recurrence, can be diagnosed depending on the presence or absence of the bladder cancer. In addition, it has not been reported that the total survival rate or disease-free survival rate may be different for each gene. The present inventors have identified for the first time that the mutation of the genes can be used as a diagnostic marker for predicting the difference in treatment effect depending on whether bladder cancer recurs or diagnosing the prognosis of a bladder cancer patient.

The method of providing information necessary for predicting the difference in the treatment effect of bladder cancer patients of the present invention can be used to diagnose a bladder cancer gene mutation, increase the survival rate of bladder cancer patients, or lower the recurrence rate. Through the method for prognostic diagnosis of bladder cancer patients of the present invention, the treatment effect can be predicted depending on whether the bladder cancer patient recurs, or the survival rate or recurrence rate of bladder cancer patients can be predicted using the mutational information of the bladder cancer gene, so each patient It can provide information on the selection of treatments as well as the discovery of suitable therapeutics for the treatment of bladder cancer, enabling efficient design of therapeutic strategies for bladder cancer.

Hereinafter, the present invention will be described in detail by way of Examples and Experimental Examples.

However, the following Examples and Experimental Examples are only for illustrating the present invention, and the content of the present invention is not limited by the following Examples and Experimental Examples.

Example

Securing genetic and clinical information

In order to derive a recurrence-specific marker that can diagnose the prognosis after treatment according to the recurrence of bladder cancer, 411 bladder cancer patients who have both genetic and clinical information from TCGA (The Cancer Genome Atlas) relapse; Data on metastasis, death, observation time, etc. were obtained and used for analysis.

number of patients ratio(%) gender male 303/411 73.7 woman 108/411 26.3 survival survival 230/411 56.0 Dead 181/411 44.0 Recurrence disease free 179/322 55.6 relapse/progression 143/322 44.4 metastasis does not exist 195/206 94.7 has exist 11/206 5.3

Selection of genes associated with recurrence

Among the above data, 322 pieces of data that can confirm whether or not recurrence is divided into two groups: a group without recurrence (R0) / a group with recurrence (R1) according to whether or not recurrence, 3 Feature Selection (Information Gain, Chi- Square, MR) method was applied to machine learning, and the following 59 genes were derived that were related to recurrence:

ABCC4, AGPS, AP2A1, AP3S1, ATP6V1A, BTBD10, C14orf39, C15orf26, C9orf84, CACHD1, CACNA1B, CCDC6, CDC42BPG, CNTN2, CSE1L, CYP24A1, DDB1, CYP24A1, DDB1, GUCY 1 GRIA3, FCAR, GUCY EXD EPAS1, GUCY EXD EPAS1 HTT, IGDCC4, ING3, ITGA3, KBTBD3, KIAA1462, LYG2, MAATS1, MED1, MTMR4, MTUS2, MYO19, NBPF12, NCAM1, OR2T6, PIK3C2A, QARS, RBP2, RIMS4, SALL1, SINSULTA, SALL1, SINSULTA, SALL1, SINSULTA TAGLN3, TEC, TFAP2C, TMPRSS9, TRIML1, TRMT61B, TXK, VLDLR.

The p-value of the analysis result is shown in Table 2 below, and for convenience in data interpretation, overall survival and disease-free survival according to the Kaplan Meier survival assay performed in Example 2 to be described later. ) and the p-value.

number of mutations Mutation (%) Cyto band Mutation type Relapse Fisher's test (p-value) Total survival (p-value) Disease-free survival (p-value) cut missense in-frame etc R0 R1 NA R1 (%) ABCC4 13 4.6% 13q32.1 4 9 0 0 10 One 2 7.7 0.026 0.123 0.0411 AGPS 5 1.8% 2q31.2 2 3 0 0 3 2 0 60.0 0.659 0.615 0.853 AP2A1 6 2.1% 19q13.33 0 6 0 0 4 0 2 66.7 0.087 0.717 0.206 AP3S1 One 0.4% 5q22.3-q23.1 0 One 0 0 0 One 0 0.0 One 0.944 0.955 ATP6V1A 11 3.9% 3q13.31 0 11 0 0 9 One One 9.1 0.047 0.136 0.151 BTBD10 8 2.8% 11p15.3 0 8 0 0 8 0 0 0.0 0.01 0.00344 0.0282 C14orf39 10 3.5% 14q23.1 3 7 0 0 5 2 3 50.0 0.092 0.221 0.419 C15orf26 4 1.4% 15q25.1 0 4 0 0 3 0 One 75.0 0.087 0.554 0.369 C9orf84 12 4.3% 9q31.3 3 9 0 0 2 10 0 16.7 0.308 0.857 0.226 CACHD1 10 3.5% 1p31.3 0 10 0 0 9 One 0 10.0 0.047 0.18 0.169 CACNA1B 17 6.0% 9q34.3 One 16 0 0 12 3 2 17.6 0.132 0.174 0.24 CCDC6 5 1.8% 10q21.2 0 4 0 One 4 0 One 0.0 0.063 0.473 0.141 CDC42BPG 7 2.5% 11q13.1 0 7 0 0 7 0 0 0.0 0.019 0.0654 0.0591 CNTN2 10 3.5% 1q32.1 0 10 0 0 0 10 0 0.0 0.019 0.115 0.0159 CSE1L 14 5.0% 20q13.13 4 10 0 0 12 One One 7.1 0.047 0.0713 0.0641 CYP24A1 6 2.1% 20q13.2 One 5 0 0 4 One One 66.7 0.175 0.214 0.439 DDB1 9 3.2% 11q12.2 2 7 0 0 0 9 0 0.0 0.068 0.68 0.0661 EAPP 6 2.1% 14q13.1 0 6 0 0 2 0 4 33.3 0.196 0.482 0.373 EPAS1 4 1.4% 2p21 0 4 0 0 3 0 One 75.0 0.087 0.0278 0.169 EXD3 8 2.8% 9q34.3 2 6 0 0 6 2 0 75.0 0.248 0.529 0.444 FCAR 5 1.8% 19q13.42 One 4 0 0 5 0 0 0.0 0.068 0.118 0.103 GPSM2 9 3.2% 1p13.3 One 8 0 0 8 0 One 0.0 0.036 0.152 0.0594 GRIA2 9 3.2% 4q32.1 0 9 0 0 8 One 0 11.1 0.047 0.014 0.0418 GUCY1A2 13 4.6% 11q22.3 2 10 One 0 12 One 0 7.7 0.008 0.0209 0.0181 HPD 4 1.4% 12q24.31 0 4 0 0 4 0 0 100.0 0.038 0.615 0.00215 HTT 17 6.0% 4p16.3 3 14 0 0 12 4 One 23.5 0.19 0.862 0.977 IGDCC4 8 2.8% 15q22.31 2 6 0 0 8 0 0 0.0 0.019 0.052 0.0488 ING3 6 2.1% 7q31.31 One 5 0 0 4 One One 66.7 0.175 0.58 0.315 ITGA3 10 3.5% 17q21.33 One 6 0 3 10 0 0 0.0 0.003 0.00799 0.0071 KBTBD3 7 2.5% 11q22.3 One 6 0 0 5 0 2 71.4 0.017 0.354 0.0157 KIAA1462 11 3.9% 10p11.23 One 10 0 0 8 One 2 9.1 0.047 0.353 0.139 LYG2 5 1.8% 2q11.2 One 4 0 0 4 One 0 80.0 0.038 0.581 0.123 MAATS1 8 2.8% 3q13.33 2 6 0 0 7 One 0 12.5 0.081 0.0438 0.0442 MED1 21 7.4% 17q12 3 18 0 0 16 4 One 19.0 0.024 0.005 0.0154 MTMR4 12 4.3% 17q22 3 9 0 0 0 12 0 0.0 0.036 0.792 0.0549 MTUS2 14 5.0% 13q12.3 One 12 One 0 14 0 0 0.0 0.005 0.0436 0.0367 MYO19 9 3.2% 17q12 0 9 0 0 One 8 0 11.1 0.137 0.68 0.143 NBPF12 7 2.5% 1q21.1 One 6 0 0 5 2 0 71.4 0.092 0.601 0.113 NCAM1 8 2.8% 11q23.2 2 6 0 0 One 7 0 12.5 0.232 0.358 0.125 OR2T6 5 1.8% 1q44 0 5 0 0 4 0 One 80.0 0.038 0.808 0.591 PIK3C2A 18 6.4% 11p15.1 4 14 0 0 17 One 0 5.6 0.001 0.00168 0.00475 QARS 6 2.1% 3p21.31 0 5 0 One 6 0 0 0.0 0.036 0.0454 0.0427 RBP2 6 2.1% 3q23 0 6 0 0 6 0 0 100.0 0.007 0.444 0.00155 RIMS4 4 1.4% 20q13.12 0 4 0 0 2 0 2 50.0 0.196 0.42 0.152 SALL1 24 8.5% 16q12.1 0 24 0 0 4 20 0 16.7 0.009 0.0328 0.028 SIN3A 14 5.0% 15q24.2 0 14 0 0 13 0 One 0.0 0.001 0.00744 0.00345 SLC45A1 11 3.9% 1p36.23 One 10 0 0 10 One 0 9.1 0.026 0.0165 0.0425 SNED1 8 2.8% 2q37.3 One 7 0 0 5 3 0 37.5 One 0.141 0.764 SP1 10 3.5% 12q13.13 2 8 0 0 One 9 0 10.0 0.081 0.0777 0.0983 SULT2A1 4 1.4% 19q13.33 0 4 0 0 4 0 0 100.0 0.038 0.598 0.00924 TAGLN3 3 1.1% 3q13.2 0 3 0 0 2 0 One 66.7 0.196 0.393 0.0632 TEC 11 3.9% 4p12-p11 2 9 0 0 One 10 0 9.1 0.047 0.168 0.0635 TFAP2C 7 2.5% 20q13.31 0 7 0 0 2 3 2 28.6 0.587 0.386 0.549 TMPRSS9 8 2.8% 19p13.3 0 8 0 0 7 0 One 0.0 0.019 0.129 0.0452 TRIML1 5 1.8% 4q35.2 One 4 0 0 4 One 0 80.0 0.175 0.771 0.0595 TRMT61B 6 2.1% 2p23.2 0 6 0 0 6 0 0 0.0 0.036 0.128 0.105 TXK 11 3.9% 4p12 3 8 0 0 10 One 0 9.1 0.047 0.0416 0.125 VLDLR 6 2.1% 9p24.2 0 6 0 0 0 6 0 0.0 0.068 0.606 0.209

Among the 59 genes in Table 2, 28 genes having a p value of 0.05 or more in Fisher's exact test are related to recurrence, but it is determined that the correlation is low. In addition, the following 31 genes (candidate gene group 1) with a p value of less than 0.05 are considered to be highly correlated with recurrence.

Candidate gene group 1: ABCC4, ATP6V1A, BTBD10, CACHD1, CDC42BPG, CNTN2, CSE1L, GPSM2, GRIA2, GUCY1A2, HPD, IGDCC4, ITGA3, KBTBD3, KIAA1462, LYG2, MED1, MTMR4, QAR MTUS2, ORTAA PI, MTUS2, ORTAA PI RBP2, SALL1, SIN3A, SLC45A1, SULT2A1, TEC, TMPRSS9, TRMT61B, TXK.

Screening and review of relapse-specific markers for prognosis

In order to confirm the possibility of use as a relapse-specific marker for prognosis prediction, comparative analysis was performed on the data of the 322 subjects for these genes, and missing values and outliers were excluded.

Based on the clinical information (event (death or recurrence), observation time) of the patients, overall survival or disease-free survival was calculated by Kaplan Meier survival analysis using SPSS. In the total survival period, the event was defined as death, and in the disease-free survival period, the event was defined as bladder cancer recurrence. In order to determine whether mutation in each of the genes is correlated with bladder cancer-caused death or bladder cancer recurrence, mutation occurrence and total survival were based on the event time of each group obtained in the Kaplan Meier survival assay. The association of duration, and association of mutagenesis and disease-free survival, was confirmed by log rank test. A p-value of less than 0.05 was considered statistically significant.

The experimental group was defined as the case with alterations in query gene, and the control group was the case without alterations in query gene. The median months survival means a value located at the center when the survival periods of patients in the corresponding group are listed. The slope in the survival curve by the Kaplan Meier survival assay is determined by the duration of survival.

As a result of the above analysis, the following 22 genes (candidate gene group 2) with a p-value of less than 0.05 for total survival or disease-free survival are considered to be highly correlated with survival or recurrence rates.

Candidate gene group 2: ABCC4, BTBD10, CNTN2, EPAS1, GRIA2, GUCY1A2, HPD, IGDCC4, ITGA3, KBTBD3, MAATS1, MED1, MTUS2, PIK3C2A, QARS, RBP2, SALL1, SIN3A, SLC45A1, SULTKA.

Table 3 below shows the results of Kaplan Meier analysis of 14 genes having a p-value of less than 0.05 in total survival among the second group of candidate genes.

Total survival (p-value) no mutation with mutation Total number of people (persons) Number of deaths (persons) death rate(%) Median survival time
(month) Total number of people (persons) Number of deaths (persons) death rate(%) Median survival time
(month) BTBD10 0.00344 401 179 44.6% 33.02 8 0 0.0% NA EPAS1 0.0278 405 175 43.2% 34.9 4 4 100.0% 5.35 GRIA2 0.014 400 179 44.8% 33.02 9 0 0.0% NA GUCY1A2 0.0209 396 178 44.9% 33.02 13 One 7.7% NA ITGA3 0.00799 399 179 44.9% 33.02 10 0 0.0% NA MAATS1 0.0438 401 178 44.4% 33.11 8 One 12.5% NA MED1 0.005 392 177 45.2% 32.98 17 2 11.8% NA MTUS2 0.0436 400 179 44.8% 33.11 9 0 0.0% NA PIK3C2A 0.00168 393 179 45.5% 32.98 16 0 0.0% NA QARS 0.0454 403 179 44.4% 33.11 6 0 0.0% NA SALL1 0.0328 386 175 45.3% 32.98 23 4 17.4% NA SIN3A 0.00744 397 178 44.8% 32.98 12 One 8.3% NA SLC45A1 0.0165 398 179 45.0% 33.02 11 0 0.0% NA TXK 0.0416 400 179 44.8% 33.11 9 0 0.0% NA

From Table 3, when mutations occur in 13 genes except for EPAS1, the mortality rate is as low as less than 18%, so it is considered to correspond to a marker with a good prognosis. On the other hand, if there is a mutation in the EPAS1 gene, 100% death and death can be confirmed within 6 months.

In addition, the results of Kaplan Meier analysis for 20 genes having a p-value of less than 0.05 for disease-free survival are shown in Table 4 below.

Disease-free survival (p-value) no mutation with mutation Total number of people (persons) Number of recurrences (persons) Relapse rate (%) Median disease-free survival (months) Total number of people (persons) Number of recurrences (persons) Relapse rate (%) Median disease-free survival (months) ABCC4 0.0411 311 142 45.7% 29.89 11 One 9.1% NA BTBD10 0.0282 314 143 45.5% 29.89 8 0 0.0% NA CNTN2 0.0159 315 143 45.4% 29.89 7 0 0.0% NA GRIA2 0.0418 313 142 45.4% 29.8 9 One 11.1% NA GUCY1A2 0.0181 309 142 46.0% 29.89 13 One 7.7% NA HPD 0.00215 318 139 43.7% 32.59 4 4 100.0% 8.8 IGDCC4 0.0488 315 143 45.4% 29.89 7 0 0.0% NA ITGA3 0.0071 312 143 45.8% 29.8 10 0 0.0% NA KBTBD3 0.0157 317 138 43.5% 30.22 5 5 100.0% 9.07 MAATS1 0.0442 314 142 45.2% 29.89 8 One 12.5% NA MED1 0.0154 305 140 45.9% 29.8 17 3 17.6% NA MTUS2 0.0367 313 143 45.7% 29.89 9 0 0.0% NA PIK3C2A 0.00475 306 142 46.4% 29.8 16 One 6.3% NA QARS 0.0427 316 143 45.3% 29.89 6 0 0.0% NA RBP2 0.00155 316 137 43.4% 35.68 6 6 100.0% 10.18 SALL1 0.028 303 140 46.2% 29.8 19 3 15.8% 82.42 SIN3A 0.00345 311 143 46.0% 29.8 11 0 0.0% NA SLC45A1 0.0425 311 142 45.7% 29.89 11 One 9.1% NA SULT2A1 0.00924 318 139 43.7% 32.59 4 4 100.0% 9.07 TMPRSS9 0.0452 315 143 45.4% 29.89 7 0 0.0% NA

In Table 4, when mutations occur in the remaining 16 genes except for HPD, KBTBD3, RBP2 and SULT2A1, the recurrence rate is low (less than 18%), so it is considered to be a marker with a good prognosis. On the other hand, if there is a mutation in the HPD, KBTBD3, RBP2 and SULT2A1 genes, 100% recurrence and recurrence within 11 months can be confirmed, and these are markers with a poor prognosis.

In addition, in the case of the following 11 genes (candidate gene group 1 & 2) overlappingly included in the first candidate gene group and the second candidate gene group, there is a mutation in the gene and whether the subject recurs is confirmed, the survival rate or recurrence rate can be determined based on this. Therefore, in the case of the corresponding 11 genes, it is considered that they have high potential for use as relapse-specific markers that can predict the prognosis.

Candidate Genes Group 1 & 2 : BTBD10, GRIA2, GUCY1A2, ITGA3, MED1, MTUS2, PIK3C2A, QARS, SALL1, SIN3A, SLC45A1.

For the 11 genes of the candidate gene group 1 & 2 of the present invention, the Kaplan Meier survival curve showing the total survival time when the event is defined as death and the log rank test results are shown in FIG. 1 and Table 5 below.

mutation Number of patients (persons) number of deaths Median survival time
(month) death rate(%) has exist 90 8 NA 8.9% does not exist 319 171 23.19 53.6% total 409 179 23.19 △44.7%

In addition, for the 11 genes of the candidate gene group 1 & 2, the Kaplan Meier survival curve and log rank test results showing the disease-free survival period when the event is defined as recurrence are shown in FIG. 2 and Table 6 below.

mutation Number of patients (persons) Relapse Median disease-free survival
(month) Relapse(%) has exist 85 10 NA 11.8% does not exist 237 133 22.31 56.1% total 322 143 22.31 △44.4%

On the other hand, among the second group of candidate genes, if there is a mutation in the following 11 genes, it is related to whether or not to relapse (gender related), and is correlated with whether or not the total survival or disease-free survival is present. These are designated as the third group of candidate genes.

Candidate gene group 3: ABCC4, CNTN2, EPAS1, HPD, IGDCC4, KBTBD3, MAATS1, RBP2, SULT2A1, TMPRSS9, TXK.

In addition, in the case of mutations in the following 12 genes among the second group of candidate genes, the overall survival rate was low, and the bladder cancer recurrence rate was high or the disease-free survival period was short. This candidate gene is designated as the 4th group.

Candidate gene group 4: BTBD10, GRIA2, GUCY1A2, ITGA3, MAATS1, MED1, MTUS2, PIK3C2A, QARS, SALL1, SIN3A, SLC45A1.

Detection of marker genes using mutation position information

Mutation position information of the genes of the second group of candidate genes is shown below.

Gene AA change Type Copy # COSMIC Chr Start Pos End Pos HGVSc ABCC4 X936_splice Splice_Site shallowdel chr13 95726579 95726579 ENST00000376887.4:c.2807-1G>A E424K Missense gain One chr13 95840790 95840790 ENST00000376887.4:c.1270G>A V776I Missense gain One chr13 95813572 95813572 ENST00000376887.4:c.2326G>A I1197M Missense diploid chr13 95696558 95696558 ENST00000376887.4:c.3591A>G L1198F Missense gain chr13 95696555 95696555 ENST00000376887.4:c.3594G>C L261= Splice_Region diploid chr13 95861690 95861690 ENST00000376887.4:c.783G>A Q699* Nonsense diploid chr13 95816712 95816712 ENST00000376887.4:c.2095C>T S736* Nonsense diploid chr13 95815870 95815870 ENST00000376887.4:c.2207C>A V569D Missense diploid chr13 95829982 95829982 ENST00000376887.4:c.1706T>A P1094A Missense diploid chr13 95715044 95715044 ENST00000376887.4:c.3280C>G I33S Missense gain chr13 95899984 95899984 ENST00000376887.4:c.98T>G E378Q Missense diploid chr13 95858815 95858815 ENST00000376887.4:c.1132G>C E920K Missense diploid chr13 95727734 95727734 ENST00000376887.4:c.2758G>A BTBD10 Q302H Missense diploid One chr11 13427306 13427306 ENST00000278174.5:c.906G>C S404Y Missense gain One chr11 13410595 13410595 ENST00000278174.5:c.1211C>A R27C Missense diploid One chr11 13466593 13466593 ENST00000278174.5:c.79C>T M292I Missense diploid One chr11 13427336 13427336 ENST00000278174.5:c.876G>C R388L Missense shallowdel chr11 13410643 13410643 ENST00000278174.5:c.1163G>T E260Q Missense shallowdel chr11 13435107 13435107 ENST00000278174.5:c.778G>C R64T Missense diploid chr11 13443296 13443296 ENST00000278174.5:c.191G>C R352T Missense shallowdel chr11 13424777 13424777 ENST00000278174.5:c.1055G>C CNTN2 D339N Missense shallowdel One chr1 205031034 205031034 ENST00000331830.4:c.1015G>A G319D Missense diploid chr1 205030531 205030531 ENST00000331830.4:c.956G>A T676N Missense diploid One chr1 205036280 205036280 ENST00000331830.4:c.2027C>A D954N Missense gain One chr1 205042211 205042211 ENST00000331830.4:c.2860G>A D389N Missense diploid chr1 205031622 205031622 ENST00000331830.4:c.1165G>A E809K Missense gain chr1 205039183 205039183 ENST00000331830.4:c.2425G>A R432G Missense diploid One chr1 205033503 205033503 ENST00000331830.4:c.1294C>G D618N Missense gain chr1 205035604 205035604 ENST00000331830.4:c.1852G>A D618V Missense gain chr1 205035605 205035605 ENST00000331830.4:c.1853A>T W852C Missense gain chr1 205041086 205041086 ENST00000331830.4:c.2556G>C EPAS1 R690Q Missense diploid One chr2 46608758 46608758 ENST00000263734.3:c.2069G>A D107N Missense diploid chr2 46583391 46583391 ENST00000263734.3:c.319G>A K7R Missense diploid chr2 46525070 46525070 ENST00000263734.3:c.20A>G G792R Missense diploid chr2 46609650 46609650 ENST00000263734.3:c.2374G>A GRIA2 R45Q Missense gain One chr4 158142864 158142864 ENST00000264426.9:c.134G>A E412Q Missense gain 2 chr4 158255240 158255240 ENST00000264426.9:c.1234G>C I819V Missense shallowdel 2 chr4 158283999 158283999 ENST00000264426.9:c.2455A>G K716T Missense gain One chr4 158281151 158281151 ENST00000264426.9:c.2147A>C L139F Missense diploid One chr4 158224891 158224891 ENST00000264426.9:c.417G>C K850N Missense gain chr4 158284094 158284094 ENST00000264426.9:c.2550G>C S585T Missense shallowdel chr4 158257809 158257809 ENST00000264426.9:c.1754G>C E190K Missense diploid chr4 158233929 158233929 ENST00000264426.9:c.568G>A N482D Missense diploid chr4 158257000 158257000 ENST00000264426.9:c.1444A>G GUCY1A2 H183Y Missense diploid chr11 106810845 106810845 ENST00000526355.2:c.547C>T E669Q Missense gain 2 chr11 106558469 106558469 ENST00000526355.2:c.2005G>C S525L Missense shallowdel 2 chr11 106680837 106680837 ENST00000526355.2:c.1574C>T S101L Missense diploid One chr11 106888480 106888480 ENST00000526355.2:c.302C>T L710V Missense diploid One chr11 106558346 106558346 ENST00000526355.2:c.2128C>G L162= Splice_Region shallowdel chr11 106849346 106849346 ENST00000526355.2:c.486C>T S101W Missense diploid One chr11 106888480 106888480 ENST00000526355.2:c.302C>G G343V Missense shallowdel chr11 106810364 106810364 ENST00000526355.2:c.1028G>T Q462H Missense diploid chr11 106681025 106681025 ENST00000526355.2:c.1386A>T L594F Missense diploid chr11 106647219 106647219 ENST00000526355.2:c.1782G>C R172T Missense gain chr11 106810877 106810877 ENST00000526355.2:c.515G>C Q217Hfs*32 Frame_Shift_Del diploid chr11 106810726 106810741 ENST00000526355.2:c.651_666del R655del In_Frame_Del gain chr11 106579265 106579267 ENST00000526355.2:c.1962_1964del HPD S293F Missense gain One chr12 122281692 122281692 ENST00000289004.4:c.878C>T P189T Missense diploid One chr12 122286936 122286936 ENST00000289004.4:c.565C>A G53S Missense gain chr12 122295275 122295275 ENST00000289004.4:c.157G>A Q341R Missense diploid chr12 122277887 122277887 ENST00000289004.4:c.1022A>G IGDCC4 F934L Missense diploid One chr15 65680830 65680830 ENST00000352385.2:c.2802C>G S235F Missense diploid 2 chr15 65693281 65693281 ENST00000352385.2:c.704C>T G510E Missense diploid One chr15 65687479 65687479 ENST00000352385.2:c.1529G>A X846_splice Splice_Site diploid chr15 65681621 65681621 ENST00000352385.2:c.2536+1G>A G510A Missense gain One chr15 65687479 65687479 ENST00000352385.2:c.1529G>C R1086W Missense diploid chr15 65677378 65677378 ENST00000352385.2:c.3256C>T D1111N Missense shallowdel One chr15 65677303 65677303 ENST00000352385.2:c.3331G>A W731* Nonsense diploid chr15 65684249 65684249 ENST00000352385.2:c.2193G>A ITGA3 P845H Missense gain chr17 48156573 48156573 ENST00000320031.8:c.2534C>A E63K Missense gain One chr17 48133990 48133990 ENST00000320031.8:c.187G>A H356Y Missense diploid One chr17 48149456 48149456 ENST00000320031.8:c.1066C>T X714_splice Splice_Site diploid chr17 48155409 48155409 ENST00000320031.8:c.2140-1G>A F543L Missense gain chr17 48153054 48153054 ENST00000320031.8:c.1629C>G W220C Missense gain chr17 48145665 48145665 ENST00000320031.8:c.660G>T S202G Missense diploid chr17 48145609 48145609 ENST00000320031.8:c.604A>G KBTBD3 W531S Missense diploid One chr11 105923824 105923824 ENST00000526793.1:c.1592G>C E464Q Missense diploid One chr11 105924026 105924026 ENST00000526793.1:c.1390G>C R14Q Missense shallowdel One chr11 105929784 105929784 ENST00000526793.1:c.41G>A E23Q Missense gain chr11 105929758 105929758 ENST00000526793.1:c.67G>C R413T Missense shallowdel chr11 105924178 105924178 ENST00000526793.1:c.1238G>C X78_splice Splice_Site diploid chr11 105925184 105925184 ENST00000526793.1:c.234-2A>G V218I Missense gain chr11 105924764 105924764 ENST00000526793.1:c.652G>A MAATS1 E758K Missense diploid chr3 119469912 119469912 ENST00000273390.5:c.2272G>A D452H Missense gain chr3 119456222 119456222 ENST00000273390.5:c.1354G>C K349N Missense shallowdel chr3 119451169 119451169 ENST00000273390.5:c.1047G>C K454N Missense diploid chr3 119456230 119456230 ENST00000273390.5:c.1362G>C E130Q Missense gain chr3 119427466 119427466 ENST00000273390.5:c.388G>C E666K Missense diploid chr3 119466055 119466055 ENST00000273390.5:c.1996G>A P464Lfs*21 Frame_Shift_Del diploid chr3 119456255 119456255 ENST00000273390.5:c.1391del S185* Nonsense gain chr3 119434462 119434462 ENST00000273390.5:c.554C>G MED1 H1526D Missense gain 2 chr17 37563898 37563898 ENST00000300651.6:c.4576C>G S387T Missense diploid One chr17 37576107 37576107 ENST00000300651.6:c.1160G>C S1227L Missense diploid One chr17 37564794 37564794 ENST00000300651.6:c.3680C>T S1379L Missense diploid One chr17 37564338 37564338 ENST00000300651.6:c.4136C>T S1218C Missense diploid One chr17 37564821 37564821 ENST00000300651.6:c.3653C>G K202N Missense diploid 2 chr17 37587411 37587411 ENST00000300651.6:c.606G>C L69I Missense diploid One chr17 37599809 37599809 ENST00000300651.6:c.205C>A K283T Missense diploid chr17 37580883 37580883 ENST00000300651.6:c.848A>C S1375C Missense gain chr17 37564350 37564350 ENST00000300651.6:c.4124C>G P1208A Missense gain chr17 37564852 37564852 ENST00000300651.6:c.3622C>G S256* Nonsense amp chr17 37580964 37580964 ENST00000300651.6:c.767C>A S682L Missense gain chr17 37566429 37566429 ENST00000300651.6:c.2045C>T S1363* Nonsense gain chr17 37564386 37564386 ENST00000300651.6:c.4088C>G S1439F Missense gain chr17 37564158 37564158 ENST00000300651.6:c.4316C>T S1558* Nonsense diploid chr17 37563801 37563801 ENST00000300651.6:c.4673C>G P381A Missense gain chr17 37576126 37576126 ENST00000300651.6:c.1141C>G S1368F Missense diploid chr17 37564371 37564371 ENST00000300651.6:c.4103C>T E8K Missense amp chr17 37607294 37607294 ENST00000300651.6:c.22G>A S1111L Missense gain chr17 37565142 37565142 ENST00000300651.6:c.3332C>T S349L Missense gain chr17 37579629 37579629 ENST00000300651.6:c.1046C>T M1172I Missense diploid chr17 37564958 37564958 ENST00000300651.6:c.3516G>A MTUS2 K741T Missense shallowdel chr13 29601027 29601027 ENST000000431530.3:c.2222A>C D444N Missense gain chr13 29600135 29600135 ENST000000431530.3:c.1330G>A K1330del In_Frame_Del gain chr13 30077186 30077188 ENST000000431530.3:c.3989_3991delAGA L935I Missense diploid chr13 29855969 29855969 ENST000000431530.3:c.2803C>A E163* Nonsense diploid chr13 29599292 29599292 ENST000000431530.3:c.487G>T E180K Missense gain chr13 29599343 29599343 ENST000000431530.3:c.538G>A D417H Missense gain chr13 29600054 29600054 ENST000000431530.3:c.1249G>C R29K Missense amp chr13 29598891 29598891 ENST000000431530.3:c.86G>A G223E Missense diploid chr13 29599473 29599473 ENST000000431530.3:c.668G>A R109T Missense amp chr13 29599131 29599131 ENST000000431530.3:c.326G>C R160S Missense amp chr13 29599285 29599285 ENST000000431530.3:c.480G>T E268D Missense amp chr13 29599609 29599609 ENST000000431530.3:c.804G>C E398K Missense amp chr13 29599997 29599997 ENST000000431530.3:c.1192G>A L688F Missense diploid chr13 29600867 29600867 ENST000000431530.3:c.2062C>T PIK3C2A L1652V Missense diploid One chr11 17111392 17111392 ENST00000265970.7:c.4954C>G D839N Missense shallowdel 2 chr11 17143877 17143877 ENST00000265970.7:c.2515G>A A1501G Missense diploid One chr11 17113773 17113773 ENST00000265970.7:c.4502C>G I1475V Missense shallowdel One chr11 17115836 17115836 ENST00000265970.7:c.4423A>G Q1349E Missense diploid One chr11 17121480 17121480 ENST00000265970.7:c.4045C>G L1034V Missense diploid One chr11 17139154 17139154 ENST00000265970.7:c.3100C>G R1570* Nonsense diploid One chr11 17113138 17113138 ENST00000265970.7:c.4708C>T Q434* Nonsense gain One chr11 17172072 17172072 ENST00000265970.7:c.1300C>T R1259* Nonsense diploid chr11 17124285 17124285 ENST00000265970.7:c.3775C>T D870N Missense diploid chr11 17143784 17143784 ENST00000265970.7:c.2608G>A S702* Nonsense shallowdel chr11 17156369 17156369 ENST00000265970.7:c.2105C>G D25Y Missense diploid chr11 17191216 17191216 ENST00000265970.7:c.73G>T S1457L Missense diploid chr11 17115889 17115889 ENST00000265970.7:c.4370C>T Q770K Missense shallowdel chr11 17150938 17150938 ENST00000265970.7:c.2308C>A S259F Missense shallowdel chr11 17190513 17190513 ENST00000265970.7:c.776C>T D846H Missense shallowdel chr11 17143856 17143856 ENST00000265970.7:c.2536G>C E865K Missense diploid chr11 17143799 17143799 ENST00000265970.7:c.2593G>A S128L Missense diploid chr11 17190906 17190906 ENST00000265970.7:c.383C>T QARS E399K Missense diploid One chr3 49137494 49137494 ENST00000306125.6:c.1195G>A E84K Missense shallowdel One chr3 49141772 49141772 ENST00000306125.6:c.250G>A R464C Missense gain One chr3 49137079 49137079 ENST00000306125.6:c.1390C>T K25N Missense diploid chr3 49142092 49142092 ENST00000306125.6:c.75G>T C687Y Missense diploid chr3 49135810 49135810 ENST00000306125.6:c.2060G>A RBP2 I26T Missense gain One chr3 139181129 139181129 ENST00000232217.2:c.77T>C Q5H Missense gain chr3 139195287 139195287 ENST00000232217.2:c.15G>C Q5H Missense diploid chr3 139195287 139195287 ENST00000232217.2:c.15G>C E119Q Missense diploid chr3 139172008 139172008 ENST00000232217.2:c.355G>C E112K Missense diploid chr3 139173591 139173591 ENST00000232217.2:c.334G>A D25Y Missense gain 2 chr3 139195229 139195229 ENST00000232217.2:c.73G>T SALL1 P675A Missense shallowdel 7 chr16 51174110 51174110 ENST00000251020.4:c.2023C>G E599K Missense shallowdel One chr16 51174338 51174338 ENST00000251020.4:c.1795G>A E51Q Missense gain 2 chr16 51175982 51175982 ENST00000251020.4:c.151G>C R276Q Missense shallowdel One chr16 51175306 51175306 ENST00000251020.4:c.827G>A E1251K Missense diploid One chr16 51171247 51171247 ENST000000251020.4:c.3751G>A D263Y Missense shallowdel chr16 51175346 51175346 ENST000000251020.4:c.787G>T L762H Missense shallowdel chr16 51173848 51173848 ENST00000251020.4:c.2285T>A I981M Missense diploid chr16 51173190 51173190 ENST00000251020.4:c.2943C>G R757G Missense diploid One chr16 51173864 51173864 ENST00000251020.4:c.2269C>G Q107E Missense diploid One chr16 51175814 51175814 ENST00000251020.4:c.319C>G V433A Missense gain chr16 51174835 51174835 ENST00000251020.4:c.1298T>C R1128S Missense diploid chr16 51172749 51172749 ENST00000251020.4:c.3384G>C S961F Missense diploid chr16 51173251 51173251 ENST00000251020.4:c.2882C>T A387P Missense diploid chr16 51174974 51174974 ENST00000251020.4:c.1159G>C D819H Missense gain chr16 51173678 51173678 ENST00000251020.4:c.2455G>C A646P Missense shallowdel One chr16 51174197 51174197 ENST00000251020.4:c.1936G>C P1069A Missense shallowdel One chr16 51172928 51172928 ENST000000251020.4:c.3205C>G L72F Missense shallowdel chr16 51175917 51175917 ENST00000251020.4:c.216A>C A214V Missense diploid chr16 51175492 51175492 ENST000000251020.4:c.641C>T A672T Missense diploid chr16 51174119 51174119 ENST00000251020.4:c.2014G>A T636A Missense diploid chr16 51174227 51174227 ENST00000251020.4:c.1906A>G P635T Missense diploid One chr16 51174230 51174230 ENST000000251020.4:c.1903C>A E515Q Missense shallowdel chr16 51174590 51174590 ENST00000251020.4:c.1543G>C S1302N Missense gain chr16 51171093 51171093 ENST000000251020.4:c.3905G>A SIN3A R471Q Missense diploid One chr15 75694307 75694307 ENST00000360439.4:c.1412G>A F1169L Missense diploid One chr15 75668090 75668090 ENST00000360439.4:c.3507C>A I1133V Missense gain One chr15 75668200 75668200 ENST00000360439.4:c.3397A>G T1049K Missense gain One chr15 75676654 75676654 ENST00000360439.4:c.3146C>A Q100H Missense diploid One chr15 75715054 75715054 ENST00000360439.4:c.300G>C E540K Missense diploid chr15 75693190 75693190 ENST00000360439.4:c.1618G>A K1148N Missense shallowdel chr15 75668153 75668153 ENST00000360439.4:c.3444G>C E513Q Missense diploid chr15 75693271 75693271 ENST00000360439.4:c.1537G>C Q805E Missense diploid chr15 75685021 75685021 ENST00000360439.4:c.2413C>G H333R Missense shallowdel chr15 75703843 75703843 ENST00000360439.4:c.998A>G D1090Y Missense shallowdel chr15 75673974 75673974 ENST00000360439.4:c.3268G>T N423K Missense diploid One chr15 75702225 75702225 ENST00000360439.4:c.1269T>A Q1208E Missense diploid chr15 75664520 75664520 ENST00000360439.4:c.3622C>G R428C Missense chr15 75702212 75702212 ENST00000360439.4:c.1282C>T SLC45A1 D220N Missense gain One chr1 8386045 8386045 ENST00000289877.8:c.658G>A Q657* Nonsense diploid One chr1 8399747 8399747 ENST00000289877.8:c.1969C>T A687S Missense shallowdel One chr1 8403885 8403885 ENST00000289877.8:c.2059G>T P295L Missense diploid chr1 8390437 8390437 ENST00000289877.8:c.884C>T L690V Missense diploid chr1 8403894 8403894 ENST00000289877.8:c.2068C>G E98Q Missense shallowdel chr1 8384681 8384681 ENST00000289877.8:c.292G>C A274E Missense diploid chr1 8390374 8390374 ENST00000289877.8:c.821C>A A587V Missense diploid chr1 8398038 8398038 ENST00000289877.8:c.1760C>T G619R Missense diploid chr1 8399633 8399633 ENST00000289877.8:c.1855G>C Q81H Missense gain chr1 8384632 8384632 ENST00000289877.8:c.243G>C S499F Missense gain chr1 8395549 8395549 ENST00000289877.8:c.1496C>T SULT2A1 W284R Missense diploid One chr19 48374720 48374720 ENST00000222002.3:c.850T>C R193K Missense gain One chr19 48378081 48378081 ENST00000222002.3:c.578G>A P278S Missense diploid chr19 48374738 48374738 ENST00000222002.3:c.832C>T K224E Missense gain chr19 48377989 48377989 ENST00000222002.3:c.670A>G TMPRSS9 P469S Missense diploid One chr19 2413950 2413950
ENST00000332578.3:c.1405C>T R221Q Missense diploid chr19 2405465 2405465 ENST00000332578.3:c.662G>A R1021W Missense diploid chr19 2425967 2425967 ENST00000332578.3:c.3061C>T A286V Missense shallowdel chr19 2408470 2408470 ENST00000332578.3:c.857C>T G689V Missense diploid chr19 2421865 2421865 ENST00000332578.3:c.2066G>T D292H Missense shallowdel chr19 2408487 2408487 ENST00000332578.3:c.874G>C S365L Missense diploid chr19 2410334 2410334 ENST00000332578.3:c.1094C>T L596V Missense shallowdel chr19 2416678 2416678 ENST00000332578.3:c.1786C>G TXK S407* Nonsense gain One chr4 48078437 48078437 ENST00000264316.4:c.1220C>G S400L Missense gain One chr4 48078458 48078458 ENST00000264316.4:c.1199C>T H323L Missense shallowdel One chr4 48082134 48082134 ENST00000264316.4:c.968A>T X149_splice Splice_Site shallowdel chr4 48106974 48106974 ENST00000264316.4:c.447-2A>G L163V Missense gain chr4 48106932 48106932 ENST00000264316.4:c.487C>G E481K Missense gain chr4 48073608 48073608 ENST00000264316.4:c.1441G>A G463V Missense gain 2 chr4 48073661 48073661 ENST00000264316.4:c.1388G>T D267Y Missense diploid chr4 48088640 48088640 ENST00000264316.4:c.799G>T E217K Missense shallowdel chr4 48096154 48096154 ENST00000264316.4:c.649G>A Q204* Nonsense diploid chr4 48096193 48096193 ENST00000264316.4:c.610C>T D408G Missense diploid chr4 48078434 48078434 ENST00000264316.4:c.1223A>G

Based on the mutation position information, it is possible to manufacture a microchip using a primer, a probe, an antibody, or an aptamer capable of detecting the marker gene, and the specific method may be according to a conventional technique.

In the above, preferred embodiments of the present invention have been exemplarily described, but the scope of the present invention is not limited to the specific embodiments as described above, and those of ordinary skill in the art will It can be appropriately changed within.

<110> THE CATHOLIC UNIVERSITY OF KOREA INDUSTRY-ACADEMIC COOPERATION FOUNDATION <120> Composition And Kit For Diagnosing Prognosis Of Bladder Cancer According To Recurrence <130> 2021-DPA-4421D <150> KR 10-2020-0037736 <151> 2020-03-27 <160> 22 <170> KoPatentIn 3.0 <210> 1 <211> 475 <212> PRT <213> Homo sapiens <400> 1 Met Ala Gly Arg Pro His Pro Tyr Asp Gly Asn Ser Ser Asp Pro Glu 1 5 10 15 Asn Trp Asp Arg Lys Leu His Ser Arg Pro Arg Lys Leu Tyr Lys His 20 25 30 Ser Ser Thr Ser Ser Arg Ile Ala Lys Gly Gly Val Asp His Thr Lys 35 40 45 Met Ser Leu His Gly Ala Ser Gly Gly His Glu Arg Ser Arg Asp Arg 50 55 60 Arg Arg Ser Ser Asp Arg Ser Arg Asp Ser Ser His Glu Arg Thr Glu 65 70 75 80 Ser Gln Leu Thr Pro Cys Ile Arg Asn Val Thr Ser Pro Thr Arg Gln 85 90 95 His His Val Glu Arg Glu Lys Asp His Ser Ser Ser Arg Pro Ser Ser 100 105 110 Pro Arg Pro Gln Lys Ala Ser Pro Asn Gly Ser Ile Ser Ser Ala Gly 115 120 125 Asn Ser Ser Arg Asn Ser Ser Gln Ser Ser Ser Asp Gly Ser Cys Lys 130 135 140 Thr Ala Gly Glu Met Val Phe Val Tyr Glu Asn Ala Lys Glu Gly Ala 145 150 155 160 Arg Asn Ile Arg Thr Ser Glu Arg Val Thr Leu Ile Val Asp Asn Thr 165 170 175 Arg Phe Val Val Asp Pro Ser Ile Phe Thr Ala Gln Pro Asn Thr Met 180 185 190 Leu Gly Arg Met Phe Gly Ser Gly Arg Glu His Asn Phe Thr Arg Pro 195 200 205 Asn Glu Lys Gly Glu Tyr Glu Val Ala Glu Gly Ile Gly Ser Thr Val 210 215 220 Phe Arg Ala Ile Leu Asp Tyr Tyr Lys Thr Gly Ile Ile Arg Cys Pro 225 230 235 240 Asp Gly Ile Ser Ile Pro Glu Leu Arg Glu Ala Cys Asp Tyr Leu Cys 245 250 255 Ile Ser Phe Glu Tyr Ser Thr Ile Lys Cys Arg Asp Leu Ser Ala Leu 260 265 270 Met His Glu Leu Ser Asn Asp Gly Ala Arg Arg Gln Phe Glu Phe Tyr 275 280 285 Leu Glu Glu Met Ile Leu Pro Leu Met Val Ala Ser Ala Gln Ser Gly 290 295 300 Glu Arg Glu Cys His Ile Val Val Leu Thr Asp Asp Asp Val Val Asp 305 310 315 320 Trp Asp Glu Glu Tyr Pro Pro Gln Met Gly Glu Glu Tyr Ser Gln Ile 325 330 335 Ile Tyr Ser Thr Lys Leu Tyr Arg Phe Phe Lys Tyr Ile Glu Asn Arg 340 345 350 Asp Val Ala Lys Ser Val Leu Lys Glu Arg Gly Leu Lys Lys Ile Arg 355 360 365 Leu Gly Ile Glu Gly Tyr Pro Thr Tyr Lys Glu Lys Val Lys Lys Arg 370 375 380 Pro Gly Gly Arg Pro Glu Val Ile Tyr Asn Tyr Val Gln Arg Pro Phe 385 390 395 400 Ile Arg Met Ser Trp Glu Lys Glu Glu Gly Lys Ser Arg His Val Asp 405 410 415 Phe Gln Cys Val Lys Ser Lys Ser Ile Thr Asn Leu Ala Ala Ala Ala 420 425 430 Ala Asp Ile Pro Gln Asp Gln Leu Val Val Met His Pro Thr Pro Gln 435 440 445 Val Asp Glu Leu Asp Ile Leu Pro Ile His Pro Pro Ser Gly Asn Ser 450 455 460 Asp Leu Asp Pro Asp Ala Gln Asn Pro Met Leu 465 470 475 <210> 2 <211> 883 <212> PRT <213> Homo sapiens <400> 2 Met Gln Lys Ile Met His Ile Ser Val Leu Leu Ser Pro Val Leu Trp 1 5 10 15 Gly Leu Ile Phe Gly Val Ser Ser Asn Ser Ile Gln Ile Gly Gly Leu 20 25 30 Phe Pro Arg Gly Ala Asp Gln Glu Tyr Ser Ala Phe Arg Val Gly Met 35 40 45 Val Gln Phe Ser Thr Ser Glu Phe Arg Leu Thr Pro His Ile Asp Asn 50 55 60 Leu Glu Val Ala Asn Ser Phe Ala Val Thr Asn Ala Phe Cys Ser Gln 65 70 75 80 Phe Ser Arg Gly Val Tyr Ala Ile Phe Gly Phe Tyr Asp Lys Lys Ser 85 90 95 Val Asn Thr Ile Thr Ser Phe Cys Gly Thr Leu His Val Ser Phe Ile 100 105 110 Thr Pro Ser Phe Pro Thr Asp Gly Thr His Pro Phe Val Ile Gln Met 115 120 125 Arg Pro Asp Leu Lys Gly Ala Leu Leu Ser Leu Ile Glu Tyr Tyr Gln 130 135 140 Trp Asp Lys Phe Ala Tyr Leu Tyr Asp Ser Asp Arg Gly Leu Ser Thr 145 150 155 160 Leu Gln Ala Val Leu Asp Ser Ala Ala Glu Lys Lys Trp Gln Val Thr 165 170 175 Ala Ile Asn Val Gly Asn Ile Asn Asn Asp Lys Lys Asp Glu Met Tyr 180 185 190 Arg Ser Leu Phe Gln Asp Leu Glu Leu Lys Lys Glu Arg Arg Val Ile 195 200 205 Leu Asp Cys Glu Arg Asp Lys Val Asn Asp Ile Val Asp Gln Val Ile 210 215 220 Thr Ile Gly Lys His Val Lys Gly Tyr His Tyr Ile Ile Ala Asn Leu 225 230 235 240 Gly Phe Thr Asp Gly Asp Leu Leu Lys Ile Gln Phe Gly Gly Ala Asn 245 250 255 Val Ser Gly Phe Gln Ile Val Asp Tyr Asp Asp Ser Leu Val Ser Lys 260 265 270 Phe Ile Glu Arg Trp Ser Thr Leu Glu Glu Lys Glu Tyr Pro Gly Ala 275 280 285 His Thr Thr Thr Ile Lys Tyr Thr Ser Ala Leu Thr Tyr Asp Ala Val 290 295 300 Gln Val Met Thr Glu Ala Phe Arg Asn Leu Arg Lys Gln Arg Ile Glu 305 310 315 320 Ile Ser Arg Arg Gly Asn Ala Gly Asp Cys Leu Ala Asn Pro Ala Val 325 330 335 Pro Trp Gly Gln Gly Val Glu Ile Glu Arg Ala Leu Lys Gln Val Gln 340 345 350 Val Glu Gly Leu Ser Gly Asn Ile Lys Phe Asp Gln Asn Gly Lys Arg 355 360 365 Ile Asn Tyr Thr Ile Asn Ile Met Glu Leu Lys Thr Asn Gly Pro Arg 370 375 380 Lys Ile Gly Tyr Trp Ser Glu Val Asp Lys Met Val Val Thr Leu Thr 385 390 395 400 Glu Leu Pro Ser Gly Asn Asp Thr Ser Gly Leu Glu Asn Lys Thr Val 405 410 415 Val Val Thr Thr Ile Leu Glu Ser Pro Tyr Val Met Met Lys Lys Asn 420 425 430 His Glu Met Leu Glu Gly Asn Glu Arg Tyr Glu Gly Tyr Cys Val Asp 435 440 445 Leu Ala Ala Glu Ile Ala Lys His Cys Gly Phe Lys Tyr Lys Leu Thr 450 455 460 Ile Val Gly Asp Gly Lys Tyr Gly Ala Arg Asp Ala Asp Thr Lys Ile 465 470 475 480 Trp Asn Gly Met Val Gly Glu Leu Val Tyr Gly Lys Ala Asp Ile Ala 485 490 495 Ile Ala Pro Leu Thr Ile Thr Leu Val Arg Glu Glu Val Ile Asp Phe 500 505 510 Ser Lys Pro Phe Met Ser Leu Gly Ile Ser Ile Met Ile Lys Lys Pro 515 520 525 Gln Lys Ser Lys Pro Gly Val Phe Ser Phe Leu Asp Pro Leu Ala Tyr 530 535 540 Glu Ile Trp Met Cys Ile Val Phe Ala Tyr Ile Gly Val Ser Val Val 545 550 555 560 Leu Phe Leu Val Ser Arg Phe Ser Pro Tyr Glu Trp His Thr Glu Glu 565 570 575 Phe Glu Asp Gly Arg Glu Thr Gln Ser Ser Glu Ser Thr Asn Glu Phe 580 585 590 Gly Ile Phe Asn Ser Leu Trp Phe Ser Leu Gly Ala Phe Met Arg Gln 595 600 605 Gly Cys Asp Ile Ser Pro Arg Ser Leu Ser Gly Arg Ile Val Gly Gly 610 615 620 Val Trp Trp Phe Phe Thr Leu Ile Ile Ile Ser Ser Tyr Thr Ala Asn 625 630 635 640 Leu Ala Ala Phe Leu Thr Val Glu Arg Met Val Ser Pro Ile Glu Ser 645 650 655 Ala Glu Asp Leu Ser Lys Gln Thr Glu Ile Ala Tyr Gly Thr Leu Asp 660 665 670 Ser Gly Ser Thr Lys Glu Phe Phe Arg Arg Ser Lys Ile Ala Val Phe 675 680 685 Asp Lys Met Trp Thr Tyr Met Arg Ser Ala Glu Pro Ser Val Phe Val 690 695 700 Arg Thr Thr Ala Glu Gly Val Ala Arg Val Arg Lys Ser Lys Gly Lys 705 710 715 720 Tyr Ala Tyr Leu Leu Glu Ser Thr Met Asn Glu Tyr Ile Glu Gln Arg 725 730 735 Lys Pro Cys Asp Thr Met Lys Val Gly Gly Asn Leu Asp Ser Lys Gly 740 745 750 Tyr Gly Ile Ala Thr Pro Lys Gly Ser Ser Leu Arg Asn Ala Val Asn 755 760 765 Leu Ala Val Leu Lys Leu Asn Glu Gln Gly Leu Leu Asp Lys Leu Lys 770 775 780 Asn Lys Trp Trp Tyr Asp Lys Gly Glu Cys Gly Ser Gly Gly Gly Asp 785 790 795 800 Ser Lys Glu Lys Thr Ser Ala Leu Ser Leu Ser Asn Val Ala Gly Val 805 810 815 Phe Tyr Ile Leu Val Gly Gly Leu Gly Leu Ala Met Leu Val Ala Leu 820 825 830 Ile Glu Phe Cys Tyr Lys Ser Arg Ala Glu Ala Lys Arg Met Lys Val 835 840 845 Ala Lys Asn Ala Gln Asn Ile Asn Pro Ser Ser Ser Gln Asn Ser Gln 850 855 860 Asn Phe Ala Thr Tyr Lys Glu Gly Tyr Asn Val Tyr Gly Ile Glu Ser 865 870 875 880 Val Lys Ile <210> 3 <211> 732 <212> PRT <213> Homo sapiens <400> 3 Met Ser Arg Arg Lys Ile Ser Ser Glu Ser Phe Ser Ser Leu Gly Ser 1 5 10 15 Asp Tyr Leu Glu Thr Ser Pro Glu Glu Glu Gly Glu Cys Pro Leu Ser 20 25 30 Arg Leu Cys Trp Asn Gly Ser Arg Ser Pro Pro Gly Pro Leu Glu Pro 35 40 45 Ser Pro Ala Ala Ala Ala Ala Ala Ala Ala Ala Pro Ala Pro Thr Pro Ala 50 55 60 Ala Ser Ala Ala Ala Ala Ala Ala Thr Ala Gly Ala Arg Arg Val Gln 65 70 75 80 Arg Arg Arg Arg Val Asn Leu Asp Ser Leu Gly Glu Ser Ile Ser Arg 85 90 95 Leu Thr Ala Pro Ser Pro Gln Thr Ile Gln Gln Thr Leu Lys Arg Thr 100 105 110 Leu Gln Tyr Tyr Glu His Gln Val Ile Gly Tyr Arg Asp Ala Glu Lys 115 120 125 Asn Phe His Asn Ile Ser Asn Arg Cys Ser Tyr Ala Asp His Ser Asn 130 135 140 Lys Glu Glu Ile Glu Asp Val Ser Gly Ile Leu Gln Cys Thr Ala Asn 145 150 155 160 Ile Leu Gly Leu Lys Phe Glu Glu Ile Gln Lys Arg Phe Gly Glu Glu 165 170 175 Phe Phe Asn Ile Cys Phe His Glu Asn Glu Arg Val Leu Arg Ala Val 180 185 190 Gly Gly Thr Leu Gln Asp Phe Phe Asn Gly Phe Asp Ala Leu Leu Glu 195 200 205 His Ile Arg Thr Ser Phe Gly Lys Gln Ala Thr Leu Glu Ser Pro Ser 210 215 220 Phe Leu Cys Lys Glu Leu Pro Glu Gly Thr Leu Met Leu His Tyr Phe 225 230 235 240 His Pro His His Ile Val Gly Phe Ala Met Leu Gly Met Ile Lys Ala 245 250 255 Ala Gly Lys Lys Ile Tyr Arg Leu Asp Val Glu Val Glu Gln Val Ala 260 265 270 Asn Glu Lys Leu Cys Ser Asp Val Ser Asn Pro Gly Asn Cys Ser Cys 275 280 285 Leu Thr Phe Leu Ile Lys Glu Cys Glu Asn Thr Asn Ile Met Lys Asn 290 295 300 Leu Pro Gln Gly Thr Ser Gln Val Pro Ala Asp Leu Arg Ile Ser Ile 305 310 315 320 Asn Thr Phe Cys Arg Ala Phe Pro Phe His Leu Met Phe Asp Pro Ser 325 330 335 Met Ser Val Leu Gln Leu Gly Glu Gly Leu Arg Lys Gln Leu Arg Cys 340 345 350 Asp Thr His Lys Val Leu Lys Phe Glu Asp Cys Phe Glu Ile Val Ser 355 360 365 Pro Lys Val Asn Ala Thr Phe Glu Arg Val Leu Leu Arg Leu Ser Thr 370 375 380 Pro Phe Val Ile Arg Thr Lys Pro Glu Ala Ser Gly Ser Glu Asn Lys 385 390 395 400 Asp Lys Val Met Glu Val Lys Gly Gln Met Ile His Val Pro Glu Ser 405 410 415 Asn Ser Ile Leu Phe Leu Gly Ser Pro Cys Val Asp Lys Leu Asp Glu 420 425 430 Leu Met Gly Arg Gly Leu His Leu Ser Asp Ile Pro Ile His Asp Ala 435 440 445 Thr Arg Asp Val Ile Leu Val Gly Glu Gln Ala Lys Ala Gln Asp Gly 450 455 460 Leu Lys Lys Arg Met Asp Lys Leu Lys Ala Thr Leu Glu Arg Thr His 465 470 475 480 Gln Ala Leu Glu Glu Glu Lys Lys Lys Thr Val Asp Leu Leu Tyr Ser 485 490 495 Ile Phe Pro Gly Asp Val Ala Gln Gln Leu Trp Gln Gly Gln Gln Val 500 505 510 Gln Ala Arg Lys Phe Asp Asp Val Thr Met Leu Phe Ser Asp Ile Val 515 520 525 Gly Phe Thr Ala Ile Cys Ala Gln Cys Thr Pro Met Gln Val Ile Ser 530 535 540 Met Leu Asn Glu Leu Tyr Thr Arg Phe Asp His Gln Cys Gly Phe Leu 545 550 555 560 Asp Ile Tyr Lys Val Glu Thr Ile Gly Asp Ala Tyr Cys Val Ala Ala 565 570 575 Gly Leu His Arg Lys Ser Leu Cys His Ala Lys Pro Ile Ala Leu Met 580 585 590 Ala Leu Lys Met Met Glu Leu Ser Glu Glu Val Leu Thr Pro Asp Gly 595 600 605 Arg Pro Ile Gln Met Arg Ile Gly Ile His Ser Gly Ser Val Leu Ala 610 615 620 Gly Val Val Gly Val Arg Met Pro Arg Tyr Cys Leu Phe Gly Asn Asn 625 630 635 640 Val Thr Leu Ala Ser Lys Phe Glu Ser Gly Ser His Pro Arg Arg Ile 645 650 655 Asn Val Ser Pro Thr Thr Tyr Gln Leu Leu Lys Arg Glu Glu Ser Phe 660 665 670 Thr Phe Ile Pro Arg Ser Arg Glu Glu Leu Pro Asp Asn Phe Pro Lys 675 680 685 Glu Ile Pro Gly Ile Cys Tyr Phe Leu Glu Val Arg Thr Gly Pro Lys 690 695 700 Pro Pro Lys Pro Ser Leu Ser Ser Ser Arg Ile Lys Lys Val Ser Tyr 705 710 715 720 Asn Ile Gly Thr Met Phe Leu Arg Glu Thr Ser Leu 725 730 <210> 4 <211> 1051 <212> PRT <213> Homo sapiens <400> 4 Met Gly Pro Gly Pro Ser Arg Ala Pro Arg Ala Pro Arg Leu Met Leu 1 5 10 15 Cys Ala Leu Ala Leu Met Val Ala Ala Gly Gly Cys Val Val Ser Ala 20 25 30 Phe Asn Leu Asp Thr Arg Phe Leu Val Val Lys Glu Ala Gly Asn Pro 35 40 45 Gly Ser Leu Phe Gly Tyr Ser Val Ala Leu His Arg Gln Thr Glu Arg 50 55 60 Gln Gln Arg Tyr Leu Leu Leu Ala Gly Ala Pro Arg Glu Leu Ala Val 65 70 75 80 Pro Asp Gly Tyr Thr Asn Arg Thr Gly Ala Val Tyr Leu Cys Pro Leu 85 90 95 Thr Ala His Lys Asp Asp Cys Glu Arg Met Asn Ile Thr Val Lys Asn 100 105 110 Asp Pro Gly His His Ile Ile Glu Asp Met Trp Leu Gly Val Thr Val 115 120 125 Ala Ser Gln Gly Pro Ala Gly Arg Val Leu Val Cys Ala His Arg Tyr 130 135 140 Thr Gln Val Leu Trp Ser Gly Ser Glu Asp Gln Arg Arg Met Val Gly 145 150 155 160 Lys Cys Tyr Val Arg Gly Asn Asp Leu Glu Leu Asp Ser Ser Asp Asp 165 170 175 Trp Gln Thr Tyr His Asn Glu Met Cys Asn Ser Asn Thr Asp Tyr Leu 180 185 190 Glu Thr Gly Met Cys Gln Leu Gly Thr Ser Gly Gly Phe Thr Gln Asn 195 200 205 Thr Val Tyr Phe Gly Ala Pro Gly Ala Tyr Asn Trp Lys Gly Asn Ser 210 215 220 Tyr Met Ile Gln Arg Lys Glu Trp Asp Leu Ser Glu Tyr Ser Tyr Lys 225 230 235 240 Asp Pro Glu Asp Gln Gly Asn Leu Tyr Ile Gly Tyr Thr Met Gln Val 245 250 255 Gly Ser Phe Ile Leu His Pro Lys Asn Ile Thr Ile Val Thr Gly Ala 260 265 270 Pro Arg His Arg His Met Gly Ala Val Phe Leu Leu Ser Gln Glu Ala 275 280 285 Gly Gly Asp Leu Arg Arg Arg Gln Val Leu Glu Gly Ser Gln Val Gly 290 295 300 Ala Tyr Phe Gly Ser Ala Ile Ala Leu Ala Asp Leu Asn Asn Asp Gly 305 310 315 320 Trp Gln Asp Leu Leu Val Gly Ala Pro Tyr Tyr Phe Glu Arg Lys Glu 325 330 335 Glu Val Gly Gly Ala Ile Tyr Val Phe Met Asn Gln Ala Gly Thr Ser 340 345 350 Phe Pro Ala His Pro Ser Leu Leu Leu His Gly Pro Ser Gly Ser Ala 355 360 365 Phe Gly Leu Ser Val Ala Ser Ile Gly Asp Ile Asn Gln Asp Gly Phe 370 375 380 Gln Asp Ile Ala Val Gly Ala Pro Phe Glu Gly Leu Gly Lys Val Tyr 385 390 395 400 Ile Tyr His Ser Ser Ser Lys Gly Leu Leu Arg Gln Pro Gln Gln Val 405 410 415 Ile His Gly Glu Lys Leu Gly Leu Pro Gly Leu Ala Thr Phe Gly Tyr 420 425 430 Ser Leu Ser Gly Gln Met Asp Val Asp Glu Asn Phe Tyr Pro Asp Leu 435 440 445 Leu Val Gly Ser Leu Ser Asp His Ile Val Leu Leu Arg Ala Arg Pro 450 455 460 Val Ile Asn Ile Val His Lys Thr Leu Val Pro Arg Pro Ala Val Leu 465 470 475 480 Asp Pro Ala Leu Cys Thr Ala Thr Ser Cys Val Gln Val Glu Leu Cys 485 490 495 Phe Ala Tyr Asn Gln Ser Ala Gly Asn Pro Asn Tyr Arg Arg Asn Ile 500 505 510 Thr Leu Ala Tyr Thr Leu Glu Ala Asp Arg Asp Arg Arg Pro Pro Arg 515 520 525 Leu Arg Phe Ala Gly Ser Glu Ser Ala Val Phe His Gly Phe Phe Ser 530 535 540 Met Pro Glu Met Arg Cys Gln Lys Leu Glu Leu Leu Leu Leu Met Asp Asn 545 550 555 560 Leu Arg Asp Lys Leu Arg Pro Ile Ile Ile Ser Met Asn Tyr Ser Leu 565 570 575 Pro Leu Arg Met Pro Asp Arg Pro Arg Leu Gly Leu Arg Ser Leu Asp 580 585 590 Ala Tyr Pro Ile Leu Asn Gln Ala Gln Ala Leu Glu Asn His Thr Glu 595 600 605 Val Gln Phe Gln Lys Glu Cys Gly Pro Asp Asn Lys Cys Glu Ser Asn 610 615 620 Leu Gln Met Arg Ala Ala Phe Val Ser Glu Gln Gln Gln Lys Leu Ser 625 630 635 640 Arg Leu Gln Tyr Ser Arg Asp Val Arg Lys Leu Leu Leu Ser Ile Asn 645 650 655 Val Thr Asn Thr Arg Thr Ser Glu Arg Ser Gly Glu Asp Ala His Glu 660 665 670 Ala Leu Leu Thr Leu Val Val Pro Ala Leu Leu Leu Ser Ser Val 675 680 685 Arg Pro Pro Gly Ala Cys Gln Ala Asn Glu Thr Ile Phe Cys Glu Leu 690 695 700 Gly Asn Pro Phe Lys Arg Asn Gln Arg Met Glu Leu Leu Ile Ala Phe 705 710 715 720 Glu Val Ile Gly Val Thr Leu His Thr Arg Asp Leu Gln Val Gln Leu 725 730 735 Gln Leu Ser Thr Ser Ser His Gln Asp Asn Leu Trp Pro Met Ile Leu 740 745 750 Thr Leu Leu Val Asp Tyr Thr Leu Gln Thr Ser Leu Ser Met Val Asn 755 760 765 His Arg Leu Gln Ser Phe Phe Gly Gly Thr Val Met Gly Glu Ser Gly 770 775 780 Met Lys Thr Val Glu Asp Val Gly Ser Pro Leu Lys Tyr Glu Phe Gln 785 790 795 800 Val Gly Pro Met Gly Glu Gly Leu Val Gly Leu Gly Thr Leu Val Leu 805 810 815 Gly Leu Glu Trp Pro Tyr Glu Val Ser Asn Gly Lys Trp Leu Leu Tyr 820 825 830 Pro Thr Glu Ile Thr Val His Gly Asn Gly Ser Trp Pro Cys Arg Pro 835 840 845 Pro Gly Asp Leu Ile Asn Pro Leu Asn Leu Thr Leu Ser Asp Pro Gly 850 855 860 Asp Arg Pro Ser Ser Pro Gln Arg Arg Arg Arg Gln Leu Asp Pro Gly 865 870 875 880 Gly Gly Gln Gly Pro Pro Pro Val Thr Leu Ala Ala Ala Lys Lys Ala 885 890 895 Lys Ser Glu Thr Val Leu Thr Cys Ala Thr Gly Arg Ala His Cys Val 900 905 910 Trp Leu Glu Cys Pro Ile Pro Asp Ala Pro Val Val Thr Asn Val Thr 915 920 925 Val Lys Ala Arg Val Trp Asn Ser Thr Phe Ile Glu Asp Tyr Arg Asp 930 935 940 Phe Asp Arg Val Arg Val Asn Gly Trp Ala Thr Leu Phe Leu Arg Thr 945 950 955 960 Ser Ile Pro Thr Ile Asn Met Glu Asn Lys Thr Thr Trp Phe Ser Val 965 970 975 Asp Ile Asp Ser Glu Leu Val Glu Glu Leu Pro Ala Glu Ile Glu Leu 980 985 990 Trp Leu Val Leu Val Ala Val Gly Ala Gly Leu Leu Leu Leu Gly Leu 995 1000 1005 Ile Ile Leu Leu Leu Trp Lys Cys Gly Phe Phe Lys Arg Ala Arg Thr 1010 1015 1020 Arg Ala Leu Tyr Glu Ala Lys Arg Gln Lys Ala Glu Met Lys Ser Gln 1025 1030 1035 1040 Pro Ser Glu Thr Glu Arg Leu Thr Asp Asp Tyr 1045 1050 <210> 5 <211> 1581 <212> PRT <213> Homo sapiens <400> 5 Met Lys Ala Gln Gly Glu Thr Glu Glu Ser Glu Lys Leu Ser Lys Met 1 5 10 15 Ser Ser Leu Leu Glu Arg Leu His Ala Lys Phe Asn Gln Asn Arg Pro 20 25 30 Trp Ser Glu Thr Ile Lys Leu Val Arg Gln Val Met Glu Lys Arg Val 35 40 45 Val Met Ser Ser Gly Gly His Gln His Leu Val Ser Cys Leu Glu Thr 50 55 60 Leu Gln Lys Ala Leu Lys Val Thr Ser Leu Pro Ala Met Thr Asp Arg 65 70 75 80 Leu Glu Ser Ile Ala Arg Gln Asn Gly Leu Gly Ser His Leu Ser Ala 85 90 95 Ser Gly Thr Glu Cys Tyr Ile Thr Ser Asp Met Phe Tyr Val Glu Val 100 105 110 Gln Leu Asp Pro Ala Gly Gln Leu Cys Asp Val Lys Val Ala His His 115 120 125 Gly Glu Asn Pro Val Ser Cys Pro Glu Leu Val Gln Gln Leu Arg Glu 130 135 140 Lys Asn Phe Asp Glu Phe Ser Lys His Leu Lys Gly Leu Val Asn Leu 145 150 155 160 Tyr Asn Leu Pro Gly Asp Asn Lys Leu Lys Thr Lys Met Tyr Leu Ala 165 170 175 Leu Gln Ser Leu Glu Gln Asp Leu Ser Lys Met Ala Ile Met Tyr Trp 180 185 190 Lys Ala Thr Asn Ala Gly Pro Leu Asp Lys Ile Leu His Gly Ser Val 195 200 205 Gly Tyr Leu Thr Pro Arg Ser Gly Gly His Leu Met Asn Leu Lys Tyr 210 215 220 Tyr Val Ser Pro Ser Asp Leu Leu Asp Asp Lys Thr Ala Ser Pro Ile 225 230 235 240 Ile Leu His Glu Asn Asn Val Ser Arg Ser Leu Gly Met Asn Ala Ser 245 250 255 Val Thr Ile Glu Gly Thr Ser Ala Val Tyr Lys Leu Pro Ile Ala Pro 260 265 270 Leu Ile Met Gly Ser His Pro Val Asp Asn Lys Trp Thr Pro Ser Phe 275 280 285 Ser Ser Ile Thr Ser Ala Asn Ser Val Asp Leu Pro Ala Cys Phe Phe 290 295 300 Leu Lys Phe Pro Gln Pro Ile Pro Val Ser Arg Ala Phe Val Gln Lys 305 310 315 320 Leu Gln Asn Cys Thr Gly Ile Pro Leu Phe Glu Thr Gln Pro Thr Tyr 325 330 335 Ala Pro Leu Tyr Glu Leu Ile Thr Gln Phe Glu Leu Ser Lys Asp Pro 340 345 350 Asp Pro Ile Pro Leu Asn His Asn Met Arg Phe Tyr Ala Ala Leu Pro 355 360 365 Gly Gln Gln His Cys Tyr Phe Leu Asn Lys Asp Ala Pro Leu Pro Asp 370 375 380 Gly Arg Ser Leu Gln Gly Thr Leu Val Ser Lys Ile Thr Phe Gln His 385 390 395 400 Pro Gly Arg Val Pro Leu Ile Leu Asn Leu Ile Arg His Gln Val Ala 405 410 415 Tyr Asn Thr Leu Ile Gly Ser Cys Val Lys Arg Thr Ile Leu Lys Glu 420 425 430 Asp Ser Pro Gly Leu Leu Gln Phe Glu Val Cys Pro Leu Ser Glu Ser 435 440 445 Arg Phe Ser Val Ser Phe Gln His Pro Val Asn Asp Ser Leu Val Cys 450 455 460 Val Val Met Asp Val Gln Asp Ser Thr His Val Ser Cys Lys Leu Tyr 465 470 475 480 Lys Gly Leu Ser Asp Ala Leu Ile Cys Thr Asp Asp Phe Ile Ala Lys 485 490 495 Val Val Gln Arg Cys Met Ser Ile Pro Val Thr Met Arg Ala Ile Arg 500 505 510 Arg Lys Ala Glu Thr Ile Gln Ala Asp Thr Pro Ala Leu Ser Leu Ile 515 520 525 Ala Glu Thr Val Glu Asp Met Val Lys Lys Asn Leu Pro Ala Ser 530 535 540 Ser Pro Gly Tyr Gly Met Thr Thr Gly Asn Asn Pro Met Ser Gly Thr 545 550 555 560 Thr Thr Pro Thr Asn Thr Phe Pro Gly Gly Pro Ile Thr Thr Leu Phe 565 570 575 Asn Met Ser Met Ser Ile Lys Asp Arg His Glu Ser Val Gly His Gly 580 585 590 Glu Asp Phe Ser Lys Val Ser Gln Asn Pro Ile Leu Thr Ser Leu Leu 595 600 605 Gln Ile Thr Gly Asn Gly Gly Ser Thr Ile Gly Ser Ser Pro Thr Pro 610 615 620 Pro His His Thr Pro Pro Pro Val Ser Ser Met Ala Gly Asn Thr Lys 625 630 635 640 Asn His Pro Met Leu Met Asn Leu Leu Lys Asp Asn Pro Ala Gln Asp 645 650 655 Phe Ser Thr Leu Tyr Gly Ser Ser Pro Leu Glu Arg Gln Asn Ser Ser 660 665 670 Ser Gly Ser Pro Arg Met Glu Ile Cys Ser Gly Ser Asn Lys Thr Lys 675 680 685 Lys Lys Lys Ser Ser Arg Leu Pro Pro Glu Lys Pro Lys His Gln Thr 690 695 700 Glu Asp Asp Phe Gln Arg Glu Leu Phe Ser Met Asp Val Asp Ser Gln 705 710 715 720 Asn Pro Ile Phe Asp Val Asn Met Thr Ala Asp Thr Leu Asp Thr Pro 725 730 735 His Ile Thr Pro Ala Pro Ser Gln Cys Ser Thr Pro Pro Thr Thr Tyr 740 745 750 Pro Gln Pro Val Pro His Pro Gln Pro Ser Ile Gln Arg Met Val Arg 755 760 765 Leu Ser Ser Ser Asp Ser Ile Gly Pro Asp Val Thr Asp Ile Leu Ser 770 775 780 Asp Ile Ala Glu Glu Ala Ser Lys Leu Pro Ser Thr Ser Asp Asp Cys 785 790 795 800 Pro Ala Ile Gly Thr Pro Leu Arg Asp Ser Ser Ser Ser Gly His Ser 805 810 815 Gln Ser Thr Leu Phe Asp Ser Asp Val Phe Gln Thr Asn Asn Asn Glu 820 825 830 Asn Pro Tyr Thr Asp Pro Ala Asp Leu Ile Ala Asp Ala Ala Gly Ser 835 840 845 Pro Ser Ser Asp Ser Pro Thr Asn His Phe Phe His Asp Gly Val Asp 850 855 860 Phe Asn Pro Asp Leu Leu Asn Ser Gln Ser Gln Ser Gly Phe Gly Glu 865 870 875 880 Glu Tyr Phe Asp Glu Ser Ser Gln Ser Gly Asp Asn Asp Asp Phe Lys 885 890 895 Gly Phe Ala Ser Gln Ala Leu Asn Thr Leu Gly Val Pro Met Leu Gly 900 905 910 Gly Asp Asn Gly Glu Thr Lys Phe Lys Gly Asn Asn Gln Ala Asp Thr 915 920 925 Val Asp Phe Ser Ile Ile Ser Val Ala Gly Lys Ala Leu Ala Pro Ala 930 935 940 Asp Leu Met Glu His His Ser Gly Ser Gln Gly Pro Leu Leu Thr Thr 945 950 955 960 Gly Asp Leu Gly Lys Glu Lys Thr Gln Lys Arg Val Lys Glu Gly Asn 965 970 975 Gly Thr Ser Asn Ser Thr Leu Ser Gly Pro Gly Leu Asp Ser Lys Pro 980 985 990 Gly Lys Arg Ser Arg Thr Pro Ser Asn Asp Gly Lys Ser Lys Asp Lys 995 1000 1005 Pro Pro Lys Arg Lys Lys Ala Asp Thr Glu Gly Lys Ser Pro Ser His 1010 1015 1020 Ser Ser Ser Asn Arg Pro Phe Thr Pro Pro Thr Ser Thr Gly Gly Ser 1025 1030 1035 1040 Lys Ser Pro Gly Ser Ala Gly Arg Ser Gln Thr Pro Pro Gly Val Ala 1045 1050 1055 Thr Pro Pro Ile Pro Lys Ile Thr Ile Gln Ile Pro Lys Gly Thr Val 1060 1065 1070 Met Val Gly Lys Pro Ser Ser His Ser Gln Tyr Thr Ser Ser Ser Gly Ser 1075 1080 1085 Val Ser Ser Ser Gly Ser Lys Ser His His Ser His Ser Ser Ser Ser 1090 1095 1100 Ser Ser Ser Ala Ser Thr Ser Gly Lys Met Lys Ser Ser Lys Ser Glu 1105 1110 1115 1120 Gly Ser Ser Ser Ser Lys Leu Ser Ser Ser Met Tyr Ser Ser Gln Gly 1125 1130 1135 Ser Ser Gly Ser Ser Gln Ser Lys Asn Ser Ser Gln Ser Gly Gly Lys 1140 1145 1150 Pro Gly Ser Ser Pro Ile Thr Lys His Gly Leu Ser Ser Gly Ser Ser 1155 1160 1165 Ser Thr Lys Met Lys Pro Gln Gly Lys Pro Ser Ser Leu Met Asn Pro 1170 1175 1180 Ser Leu Ser Lys Pro Asn Ile Ser Pro Ser His Ser Arg Pro Pro Gly 1185 1190 1195 1200 Gly Ser Asp Lys Leu Ala Ser Pro Met Lys Pro Val Pro Gly Thr Pro 1205 1210 1215 Pro Ser Ser Lys Ala Lys Ser Pro Ile Ser Ser Gly Ser Gly Gly Ser 1220 1225 1230 His Met Ser Gly Thr Ser Ser Ser Ser Gly Met Lys Ser Ser Ser Gly 1235 1240 1245 Leu Gly Ser Ser Gly Ser Leu Ser Gln Lys Thr Pro Pro Ser Ser Asn 1250 1255 1260 Ser Cys Thr Ala Ser Ser Ser Ser Phe Ser Ser Ser Gly Ser Ser Met 1265 1270 1275 1280 Ser Ser Ser Gln Asn Gln His Gly Ser Ser Lys Gly Lys Ser Pro Ser 1285 1290 1295 Arg Asn Lys Lys Pro Ser Leu Thr Ala Val Ile Asp Lys Leu Lys His 1300 1305 1310 Gly Val Val Thr Ser Gly Pro Gly Gly Glu Asp Pro Leu Asp Gly Gln 1315 1320 1325 Met Gly Val Ser Thr Asn Ser Ser Ser His Pro Met Ser Ser Lys His 1330 1335 1340 Asn Met Ser Gly Gly Glu Phe Gln Gly Lys Arg Glu Lys Ser Asp Lys 1345 1350 1355 1360 Asp Lys Ser Lys Val Ser Thr Ser Gly Ser Ser Val Asp Ser Ser Lys 1365 1370 1375 Lys Thr Ser Glu Ser Lys Asn Val Gly Ser Thr Gly Val Ala Lys Ile 1380 1385 1390 Ile Ile Ser Lys His Asp Gly Gly Ser Pro Ser Ile Lys Ala Lys Val 1395 1400 1405 Thr Leu Gln Lys Pro Gly Glu Ser Ser Gly Glu Gly Leu Arg Pro Gln 1410 1415 1420 Met Ala Ser Ser Lys Asn Tyr Gly Ser Pro Leu Ile Ser Gly Ser Thr 1425 1430 1435 1440 Pro Lys His Glu Arg Gly Ser Pro Ser His Ser Lys Ser Pro Ala Tyr 1445 1450 1455 Thr Pro Gln Asn Leu Asp Ser Glu Ser Glu Ser Gly Ser Ser Ile Ala 1460 1465 1470 Glu Lys Ser Tyr Gln Asn Ser Pro Ser Ser Asp Asp Gly Ile Arg Pro 1475 1480 1485 Leu Pro Glu Tyr Ser Thr Glu Lys His Lys Lys His Lys Lys Glu Lys 1490 1495 1500 Lys Lys Val Lys Asp Lys Asp Arg Asp Arg Asp Arg Asp Lys Asp Arg 1505 1510 1515 1520 Asp Lys Lys Lys Ser His Ser Ile Lys Pro Glu Ser Trp Ser Lys Ser 1525 1530 1535 Pro Ile Ser Ser Asp Gln Ser Leu Ser Met Thr Ser Asn Thr Ile Leu 1540 1545 1550 Ser Ala Asp Arg Pro Ser Arg Leu Ser Pro Asp Phe Met Ile Gly Glu 1555 1560 1565 Glu Asp Asp Asp Leu Met Asp Val Ala Leu Ile Gly Asn 1570 1575 1580 <210> 6 <211> 1369 <212> PRT <213> Homo sapiens <400> 6 Met Ser Val Pro Val Ala Pro Lys Lys Ser Cys Tyr Thr Gln Leu Arg 1 5 10 15 Asp Asn Arg Asn Ala Ala Arg Asn Asn Asn Glu Ser Ile Leu Ser Leu 20 25 30 Gly Asp Thr Asn Ala Asn Gln Ile Met Leu Glu Val Ser Ser Ser His 35 40 45 Asp Glu Ser Lys Thr Cys Asp Leu Gly Asp Glu Ile Gly Asn Thr Asn 50 55 60 Ser Ser Glu Pro Glu Asn Arg Thr His Phe His Lys Glu Phe His Gln 65 70 75 80 Leu Gln Gly Phe Gly Lys Gly Ser Gln Ala Gly Ser Ala Ser Leu Lys 85 90 95 Asp Phe Arg Leu Ser Ser Thr Ile Gln Arg Glu Leu Asn Glu Glu His 100 105 110 Thr Val Glu Arg Gly Thr Asp Ser Leu Gln Thr Thr Arg Ser Ile Gln 115 120 125 Gly Pro Ser Leu Ser Ser Ser Trp Arg Asn Val Met Ser Glu Ala Ser Leu 130 135 140 Asp Val Leu Ala Lys Arg Asp Ala Glu Ile Pro Arg His Val Pro Lys 145 150 155 160 Asp Lys Leu Ala Lys Thr Leu Asp Asn Glu Glu Leu Arg Arg His Ser 165 170 175 Leu Glu Arg Ala Ser Ser Ser Val Ala Ala Val Gly Ser Leu Thr Pro 180 185 190 Gln His Pro Gln Pro Leu Ser Leu Asp Ser Arg Glu Ala Arg Gly Gln 195 200 205 Ile Pro Gly Gly Gly Glu Gly Pro Gln Lys Thr Leu Pro Asp His Ala 210 215 220 Val Pro Ala Ala Phe Pro Ala Thr Asp Ser Thr Ser Glu Gly Lys Ser 225 230 235 240 Val Arg His Pro Lys Pro Ser Thr Ser Glu Ser Lys Gln Ser Thr Pro 245 250 255 Ser Glu Thr Gln Thr Val Gly Ala His Val Leu Gln Val Cys Ser Glu 260 265 270 His Thr Ser His Ser Ala His Pro Glu Pro Ala Leu Asn Leu Thr Leu 275 280 285 Ala Ser Lys Glu Ile Pro Ser Lys Leu Glu Ala Gln Leu Gly Gln Gly 290 295 300 Lys Gly Glu Ala Lys Leu Asp Leu Lys Tyr Val Pro Arg Arg Val 305 310 315 320 Glu Gln Glu Gly Lys Ala Ala Gln Glu Gly Tyr Leu Gly Cys His Lys 325 330 335 Glu Glu Asn Leu Ser Ala Leu Glu Gly Arg Asp Pro Cys Gly Glu Ala 340 345 350 His Pro Glu Ala Thr Asp Ala Leu Gly His Leu Leu Asn Ser Asp Leu 355 360 365 His His Leu Gly Val Gly Arg Gly Asn Cys Glu Glu Lys Arg Gly Val 370 375 380 Asn Pro Gly Glu Gln Asp Ser Leu His Thr Thr Pro Lys Gln Gly Ser 385 390 395 400 Ala Ser Leu Gly Gly Ala Asp Asn Gln Pro Thr Gly Lys Ile Ser Pro 405 410 415 Cys Ala Gly Glu Lys Leu Gly Glu Arg Thr Ser Ser Ser Phe Ser Pro 420 425 430 Gly Asp Ser His Val Ala Phe Ile Pro Asn Asn Leu Thr Asp Ser Lys 435 440 445 Pro Leu Asp Val Ile Glu Glu Glu Arg Arg Leu Gly Ser Gly Asn Lys 450 455 460 Asp Ser Val Met Val Leu Val Phe Asn Pro Ser Val Gly Glu Asn Lys 465 470 475 480 Thr Glu Val Pro Glu Pro Leu Asp Pro Gln Ser Gly Arg Ser Glu Ala 485 490 495 Arg Glu Ser Lys Glu Val Thr Thr Ser Val Ala Glu Asn Arg Asn Leu 500 505 510 Leu Glu Asn Ala Asp Lys Ile Glu Ser Thr Ser Ala Arg Ala Asp Ser 515 520 525 Val Leu Asn Ile Pro Ala Pro Leu His Pro Glu Thr Thr Val Asn Met 530 535 540 Thr Tyr Gln Pro Thr Thr Pro Ser Ser Ser Phe Gln Asp Val Ser Val 545 550 555 560 Phe Gly Met Asp Ala Gly Ser Pro Leu Val Val Pro Pro Pro Thr Asp 565 570 575 Ser Ala Arg Leu Leu Asn Thr Ser Pro Lys Val Pro Asp Lys Asn Thr 580 585 590 Cys Pro Ser Gly Ile Pro Lys Pro Val Phe Thr His Ser Lys Asp Thr 595 600 605 Pro Ser Ser Gln Glu Gly Met Glu Asn Tyr Gln Val Glu Lys Thr Glu 610 615 620 Glu Arg Thr Glu Thr Lys Pro Ile Ile Met Pro Lys Pro Lys His Val 625 630 635 640 Arg Pro Lys Ile Ile Thr Tyr Ile Arg Arg Asn Pro Gln Ala Leu Gly 645 650 655 Gln Val Asp Ala Ser Leu Val Pro Val Gly Leu Pro Tyr Ala Pro Pro 660 665 670 Thr Cys Thr Met Pro Leu Pro His Glu Glu Lys Ala Ala Gly Gly Asp 675 680 685 Leu Lys Pro Ser Ala Asn Leu Tyr Glu Lys Phe Lys Pro Asp Leu Gln 690 695 700 Lys Pro Arg Val Phe Ser Ser Gly Leu Met Val Ser Gly Ile Lys Pro 705 710 715 720 Pro Gly His Pro Phe Ser Gln Met Ser Glu Lys Phe Leu Gln Glu Val 725 730 735 Thr Asp His Pro Gly Lys Glu Glu Phe Cys Ser Pro Pro Tyr Ala His 740 745 750 Tyr Glu Val Pro Pro Thr Phe Tyr Arg Ser Ala Met Leu Leu Lys Pro 755 760 765 Gln Leu Gly Leu Gly Ala Met Ser Arg Leu Pro Ser Ala Lys Ser Arg 770 775 780 Ile Leu Ile Ala Ser Gln Arg Ser Ser Ala Ser Ala Ile His Pro Pro 785 790 795 800 Gly Pro Ile Thr Thr Ala Thr Ser Leu Tyr Ser Ser Asp Pro Ser Ala 805 810 815 Asp Leu Lys Lys Ala Ser Ser Ser Asn Ala Ala Lys Ser Asn Leu Pro 820 825 830 Lys Ser Gly Leu Arg Pro Pro Gly Tyr Ser Arg Leu Pro Ala Ala Lys 835 840 845 Leu Ala Ala Phe Gly Phe Val Arg Ser Ser Ser Val Ser Ser Val Ser 850 855 860 Ser Thr Gln Ser Gly Asp Ser Ala Gln Pro Glu Gln Gly Arg Pro Ala 865 870 875 880 Thr Arg Ser Thr Phe Gly Asn Glu Glu Gln Pro Val Leu Lys Ala Ser 885 890 895 Leu Pro Ser Lys Asp Thr Pro Lys Gly Ala Gly Arg Val Ala Pro Pro 900 905 910 Ala Ser Ser Ser Val Thr Ala Pro Arg Arg Ser Leu Leu Pro Ala Pro 915 920 925 Lys Ser Thr Ser Thr Pro Ala Gly Thr Lys Lys Asp Ala Gln Lys Asp 930 935 940 Gln Asp Thr Asn Lys Pro Ala Val Ser Ser Pro Lys Arg Val Ala Ala 945 950 955 960 Ser Thr Thr Lys Leu His Ser Pro Gly Tyr Pro Lys Gln Arg Thr Ala 965 970 975 Ala Ala Arg Asn Gly Phe Pro Lys Pro Asp Pro Gln Ala Arg Glu 980 985 990 Ala Glu Arg Gln Leu Val Leu Arg Leu Lys Glu Arg Cys Glu Gln Gln 995 1000 1005 Thr Arg Gln Leu Gly Val Ala Gln Gly Glu Leu Lys Arg Ala Ile Cys 1010 1015 1020 Gly Phe Asp Ala Leu Ala Val Ala Thr Gln His Phe Phe Arg Lys Asn 1025 1030 1035 1040 Glu Ser Ala Leu Val Lys Glu Lys Glu Leu Ser Ile Glu Leu Ala Asn 1045 1050 1055 Ile Arg Asp Glu Val Ala Phe His Thr Ala Lys Cys Glu Lys Leu Gln 1060 1065 1070 Lys Glu Lys Glu Glu Leu Glu Arg Arg Phe Glu Asp Glu Val Lys Arg 1075 1080 1085 Leu Gly Trp Gln Gln Gln Ala Glu Leu Gln Glu Leu Glu Glu Arg Leu 1090 1095 1100 Gln Leu Gln Phe Glu Ala Glu Met Ala Arg Leu Gln Glu Glu His Gly 1105 1110 1115 1120 Asp Gln Leu Leu Ser Ile Arg Cys Gln His Gln Glu Gln Val Glu Asp 1125 1130 1135 Leu Thr Ala Ser His Asp Ala Ala Leu Leu Glu Met Glu Asn Asn His 1140 1145 1150 Thr Val Ala Ile Thr Ile Leu Gln Asp Asp His Asp His Lys Val Gln 1155 1160 1165 Glu Leu Met Ser Thr His Glu Leu Glu Lys Lys Glu Leu Glu Glu Asn 1170 1175 1180 Phe Glu Lys Leu Arg Leu Ser Leu Gln Asp Gln Val Asp Thr Leu Thr 1185 1190 1195 1200 Phe Gln Ser Gln Ser Leu Arg Asp Arg Ala Arg Arg Phe Glu Glu Ala 1205 1210 1215 Leu Arg Lys Asn Thr Glu Glu Gln Leu Glu Ile Ala Leu Ala Pro Tyr 1220 1225 1230 Gln His Leu Glu Glu Asp Met Lys Ser Leu Lys Gln Val Leu Glu Met 1235 1240 1245 Lys Asn Gln Gln Ile His Glu Gln Glu Lys Lys Ile Leu Glu Leu Glu 1250 1255 1260 Lys Leu Ala Glu Lys Asn Ile Ile Leu Glu Glu Lys Ile Gln Val Leu 1265 1270 1275 1280 Gln Gln Gln Asn Glu Asp Leu Lys Ala Arg Ile Asp Gln Asn Thr Val 1285 1290 1295 Val Thr Arg Gln Leu Ser Glu Glu Asn Ala Asn Leu Gln Glu Tyr Val 1300 1305 1310 Glu Lys Glu Thr Gln Glu Lys Lys Arg Leu Ser Arg Thr Asn Glu Glu 1315 1320 1325 Leu Leu Trp Lys Leu Gln Thr Gly Asp Pro Thr Ser Pro Ile Lys Leu 1330 1335 1340 Ser Pro Thr Ser Pro Val Tyr Arg Gly Ser Ser Ser Gly Pro Ser Ser 1345 1350 1355 1360 Pro Ala Arg Val Ser Thr Thr Pro Arg 1365 <210> 7 <211> 1686 <212> PRT <213> Homo sapiens <400> 7 Met Ala Gln Ile Ser Ser Asn Ser Gly Phe Lys Glu Cys Pro Ser Ser 1 5 10 15 His Pro Glu Pro Thr Arg Ala Lys Asp Val Asp Lys Glu Glu Ala Leu 20 25 30 Gln Met Glu Ala Glu Ala Leu Ala Lys Leu Gln Lys Asp Arg Gln Val 35 40 45 Thr Asp Asn Gln Arg Gly Phe Glu Leu Ser Ser Ser Thr Arg Lys Lys 50 55 60 Ala Gln Val Tyr Asn Lys Gln Asp Tyr Asp Leu Met Val Phe Pro Glu 65 70 75 80 Ser Asp Ser Gln Lys Arg Ala Leu Asp Ile Asp Val Glu Lys Leu Thr 85 90 95 Gln Ala Glu Leu Glu Lys Leu Leu Leu Asp Asp Ser Phe Glu Thr Lys 100 105 110 Lys Thr Pro Val Leu Pro Val Thr Pro Ile Leu Ser Pro Ser Phe Ser 115 120 125 Ala Gln Leu Tyr Phe Arg Pro Thr Ile Gln Arg Gly Gln Trp Pro Pro 130 135 140 Gly Leu Pro Gly Pro Ser Thr Tyr Ala Leu Pro Ser Ile Tyr Pro Ser 145 150 155 160 Thr Tyr Ser Lys Gln Ala Ala Phe Gln Asn Gly Phe Asn Pro Arg Met 165 170 175 Pro Thr Phe Pro Ser Thr Glu Pro Ile Tyr Leu Ser Leu Pro Gly Gln 180 185 190 Ser Pro Tyr Phe Ser Tyr Pro Leu Thr Pro Ala Thr Pro Phe His Pro 195 200 205 Gln Gly Ser Leu Pro Ile Tyr Arg Pro Val Val Ser Thr Asp Met Ala 210 215 220 Lys Leu Phe Asp Lys Ile Ala Ser Thr Ser Glu Phe Leu Lys Asn Gly 225 230 235 240 Lys Ala Arg Thr Asp Leu Glu Ile Thr Asp Ser Lys Val Ser Asn Leu 245 250 255 Gln Val Ser Pro Lys Ser Glu Asp Ile Ser Lys Phe Asp Trp Leu Asp 260 265 270 Leu Asp Pro Leu Ser Lys Pro Lys Val Asp Asn Val Glu Val Leu Asp 275 280 285 His Glu Glu Glu Lys Asn Val Ser Ser Leu Leu Ala Lys Asp Pro Trp 290 295 300 Asp Ala Val Leu Leu Glu Glu Arg Ser Thr Ala Asn Cys His Leu Glu 305 310 315 320 Arg Lys Val Asn Gly Lys Ser Leu Ser Val Ala Thr Val Thr Arg Ser 325 330 335 Gln Ser Leu Asn Ile Arg Thr Thr Gln Leu Ala Lys Ala Gln Gly His 340 345 350 Ile Ser Gln Lys Asp Pro Asn Gly Thr Ser Ser Leu Pro Thr Gly Ser 355 360 365 Ser Leu Leu Gln Glu Val Glu Val Gln Asn Glu Glu Met Ala Ala Phe 370 375 380 Cys Arg Ser Ile Thr Lys Leu Lys Thr Lys Phe Pro Tyr Thr Asn His 385 390 395 400 Arg Thr Asn Pro Gly Tyr Leu Leu Ser Pro Val Thr Ala Gln Arg Asn 405 410 415 Ile Cys Gly Glu Asn Ala Ser Val Lys Val Ser Ile Asp Ile Glu Gly 420 425 430 Phe Gln Leu Pro Val Thr Phe Thr Cys Asp Val Ser Ser Thr Val Glu 435 440 445 Ile Ile Ile Met Gln Ala Leu Cys Trp Val His Asp Asp Leu Asn Gln 450 455 460 Val Asp Val Gly Ser Tyr Val Leu Lys Val Cys Gly Gln Glu Glu Val 465 470 475 480 Leu Gln Asn Asn His Cys Leu Gly Ser His Glu His Ile Gln Asn Cys 485 490 495 Arg Lys Trp Asp Thr Glu Ile Arg Leu Gln Leu Leu Thr Phe Ser Ala 500 505 510 Met Cys Gln Asn Leu Ala Arg Thr Ala Glu Asp Asp Glu Thr Pro Val 515 520 525 Asp Leu Asn Lys His Leu Tyr Gln Ile Glu Lys Pro Cys Lys Glu Ala 530 535 540 Met Thr Arg His Pro Val Glu Glu Leu Leu Asp Ser Tyr His Asn Gln 545 550 555 560 Val Glu Leu Ala Leu Gln Ile Glu Asn Gln His Arg Ala Val Asp Gln 565 570 575 Val Ile Lys Ala Val Arg Lys Ile Cys Ser Ala Leu Asp Gly Val Glu 580 585 590 Thr Leu Ala Ile Thr Glu Ser Val Lys Lys Leu Lys Arg Ala Val Asn 595 600 605 Leu Pro Arg Ser Lys Thr Ala Asp Val Thr Ser Leu Phe Gly Gly Glu 610 615 620 Asp Thr Ser Arg Ser Ser Thr Arg Gly Ser Leu Asn Pro Glu Asn Pro 625 630 635 640 Val Gln Val Ser Ile Asn Gln Leu Thr Ala Ala Ile Tyr Asp Leu Leu 645 650 655 Arg Leu His Ala Asn Ser Gly Arg Ser Pro Thr Asp Cys Ala Gln Ser 660 665 670 Ser Lys Ser Val Lys Glu Ala Trp Thr Thr Thr Glu Gln Leu Gln Phe 675 680 685 Thr Ile Phe Ala Ala His Gly Ile Ser Ser Asn Trp Val Ser Asn Tyr 690 695 700 Glu Lys Tyr Tyr Leu Ile Cys Ser Leu Ser His Asn Gly Lys Asp Leu 705 710 715 720 Phe Lys Pro Ile Gln Ser Lys Lys Val Gly Thr Tyr Lys Asn Phe Phe 725 730 735 Tyr Leu Ile Lys Trp Asp Glu Leu Ile Ile Phe Pro Ile Gln Ile Ser 740 745 750 Gln Leu Pro Leu Glu Ser Val Leu His Leu Thr Leu Phe Gly Ile Leu 755 760 765 Asn Gln Ser Ser Gly Ser Ser Pro Asp Ser Asn Lys Gln Arg Lys Gly 770 775 780 Pro Glu Ala Leu Gly Lys Val Ser Leu Pro Leu Phe Asp Phe Lys Arg 785 790 795 800 Phe Leu Thr Cys Gly Thr Lys Leu Leu Tyr Leu Trp Thr Ser Ser His 805 810 815 Thr Asn Ser Val Pro Gly Thr Val Thr Lys Lys Gly Tyr Val Met Glu 820 825 830 Arg Ile Val Leu Gln Val Asp Phe Pro Ser Pro Ala Phe Asp Ile Ile 835 840 845 Tyr Thr Thr Pro Gln Val Asp Arg Ser Ile Ile Gln Gln His Asn Leu 850 855 860 Glu Thr Leu Glu Asn Asp Ile Lys Gly Lys Leu Leu Asp Ile Leu His 865 870 875 880 Lys Asp Ser Ser Leu Gly Leu Ser Lys Glu Asp Lys Ala Phe Leu Trp 885 890 895 Glu Lys Arg Tyr Tyr Cys Phe Lys His Pro Asn Cys Leu Pro Lys Ile 900 905 910 Leu Ala Ser Ala Pro Asn Trp Lys Trp Val Asn Leu Ala Lys Thr Tyr 915 920 925 Ser Leu Leu His Gln Trp Pro Ala Leu Tyr Pro Leu Ile Ala Leu Glu 930 935 940 Leu Leu Asp Ser Lys Phe Ala Asp Gln Glu Val Arg Ser Leu Ala Val 945 950 955 960 Thr Trp Ile Glu Ala Ile Ser Asp Asp Glu Leu Thr Asp Leu Leu Pro 965 970 975 Gln Phe Val Gln Ala Leu Lys Tyr Glu Ile Tyr Leu Asn Ser Ser Leu 980 985 990 Val Gln Phe Leu Leu Ser Arg Ala Leu Gly Asn Ile Gln Ile Ala His 995 1000 1005 Asn Leu Tyr Trp Leu Leu Lys Asp Ala Leu His Asp Val Gln Phe Ser 1010 1015 1020 Thr Arg Tyr Glu His Val Leu Gly Ala Leu Leu Ser Val Gly Gly Lys 1025 1030 1035 1040 Arg Leu Arg Glu Glu Leu Leu Lys Gln Thr Lys Leu Val Gln Leu Leu 1045 1050 1055 Gly Gly Val Ala Glu Lys Val Arg Gln Ala Ser Gly Ser Ala Arg Gln 1060 1065 1070 Val Val Leu Gln Arg Ser Met Glu Arg Val Gln Ser Phe Phe Gln Lys 1075 1080 1085 Asn Lys Cys Arg Leu Pro Leu Lys Pro Ser Leu Val Ala Lys Glu Leu 1090 1095 1100 Asn Ile Lys Ser Cys Ser Phe Phe Ser Ser Asn Ala Val Pro Leu Lys 1105 1110 1115 1120 Val Thr Met Val Asn Ala Asp Pro Met Gly Glu Glu Ile Asn Val Met 1125 1130 1135 Phe Lys Val Gly Glu Asp Leu Arg Gln Asp Met Leu Ala Leu Gln Met 1140 1145 1150 Ile Lys Ile Met Asp Lys Ile Trp Leu Lys Glu Gly Leu Asp Leu Arg 1155 1160 1165 Met Val Ile Phe Lys Cys Leu Ser Thr Gly Arg Asp Arg Gly Met Val 1170 1175 1180 Glu Leu Val Pro Ala Ser Asp Thr Leu Arg Lys Ile Gln Val Glu Tyr 1185 1190 1195 1200 Gly Val Thr Gly Ser Phe Lys Asp Lys Pro Leu Ala Glu Trp Leu Arg 1205 1210 1215 Lys Tyr Asn Pro Ser Glu Glu Glu Tyr Glu Lys Ala Ser Glu Asn Phe 1220 1225 1230 Ile Tyr Ser Cys Ala Gly Cys Cys Val Ala Thr Tyr Val Leu Gly Ile 1235 1240 1245 Cys Asp Arg His Asn Asp Asn Ile Met Leu Arg Ser Thr Gly His Met 1250 1255 1260 Phe His Ile Asp Phe Gly Lys Phe Leu Gly His Ala Gln Met Phe Gly 1265 1270 1275 1280 Ser Phe Lys Arg Asp Arg Ala Pro Phe Val Leu Thr Ser Asp Met Ala 1285 1290 1295 Tyr Val Ile Asn Gly Gly Glu Lys Pro Thr Ile Arg Phe Gln Leu Phe 1300 1305 1310 Val Asp Leu Cys Cys Gln Ala Tyr Asn Leu Ile Arg Lys Gln Thr Asn 1315 1320 1325 Leu Phe Leu Asn Leu Leu Ser Leu Met Ile Pro Ser Gly Leu Pro Glu 1330 1335 1340 Leu Thr Ser Ile Gln Asp Leu Lys Tyr Val Arg Asp Ala Leu Gln Pro 1345 1350 1355 1360 Gln Thr Thr Asp Ala Glu Ala Thr Ile Phe Phe Thr Arg Leu Ile Glu 1365 1370 1375 Ser Ser Leu Gly Ser Ile Ala Thr Lys Phe Asn Phe Phe Ile His Asn 1380 1385 1390 Leu Ala Gln Leu Arg Phe Ser Gly Leu Pro Ser Asn Asp Glu Pro Ile 1395 1400 1405 Leu Ser Phe Ser Pro Lys Thr Tyr Ser Phe Arg Gln Asp Gly Arg Ile 1410 1415 1420 Lys Glu Val Ser Val Phe Thr Tyr His Lys Lys Tyr Asn Pro Asp Lys 1425 1430 1435 1440 His Tyr Ile Tyr Val Val Arg Ile Leu Arg Glu Gly Gln Ile Glu Pro 1445 1450 1455 Ser Phe Val Phe Arg Thr Phe Asp Glu Phe Gln Glu Leu His Asn Lys 1460 1465 1470 Leu Ser Ile Ile Phe Pro Leu Trp Lys Leu Pro Gly Phe Pro Asn Arg 1475 1480 1485 Met Val Leu Gly Arg Thr His Ile Lys Asp Val Ala Ala Lys Arg Lys 1490 1495 1500 Ile Glu Leu Asn Ser Tyr Leu Gln Ser Leu Met Asn Ala Ser Thr Asp 1505 1510 1515 1520 Val Ala Glu Cys Asp Leu Val Cys Thr Phe Phe His Pro Leu Leu Arg 1525 1530 1535 Asp Glu Lys Ala Glu Gly Ile Ala Arg Ser Ala Asp Ala Gly Ser Phe 1540 1545 1550 Ser Pro Thr Pro Gly Gln Ile Gly Gly Ala Val Lys Leu Ser Ile Ser 1555 1560 1565 Tyr Arg Asn Gly Thr Leu Phe Ile Met Val Met His Ile Lys Asp Leu 1570 1575 1580 Val Thr Glu Asp Gly Ala Asp Pro Asn Pro Tyr Val Lys Thr Tyr Leu 1585 1590 1595 1600 Leu Pro Asp Asn His Lys Thr Ser Lys Arg Lys Thr Lys Ile Ser Arg 1605 1610 1615 Lys Thr Arg Asn Pro Thr Phe Asn Glu Met Leu Val Tyr Ser Gly Tyr 1620 1625 1630 Ser Lys Glu Thr Leu Arg Gln Arg Glu Leu Gln Leu Ser Val Leu Ser 1635 1640 1645 Ala Glu Ser Leu Arg Glu Asn Phe Phe Leu Gly Gly Val Thr Leu Pro 1650 1655 1660 Leu Lys Asp Phe Asn Leu Ser Lys Glu Thr Val Lys Trp Tyr Gln Leu 1665 1670 1675 1680 Thr Ala Ala Thr Tyr Leu 1685 <210> 8 <211> 775 <212> PRT <213> Homo sapiens <400> 8 Met Ala Ala Leu Asp Ser Leu Ser Leu Phe Thr Ser Leu Gly Leu Ser 1 5 10 15 Glu Gln Lys Ala Arg Glu Thr Leu Lys Asn Ser Ala Leu Ser Ala Gln 20 25 30 Leu Arg Glu Ala Ala Thr Gln Ala Gln Gln Thr Leu Gly Ser Thr Ile 35 40 45 Asp Lys Ala Thr Gly Ile Leu Leu Tyr Gly Leu Ala Ser Arg Leu Arg 50 55 60 Asp Thr Arg Arg Leu Ser Phe Leu Val Ser Tyr Ile Ala Ser Lys Lys 65 70 75 80 Ile His Thr Glu Pro Gln Leu Ser Ala Ala Leu Glu Tyr Val Arg Ser 85 90 95 His Pro Leu Asp Pro Ile Asp Thr Val Asp Phe Glu Arg Glu Cys Gly 100 105 110 Val Gly Val Ile Val Thr Pro Glu Gln Ile Glu Glu Ala Val Glu Ala 115 120 125 Ala Ile Asn Arg His Arg Pro Gln Leu Leu Val Glu Arg Tyr His Phe 130 135 140 Asn Met Gly Leu Leu Met Gly Glu Ala Arg Ala Val Leu Lys Trp Ala 145 150 155 160 Asp Gly Lys Met Ile Lys Asn Glu Val Asp Met Gln Val Leu His Leu 165 170 175 Leu Gly Pro Lys Leu Glu Ala Asp Leu Glu Lys Lys Phe Lys Val Ala 180 185 190 Lys Ala Arg Leu Glu Glu Thr Asp Arg Arg Thr Ala Lys Asp Val Val 195 200 205 Glu Asn Gly Glu Thr Ala Asp Gln Thr Leu Ser Leu Met Glu Gln Leu 210 215 220 Arg Gly Glu Ala Leu Lys Phe His Lys Pro Gly Glu Asn Tyr Lys Thr 225 230 235 240 Pro Gly Tyr Val Val Thr Pro His Thr Met Asn Leu Leu Lys Gln His 245 250 255 Leu Glu Ile Thr Gly Gly Gln Val Arg Thr Arg Phe Pro Pro Glu Pro 260 265 270 Asn Gly Ile Leu His Ile Gly His Ala Lys Ala Ile Asn Phe Asn Phe 275 280 285 Gly Tyr Ala Lys Ala Asn Asn Gly Ile Cys Phe Leu Arg Phe Asp Asp 290 295 300 Thr Asn Pro Glu Lys Glu Glu Ala Lys Phe Phe Thr Ala Ile Cys Asp 305 310 315 320 Met Val Ala Trp Leu Gly Tyr Thr Pro Tyr Lys Val Thr Tyr Ala Ser 325 330 335 Asp Tyr Phe Asp Gln Leu Tyr Ala Trp Ala Val Glu Leu Ile Arg Arg 340 345 350 Gly Leu Ala Tyr Val Cys His Gln Arg Gly Glu Glu Leu Lys Gly His 355 360 365 Asn Thr Leu Pro Ser Pro Trp Arg Asp Arg Pro Met Glu Glu Ser Leu 370 375 380 Leu Leu Phe Glu Ala Met Arg Lys Gly Lys Phe Ser Glu Gly Glu Ala 385 390 395 400 Thr Leu Arg Met Lys Leu Val Met Glu Asp Gly Lys Met Asp Pro Val 405 410 415 Ala Tyr Arg Val Lys Tyr Thr Pro His His Arg Thr Gly Asp Lys Trp 420 425 430 Cys Ile Tyr Pro Thr Tyr Asp Tyr Thr His Cys Leu Cys Asp Ser Ile 435 440 445 Glu His Ile Thr His Ser Leu Cys Thr Lys Glu Phe Gln Ala Arg Arg 450 455 460 Ser Ser Tyr Phe Trp Leu Cys Asn Ala Leu Asp Val Tyr Cys Pro Val 465 470 475 480 Gln Trp Glu Tyr Gly Arg Leu Asn Leu His Tyr Ala Val Val Ser Lys 485 490 495 Arg Lys Ile Leu Gln Leu Val Ala Thr Gly Ala Val Arg Asp Trp Asp 500 505 510 Asp Pro Arg Leu Phe Thr Leu Thr Ala Leu Arg Arg Arg Gly Phe Pro 515 520 525 Pro Glu Ala Ile Asn Asn Phe Cys Ala Arg Val Gly Val Thr Val Ala 530 535 540 Gln Thr Thr Met Glu Pro His Leu Leu Glu Ala Cys Val Arg Asp Val 545 550 555 560 Leu Asn Asp Thr Ala Pro Arg Ala Met Ala Val Leu Glu Ser Leu Arg 565 570 575 Val Ile Ile Thr Asn Phe Pro Ala Ala Lys Ser Leu Asp Ile Gln Val 580 585 590 Pro Asn Phe Pro Ala Asp Glu Thr Lys Gly Phe His Gln Val Pro Phe 595 600 605 Ala Pro Ile Val Phe Ile Glu Arg Thr Asp Phe Lys Glu Glu Pro Glu 610 615 620 Pro Gly Phe Lys Arg Leu Ala Trp Gly Gln Pro Val Gly Leu Arg His 625 630 635 640 Thr Gly Tyr Val Ile Glu Leu Gln His Val Val Lys Gly Pro Ser Gly 645 650 655 Cys Val Glu Ser Leu Glu Val Thr Cys Arg Arg Ala Asp Ala Gly Glu 660 665 670 Lys Pro Lys Ala Phe Ile His Trp Val Ser Gln Pro Leu Met Cys Glu 675 680 685 Val Arg Leu Tyr Glu Arg Leu Phe Gln His Lys Asn Pro Glu Asp Pro 690 695 700 Thr Glu Val Pro Gly Gly Phe Leu Ser Asp Leu Asn Leu Ala Ser Leu 705 710 715 720 His Val Val Asp Ala Ala Leu Val Asp Cys Ser Val Ala Leu Ala Lys 725 730 735 Pro Phe Asp Lys Phe Gln Phe Glu Arg Leu Gly Tyr Phe Ser Val Asp 740 745 750 Pro Asp Ser His Gln Gly Lys Leu Val Phe Asn Arg Thr Val Thr Leu 755 760 765 Lys Glu Asp Pro Gly Lys Val 770 775 <210> 9 <211> 1324 <212> PRT <213> Homo sapiens <400> 9 Met Ser Arg Arg Lys Gln Ala Lys Pro Gln His Phe Gln Ser Asp Pro 1 5 10 15 Glu Val Ala Ser Leu Pro Arg Arg Asp Gly Asp Thr Glu Lys Gly Gln 20 25 30 Pro Ser Arg Pro Thr Lys Ser Lys Asp Ala His Val Cys Gly Arg Cys 35 40 45 Cys Ala Glu Phe Phe Glu Leu Ser Asp Leu Leu Leu His Lys Lys Asn 50 55 60 Cys Thr Lys Asn Gln Leu Val Leu Ile Val Asn Glu Asn Pro Ala Ser 65 70 75 80 Pro Pro Glu Thr Phe Ser Pro Ser Pro Pro Pro Asp Asn Pro Asp Glu 85 90 95 Gln Met Asn Asp Thr Val Asn Lys Thr Asp Gln Val Asp Cys Ser Asp 100 105 110 Leu Ser Glu His Asn Gly Leu Asp Arg Glu Glu Ser Met Glu Val Glu 115 120 125 Ala Pro Val Ala Asn Lys Ser Gly Ser Gly Thr Ser Ser Gly Ser His 130 135 140 Ser Ser Thr Ala Pro Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Gly 145 150 155 160 Gly Gly Gly Ser Ser Ser Thr Gly Thr Ser Ala Ile Thr Thr Ser Leu 165 170 175 Pro Gln Leu Gly Asp Leu Thr Thr Leu Gly Asn Phe Ser Val Ile Asn 180 185 190 Ser Asn Val Ile Ile Glu Asn Leu Gln Ser Thr Lys Val Ala Val Ala 195 200 205 Gln Phe Ser Gln Glu Ala Arg Cys Gly Gly Ala Ser Gly Gly Lys Leu 210 215 220 Ala Val Pro Ala Leu Met Glu Gln Leu Leu Ala Leu Gln Gln Gln Gln 225 230 235 240 Ile His Gln Leu Gln Leu Ile Glu Gln Ile Arg His Gln Ile Leu Leu 245 250 255 Leu Ala Ser Gln Asn Ala Asp Leu Pro Thr Ser Ser Ser Pro Ser Gln 260 265 270 Gly Thr Leu Arg Thr Ser Ala Asn Pro Leu Ser Thr Leu Ser Ser His 275 280 285 Leu Ser Gln Gln Leu Ala Ala Ala Ala Gly Leu Ala Gln Ser Leu Ala 290 295 300 Ser Gln Ser Ala Ser Ile Ser Gly Val Lys Gln Leu Pro Pro Ile Gln 305 310 315 320 Leu Pro Gln Ser Ser Ser Gly Asn Thr Ile Ile Pro Ser Asn Ser Gly 325 330 335 Ser Ser Pro Asn Met Asn Ile Leu Ala Ala Ala Val Thr Thr Pro Ser 340 345 350 Ser Glu Lys Val Ala Ser Ser Ala Gly Ala Ser His Val Ser Asn Pro 355 360 365 Ala Val Ser Ser Ser Ser Ser Ser Pro Ala Phe Ala Ile Ser Ser Leu Leu 370 375 380 Ser Pro Ala Ser Asn Pro Leu Leu Pro Gln Gln Ala Ser Ala Asn Ser 385 390 395 400 Val Phe Pro Ser Pro Leu Pro Asn Ile Gly Thr Thr Ala Glu Asp Leu 405 410 415 Asn Ser Leu Ser Ala Leu Ala Gln Gln Arg Lys Ser Lys Pro Pro Asn 420 425 430 Val Thr Ala Phe Glu Ala Lys Ser Thr Ser Asp Glu Ala Phe Phe Lys 435 440 445 His Lys Cys Arg Phe Cys Ala Lys Val Phe Gly Ser Asp Ser Ala Leu 450 455 460 Gln Ile His Leu Arg Ser His Thr Gly Glu Arg Pro Phe Lys Cys Asn 465 470 475 480 Ile Cys Gly Asn Arg Phe Ser Thr Lys Gly Asn Leu Lys Val His Phe 485 490 495 Gln Arg His Lys Glu Lys Tyr Pro His Ile Gln Met Asn Pro Tyr Pro 500 505 510 Val Pro Glu His Leu Asp Asn Ile Pro Thr Ser Thr Gly Ile Pro Tyr 515 520 525 Gly Met Ser Ile Pro Glu Lys Pro Val Thr Ser Trp Leu Asp Thr 530 535 540 Lys Pro Val Leu Pro Thr Leu Thr Thr Ser Val Gly Leu Pro Leu Pro 545 550 555 560 Pro Thr Leu Pro Ser Leu Ile Pro Phe Ile Lys Thr Glu Glu Pro Ala 565 570 575 Pro Ile Pro Ile Ser His Ser Ala Thr Ser Pro Pro Gly Ser Val Lys 580 585 590 Ser Asp Ser Gly Gly Pro Glu Ser Ala Thr Arg Asn Leu Gly Gly Leu 595 600 605 Pro Glu Glu Ala Glu Gly Ser Thr Leu Pro Ser Gly Gly Lys Ser 610 615 620 Glu Glu Ser Gly Met Val Thr Asn Ser Val Pro Thr Ala Ser Ser Ser 625 630 635 640 Val Leu Ser Ser Pro Ala Ala Asp Cys Gly Pro Ala Gly Ser Ala Thr 645 650 655 Thr Phe Thr Asn Pro Leu Leu Pro Leu Met Ser Glu Gln Phe Lys Ala 660 665 670 Lys Phe Pro Phe Gly Gly Leu Leu Asp Ser Ala Gln Ala Ser Glu Thr 675 680 685 Ser Lys Leu Gln Gln Leu Val Glu Asn Ile Asp Lys Lys Ala Thr Asp 690 695 700 Pro Asn Glu Cys Ile Ile Cys His Arg Val Leu Ser Cys Gln Ser Ala 705 710 715 720 Leu Lys Met His Tyr Arg Thr His Thr Gly Glu Arg Pro Phe Lys Cys 725 730 735 Lys Ile Cys Gly Arg Ala Phe Thr Thr Lys Gly Asn Leu Lys Thr His 740 745 750 Tyr Ser Val His Arg Ala Met Pro Pro Leu Arg Val Gln His Ser Cys 755 760 765 Pro Ile Cys Gln Lys Lys Phe Thr Asn Ala Val Val Leu Gln Gln His 770 775 780 Ile Arg Met His Met Gly Gly Gln Ile Pro Asn Thr Pro Val Pro Asp 785 790 795 800 Ser Tyr Ser Glu Ser Met Glu Ser Asp Thr Gly Ser Phe Asp Glu Lys 805 810 815 Asn Phe Asp Asp Leu Asp Asn Phe Ser Asp Glu Asn Met Glu Asp Cys 820 825 830 Pro Glu Gly Ser Ile Pro Asp Thr Pro Lys Ser Ala Asp Ala Ser Gln 835 840 845 Asp Ser Leu Ser Ser Ser Pro Leu Pro Leu Glu Met Ser Ser Ile Ala 850 855 860 Ala Leu Glu Asn Gln Met Lys Met Ile Asn Ala Gly Leu Ala Glu Gln 865 870 875 880 Leu Gln Ala Ser Leu Lys Ser Val Glu Asn Gly Ser Ile Glu Gly Asp 885 890 895 Val Leu Thr Asn Asp Ser Ser Ser Val Gly Gly Asp Met Glu Ser Gln 900 905 910 Ser Ala Gly Ser Pro Ala Ile Ser Glu Ser Thr Ser Ser Met Gln Ala 915 920 925 Leu Ser Pro Ser Asn Ser Thr Gln Glu Phe His Lys Ser Pro Ser Ile 930 935 940 Glu Glu Lys Pro Gln Arg Ala Val Pro Ser Glu Phe Ala Asn Gly Leu 945 950 955 960 Ser Pro Thr Pro Val Asn Gly Gly Ala Leu Asp Leu Thr Ser Ser His 965 970 975 Ala Glu Lys Ile Ile Lys Glu Asp Ser Leu Gly Ile Leu Phe Pro Phe 980 985 990 Arg Asp Arg Gly Lys Phe Lys Asn Thr Ala Cys Asp Ile Cys Gly Lys 995 1000 1005 Thr Phe Ala Cys Gln Ser Ala Leu Asp Ile His Tyr Arg Ser His Thr 1010 1015 1020 Lys Glu Arg Pro Phe Ile Cys Thr Val Cys Asn Arg Gly Phe Ser Thr 1025 1030 1035 1040 Lys Gly Asn Leu Lys Gln His Met Leu Thr His Gln Met Arg Asp Leu 1045 1050 1055 Pro Ser Gln Leu Phe Glu Pro Ser Ser Asn Leu Gly Pro Asn Gln Asn 1060 1065 1070 Ser Ala Val Ile Pro Ala Asn Ser Leu Ser Ser Leu Ile Lys Thr Glu 1075 1080 1085 Val Asn Gly Phe Val His Val Ser Pro Gln Asp Ser Lys Asp Thr Pro 1090 1095 1100 Thr Ser His Val Pro Ser Gly Pro Leu Ser Ser Ser Ala Thr Ser Pro 1105 1110 1115 1120 Val Leu Leu Pro Ala Leu Pro Arg Arg Thr Pro Lys Gln His Tyr Cys 1125 1130 1135 Asn Thr Cys Gly Lys Thr Phe Ser Ser Ser Ser Ala Leu Gln Ile His 1140 1145 1150 Glu Arg Thr His Thr Gly Glu Lys Pro Phe Ala Cys Thr Ile Cys Gly 1155 1160 1165 Arg Ala Phe Thr Thr Lys Gly Asn Leu Lys Val His Met Gly Thr His 1170 1175 1180 Met Trp Asn Ser Thr Pro Ala Arg Arg Gly Arg Arg Leu Ser Val Asp 1185 1190 1195 1200 Gly Pro Met Thr Phe Leu Gly Gly Asn Pro Val Lys Phe Pro Glu Met 1205 1210 1215 Phe Gln Lys Asp Leu Ala Ala Arg Ser Gly Ser Gly Asp Pro Ser Ser 1220 1225 1230 Phe Trp Asn Gln Tyr Ala Ala Ala Leu Ser Asn Gly Leu Ala Met Lys 1235 1240 1245 Ala Asn Glu Ile Ser Val Ile Gln Asn Gly Gly Ile Pro Pro Ile Pro 1250 1255 1260 Gly Ser Leu Gly Ser Gly Asn Ser Ser Pro Val Ser Gly Leu Thr Gly 1265 1270 1275 1280 Asn Leu Glu Arg Leu Gln Asn Ser Glu Pro Asn Ala Pro Leu Ala Gly 1285 1290 1295 Leu Glu Lys Met Ala Ser Ser Glu Asn Gly Thr Asn Phe Arg Phe Thr 1300 1305 1310 Arg Phe Val Glu Asp Ser Lys Glu Ile Val Thr Ser 1315 1320 <210> 10 <211> 1273 <212> PRT <213> Homo sapiens <400> 10 Met Lys Arg Arg Leu Asp Asp Gln Glu Ser Pro Val Tyr Ala Ala Gln 1 5 10 15 Gln Arg Arg Ile Pro Gly Ser Thr Glu Ala Phe Pro His Gln His Arg 20 25 30 Val Leu Ala Pro Ala Pro Pro Val Tyr Glu Ala Val Ser Glu Thr Met 35 40 45 Gln Ser Ala Thr Gly Ile Gln Tyr Ser Val Thr Pro Ser Tyr Gln Val 50 55 60 Ser Ala Met Pro Gln Ser Ser Gly Ser His Gly Pro Ala Ile Ala Ala 65 70 75 80 Val His Ser Ser His His His Pro Thr Ala Val Gln Pro His Gly Gly 85 90 95 Gln Val Val Gln Ser His Ala His Pro Ala Pro Pro Val Ala Pro Val 100 105 110 Gln Gly Gln Gln Gln Phe Gln Arg Leu Lys Val Glu Asp Ala Leu Ser 115 120 125 Tyr Leu Asp Gln Val Lys Leu Gln Phe Gly Ser Gln Pro Gln Val Tyr 130 135 140 Asn Asp Phe Leu Asp Ile Met Lys Glu Phe Lys Ser Gln Ser Ile Asp 145 150 155 160 Thr Pro Gly Val Ile Ser Arg Val Ser Gln Leu Phe Lys Gly His Pro 165 170 175 Asp Leu Ile Met Gly Phe Asn Thr Phe Leu Pro Pro Gly Tyr Lys Ile 180 185 190 Glu Val Gln Thr Asn Asp Met Val Asn Val Thr Thr Pro Gly Gln Val 195 200 205 His Gln Ile Pro Thr His Gly Ile Gln Pro Gln Pro Gln Pro Pro Pro 210 215 220 Gln His Pro Ser Gln Pro Ser Ala Gln Ser Ala Pro Ala Pro Ala Gln 225 230 235 240 Pro Ala Pro Gln Pro Pro Pro Ala Lys Val Ser Lys Pro Ser Gln Leu 245 250 255 Gln Ala His Thr Pro Ala Ser Gln Gln Thr Pro Pro Leu Pro Pro Tyr 260 265 270 Ala Ser Pro Arg Ser Pro Pro Val Gln Pro His Thr Pro Val Thr Ile 275 280 285 Ser Leu Gly Thr Ala Pro Ser Leu Gln Asn Asn Gln Pro Val Glu Phe 290 295 300 Asn His Ala Ile Asn Tyr Val Asn Lys Ile Lys Asn Arg Phe Gln Gly 305 310 315 320 Gln Pro Asp Ile Tyr Lys Ala Phe Leu Glu Ile Leu His Thr Tyr Gln 325 330 335 Lys Glu Gln Arg Asn Ala Lys Glu Ala Gly Gly Asn Tyr Thr Pro Ala 340 345 350 Leu Thr Glu Gln Glu Val Tyr Ala Gln Val Ala Arg Leu Phe Lys Asn 355 360 365 Gln Glu Asp Leu Leu Ser Glu Phe Gly Gln Phe Leu Pro Asp Ala Asn 370 375 380 Ser Ser Val Leu Leu Ser Lys Thr Thr Ala Glu Lys Val Asp Ser Val 385 390 395 400 Arg Asn Asp His Gly Gly Thr Val Lys Lys Pro Gln Leu Asn Asn Lys 405 410 415 Pro Gln Arg Pro Ser Gln Asn Gly Cys Gln Ile Arg Arg His Pro Thr 420 425 430 Gly Thr Thr Pro Pro Val Lys Lys Lys Lys Pro Lys Leu Leu Asn Leu Lys 435 440 445 Asp Ser Ser Met Ala Asp Ala Ser Lys His Gly Gly Gly Thr Glu Ser 450 455 460 Leu Phe Phe Asp Lys Val Arg Lys Ala Leu Arg Ser Ala Glu Ala Tyr 465 470 475 480 Glu Asn Phe Leu Arg Cys Leu Val Ile Phe Asn Gln Glu Val Ile Ser 485 490 495 Arg Ala Glu Leu Val Gln Leu Val Ser Pro Phe Leu Gly Lys Phe Pro 500 505 510 Glu Leu Phe Asn Trp Phe Lys Asn Phe Leu Gly Tyr Lys Glu Ser Val 515 520 525 His Leu Glu Thr Tyr Pro Lys Glu Arg Ala Thr Glu Gly Ile Ala Met 530 535 540 Glu Ile Asp Tyr Ala Ser Cys Lys Arg Leu Gly Ser Ser Tyr Arg Ala 545 550 555 560 Leu Pro Lys Ser Tyr Gln Gln Pro Lys Cys Thr Gly Arg Thr Pro Leu 565 570 575 Cys Lys Glu Val Leu Asn Asp Thr Trp Val Ser Phe Pro Ser Trp Ser 580 585 590 Glu Asp Ser Thr Phe Val Ser Ser Lys Lys Thr Gln Tyr Glu Glu His 595 600 605 Ile Tyr Arg Cys Glu Asp Glu Arg Phe Glu Leu Asp Val Val Leu Glu 610 615 620 Thr Asn Leu Ala Thr Ile Arg Val Leu Glu Ala Ile Gln Lys Lys Leu 625 630 635 640 Ser Arg Leu Ser Ala Glu Glu Gln Ala Lys Phe Arg Leu Asp Asn Thr 645 650 655 Leu Gly Gly Thr Ser Glu Val Ile His Arg Lys Ala Leu Gln Arg Ile 660 665 670 Tyr Ala Asp Lys Ala Ala Asp Ile Ile Asp Gly Leu Arg Lys Asn Pro 675 680 685 Ser Ile Ala Val Pro Ile Val Leu Lys Arg Leu Lys Met Lys Glu Glu 690 695 700 Glu Trp Arg Glu Ala Gln Arg Gly Phe Asn Lys Val Trp Arg Glu Gln 705 710 715 720 Asn Glu Lys Tyr Tyr Leu Lys Ser Leu Asp His Gln Gly Ile Asn Phe 725 730 735 Lys Gln Asn Asp Thr Lys Val Leu Arg Ser Lys Ser Leu Leu Asn Glu 740 745 750 Ile Glu Ser Ile Tyr Asp Glu Arg Gln Glu Gln Ala Thr Glu Glu Asn 755 760 765 Ala Gly Val Pro Val Gly Pro His Leu Ser Leu Ala Tyr Glu Asp Lys 770 775 780 Gln Ile Leu Glu Asp Ala Ala Ala Leu Ile Ile His His Val Lys Arg 785 790 795 800 Gln Thr Gly Ile Gln Lys Glu Asp Lys Tyr Lys Ile Lys Gln Ile Met 805 810 815 His His Phe Ile Pro Asp Leu Leu Phe Ala Gln Arg Gly Asp Leu Ser 820 825 830 Asp Val Glu Glu Glu Glu Glu Glu Glu Met Asp Val Asp Glu Ala Thr 835 840 845 Gly Ala Val Lys Lys His Asn Gly Val Gly Gly Ser Pro Lys Ser 850 855 860 Lys Leu Leu Phe Ser Asn Thr Ala Ala Gln Lys Leu Arg Gly Met Asp 865 870 875 880 Glu Val Tyr Asn Leu Phe Tyr Val Asn Asn Asn Trp Tyr Ile Phe Met 885 890 895 Arg Leu His Gln Ile Leu Cys Leu Arg Leu Leu Arg Ile Cys Ser Gln 900 905 910 Ala Glu Arg Gln Ile Glu Glu Glu Asn Arg Glu Arg Glu Trp Glu Arg 915 920 925 Glu Val Leu Gly Ile Lys Arg Asp Lys Ser Asp Ser Pro Ala Ile Gln 930 935 940 Leu Arg Leu Lys Glu Pro Met Asp Val Asp Val Glu Asp Tyr Tyr Pro 945 950 955 960 Ala Phe Leu Asp Met Val Arg Ser Leu Leu Asp Gly Asn Ile Asp Ser 965 970 975 Ser Gln Tyr Glu Asp Ser Leu Arg Glu Met Phe Thr Ile His Ala Tyr 980 985 990 Ile Ala Phe Thr Met Asp Lys Leu Ile Gln Ser Ile Val Arg Gln Leu 995 1000 1005 Gln His Ile Val Ser Asp Glu Ile Cys Val Gln Val Thr Asp Leu Tyr 1010 1015 1020 Leu Ala Glu Asn Asn Asn Gly Ala Thr Gly Gly Gln Leu Asn Thr Gln 1025 1030 1035 1040 Asn Ser Arg Ser Leu Leu Glu Ser Thr Tyr Gln Arg Lys Ala Glu Gln 1045 1050 1055 Leu Met Ser Asp Glu Asn Cys Phe Lys Leu Met Phe Ile Gln Ser Gln 1060 1065 1070 Gly Gln Val Gln Leu Thr Ile Glu Leu Leu Asp Thr Glu Glu Glu Asn 1075 1080 1085 Ser Asp Asp Pro Val Glu Ala Glu Arg Trp Ser Asp Tyr Val Glu Arg 1090 1095 1100 Tyr Met Asn Ser Asp Thr Thr Ser Pro Glu Leu Arg Glu His Leu Ala 1105 1110 1115 1120 Gln Lys Pro Val Phe Leu Pro Arg Asn Leu Arg Arg Ile Arg Lys Cys 1125 1130 1135 Gln Arg Gly Arg Glu Gln Gln Glu Lys Glu Gly Lys Glu Gly Asn Ser 1140 1145 1150 Lys Lys Thr Met Glu Asn Val Asp Ser Leu Asp Lys Leu Glu Cys Arg 1155 1160 1165 Phe Lys Leu Asn Ser Tyr Lys Met Val Tyr Val Ile Lys Ser Glu Asp 1170 1175 1180 Tyr Met Tyr Arg Arg Thr Ala Leu Leu Arg Ala His Gln Ser His Glu 1185 1190 1195 1200 Arg Val Ser Lys Arg Leu His Gln Arg Phe Gln Ala Trp Val Asp Lys 1205 1210 1215 Trp Thr Lys Glu His Val Pro Arg Glu Met Ala Ala Glu Thr Ser Lys 1220 1225 1230 Trp Leu Met Gly Glu Gly Leu Glu Gly Leu Val Pro Cys Thr Thr Thr 1235 1240 1245 Cys Asp Thr Glu Thr Leu His Phe Val Ser Ile Asn Lys Tyr Arg Val 1250 1255 1260 Lys Tyr Gly Thr Val Phe Lys Ala Pro 1265 1270 <210> 11 <211> 782 <212> PRT <213> Homo sapiens <400> 11 Met Leu Gln Gln Pro Gly Pro Arg Pro Gly Arg Gln Gln Pro Ser Gly 1 5 10 15 Asp Arg Asp Ala Cys Arg Leu His Pro Gln Gly Arg Pro Pro Ala Leu 20 25 30 Pro Thr Met Ile Pro Ala Ala Ser Ser Thr Pro Pro Gly Asp Ala Leu 35 40 45 Phe Pro Ser Val Ala Pro Gln Asp Phe Trp Arg Ser Gln Val Thr Gly 50 55 60 Tyr Ser Gly Ser Val Thr Arg His Leu Ser His Arg Ala Asn Asn Phe 65 70 75 80 Lys Arg His Pro Lys Arg Arg Lys Cys Ile Arg Pro Ser Pro Pro Pro 85 90 95 Pro Pro Asn Thr Pro Cys Pro Leu Glu Leu Val Asp Phe Gly Asp Leu 100 105 110 His Pro Gln Arg Ser Phe Arg Glu Leu Leu Phe Asn Gly Cys Ile Leu 115 120 125 Phe Gly Ile Glu Phe Ser Tyr Ala Met Glu Thr Ala Tyr Val Thr Pro 130 135 140 Val Leu Leu Gln Met Gly Leu Pro Asp Gln Leu Tyr Ser Leu Val Trp 145 150 155 160 Phe Ile Ser Pro Ile Leu Gly Phe Leu Leu Gln Pro Leu Leu Gly Ala 165 170 175 Trp Ser Asp Arg Cys Thr Ser Arg Phe Gly Arg Arg Arg Pro Phe Ile 180 185 190 Leu Val Leu Ala Ile Gly Ala Leu Leu Gly Leu Ser Leu Leu Leu Asn 195 200 205 Gly Arg Asp Ile Gly Ile Ala Leu Ala Asp Val Thr Gly Asn His Lys 210 215 220 Trp Gly Leu Leu Leu Thr Val Cys Gly Val Val Leu Met Asp Phe Ser 225 230 235 240 Ala Asp Ser Ala Asp Asn Pro Ser His Ala Tyr Met Met Asp Val Cys 245 250 255 Ser Pro Ala Asp Gln Asp Arg Gly Leu Asn Ile His Ala Leu Leu Ala 260 265 270 Gly Leu Gly Gly Gly Phe Gly Tyr Val Val Gly Gly Ile His Trp Asp 275 280 285 Lys Thr Gly Phe Gly Arg Ala Leu Gly Gly Gln Leu Arg Val Ile Tyr 290 295 300 Leu Phe Thr Ala Val Thr Leu Ser Val Thr Thr Val Leu Thr Leu Val 305 310 315 320 Ser Ile Pro Glu Arg Pro Leu Arg Pro Pro Ser Glu Lys Arg Ala Ala 325 330 335 Met Lys Ser Pro Ser Leu Pro Leu Pro Pro Ser Pro Pro Val Leu Pro 340 345 350 Glu Glu Gly Pro Gly Asp Ser Leu Pro Ser His Thr Ala Thr Asn Phe 355 360 365 Ser Ser Pro Ile Ser Pro Pro Ser Pro Leu Thr Pro Lys Tyr Gly Ser 370 375 380 Phe Ile Ser Arg Asp Ser Ser Leu Thr Gly Ile Ser Glu Phe Ala Ser 385 390 395 400 Ser Phe Gly Thr Ala Asn Ile Asp Ser Val Leu Ile Asp Cys Phe Thr 405 410 415 Gly Gly His Asp Ser Tyr Leu Ala Ile Pro Gly Ser Val Pro Arg Pro 420 425 430 Pro Ile Ser Val Ser Phe Pro Arg Ala Pro Asp Gly Phe Tyr Arg Gln 435 440 445 Asp Arg Gly Leu Leu Glu Gly Arg Glu Gly Ala Leu Thr Ser Gly Cys 450 455 460 Asp Gly Asp Ile Leu Arg Val Gly Ser Leu Asp Thr Ser Lys Pro Arg 465 470 475 480 Ser Ser Gly Ile Leu Lys Arg Pro Gln Thr Leu Ala Ile Pro Asp Ala 485 490 495 Ala Gly Gly Gly Gly Pro Glu Thr Ser Arg Arg Arg Asn Val Thr Phe 500 505 510 Ser Gln Gln Val Ala Asn Ile Leu Leu Asn Gly Val Lys Tyr Glu Ser 515 520 525 Glu Leu Thr Gly Ser Ser Glu Arg Ala Glu Gln Pro Leu Ser Val Gly 530 535 540 Arg Leu Cys Ser Thr Ile Cys Asn Met Pro Lys Ala Leu Arg Thr Leu 545 550 555 560 Cys Val Asn His Phe Leu Gly Trp Leu Ser Phe Glu Gly Met Leu Leu 565 570 575 Phe Tyr Thr Asp Phe Met Gly Glu Val Val Phe Gln Gly Asp Pro Lys 580 585 590 Ala Pro His Thr Ser Glu Ala Tyr Gln Lys Tyr Asn Ser Gly Val Thr 595 600 605 Met Gly Cys Trp Gly Met Cys Ile Tyr Ala Phe Ser Ala Ala Phe Tyr 610 615 620 Ser Ala Ile Leu Glu Lys Leu Glu Glu Phe Leu Ser Val Arg Thr Leu 625 630 635 640 Tyr Phe Ile Ala Tyr Leu Ala Phe Gly Leu Gly Thr Gly Leu Ala Thr 645 650 655 Leu Ser Arg Asn Leu Tyr Val Val Leu Ser Leu Cys Ile Thr Tyr Gly 660 665 670 Ile Leu Phe Ser Thr Leu Cys Thr Leu Pro Tyr Ser Leu Leu Cys Asp 675 680 685 Tyr Tyr Gln Ser Lys Lys Phe Ala Gly Ser Ser Ala Asp Gly Thr Arg 690 695 700 Arg Gly Met Gly Val Asp Ile Ser Leu Leu Ser Cys Gln Tyr Phe Leu 705 710 715 720 Ala Gln Ile Leu Val Ser Leu Val Leu Gly Pro Leu Thr Ser Ala Val 725 730 735 Gly Ser Ala Asn Gly Val Met Tyr Phe Ser Ser Leu Val Ser Phe Leu 740 745 750 Gly Cys Leu Tyr Ser Ser Leu Phe Val Ile Tyr Glu Ile Pro Ser Ser 755 760 765 Asp Ala Ala Asp Glu Glu His Arg Pro Leu Leu Leu Asn Val 770 775 780 <210> 12 <211> 1325 <212> PRT <213> Homo sapiens <400> 12 Met Leu Pro Val Tyr Gln Glu Val Lys Pro Asn Pro Leu Gln Asp Ala 1 5 10 15 Asn Leu Cys Ser Arg Val Phe Phe Trp Trp Leu Asn Pro Leu Phe Lys 20 25 30 Ile Gly His Lys Arg Arg Leu Glu Glu Asp Asp Met Tyr Ser Val Leu 35 40 45 Pro Glu Asp Arg Ser Gln His Leu Gly Glu Glu Leu Gln Gly Phe Trp 50 55 60 Asp Lys Glu Val Leu Arg Ala Glu Asn Asp Ala Gln Lys Pro Ser Leu 65 70 75 80 Thr Arg Ala Ile Ile Lys Cys Tyr Trp Lys Ser Tyr Leu Val Leu Gly 85 90 95 Ile Phe Thr Leu Ile Glu Glu Ser Ala Lys Val Ile Gln Pro Ile Phe 100 105 110 Leu Gly Lys Ile Ile Asn Tyr Phe Glu Asn Tyr Asp Pro Met Asp Ser 115 120 125 Val Ala Leu Asn Thr Ala Tyr Ala Tyr Ala Thr Val Leu Thr Phe Cys 130 135 140 Thr Leu Ile Leu Ala Ile Leu His His Leu Tyr Phe Tyr His Val Gln 145 150 155 160 Cys Ala Gly Met Arg Leu Arg Val Ala Met Cys His Met Ile Tyr Arg 165 170 175 Lys Ala Leu Arg Leu Ser Asn Met Ala Met Gly Lys Thr Thr Thr Gly 180 185 190 Gln Ile Val Asn Leu Leu Ser Asn Asp Val Asn Lys Phe Asp Gln Val 195 200 205 Thr Val Phe Leu His Phe Leu Trp Ala Gly Pro Leu Gln Ala Ile Ala 210 215 220 Val Thr Ala Leu Leu Trp Met Glu Ile Gly Ile Ser Cys Leu Ala Gly 225 230 235 240 Met Ala Val Leu Ile Ile Leu Leu Pro Leu Gln Ser Cys Phe Gly Lys 245 250 255 Leu Phe Ser Ser Leu Arg Ser Lys Thr Ala Thr Phe Thr Asp Ala Arg 260 265 270 Ile Arg Thr Met Asn Glu Val Ile Thr Gly Ile Arg Ile Ile Lys Met 275 280 285 Tyr Ala Trp Glu Lys Ser Phe Ser Asn Leu Ile Thr Asn Leu Arg Lys 290 295 300 Lys Glu Ile Ser Lys Ile Leu Arg Ser Ser Cys Leu Arg Gly Met Asn 305 310 315 320 Leu Ala Ser Phe Phe Ser Ala Ser Lys Ile Ile Val Phe Val Thr Phe 325 330 335 Thr Thr Tyr Val Leu Leu Gly Ser Val Ile Thr Ala Ser Arg Val Phe 340 345 350 Val Ala Val Thr Leu Tyr Gly Ala Val Arg Leu Thr Val Thr Leu Phe 355 360 365 Phe Pro Ser Ala Ile Glu Arg Val Ser Glu Ala Ile Val Ser Ile Arg 370 375 380 Arg Ile Gln Thr Phe Leu Leu Leu Asp Glu Ile Ser Gln Arg Asn Arg 385 390 395 400 Gln Leu Pro Ser Asp Gly Lys Lys Met Val His Val Gln Asp Phe Thr 405 410 415 Ala Phe Trp Asp Lys Ala Ser Glu Thr Pro Thr Leu Gln Gly Leu Ser 420 425 430 Phe Thr Val Arg Pro Gly Glu Leu Leu Ala Val Val Gly Pro Val Gly 435 440 445 Ala Gly Lys Ser Ser Leu Leu Ser Ala Val Leu Gly Glu Leu Ala Pro 450 455 460 Ser His Gly Leu Val Ser Val His Gly Arg Ile Ala Tyr Val Ser Gln 465 470 475 480 Gln Pro Trp Val Phe Ser Gly Thr Leu Arg Ser Asn Ile Leu Phe Gly 485 490 495 Lys Lys Tyr Glu Lys Glu Arg Tyr Glu Lys Val Ile Lys Ala Cys Ala 500 505 510 Leu Lys Lys Asp Leu Gln Leu Leu Glu Asp Gly Asp Leu Thr Val Ile 515 520 525 Gly Asp Arg Gly Thr Thr Leu Ser Gly Gly Gln Lys Ala Arg Val Asn 530 535 540 Leu Ala Arg Ala Val Tyr Gln Asp Ala Asp Ile Tyr Leu Leu Asp Asp 545 550 555 560 Pro Leu Ser Ala Val Asp Ala Glu Val Ser Arg His Leu Phe Glu Leu 565 570 575 Cys Ile Cys Gln Ile Leu His Glu Lys Ile Thr Ile Leu Val Thr His 580 585 590 Gln Leu Gln Tyr Leu Lys Ala Ala Ser Gln Ile Leu Ile Leu Lys Asp 595 600 605 Gly Lys Met Val Gln Lys Gly Thr Tyr Thr Glu Phe Leu Lys Ser Gly 610 615 620 Ile Asp Phe Gly Ser Leu Leu Lys Lys Asp Asn Glu Glu Ser Glu Gln 625 630 635 640 Pro Pro Val Pro Gly Thr Pro Thr Leu Arg Asn Arg Thr Phe Ser Glu 645 650 655 Ser Ser Val Trp Ser Gln Gln Ser Ser Arg Pro Ser Leu Lys Asp Gly 660 665 670 Ala Leu Glu Ser Gln Asp Thr Glu Asn Val Pro Val Thr Leu Ser Glu 675 680 685 Glu Asn Arg Ser Glu Gly Lys Val Gly Phe Gln Ala Tyr Lys Asn Tyr 690 695 700 Phe Arg Ala Gly Ala His Trp Ile Val Phe Ile Phe Leu Ile Leu Leu 705 710 715 720 Asn Thr Ala Ala Gln Val Ala Tyr Val Leu Gln Asp Trp Trp Leu Ser 725 730 735 Tyr Trp Ala Asn Lys Gln Ser Met Leu Asn Val Thr Val Asn Gly Gly 740 745 750 Gly Asn Val Thr Glu Lys Leu Asp Leu Asn Trp Tyr Leu Gly Ile Tyr 755 760 765 Ser Gly Leu Thr Val Ala Thr Val Leu Phe Gly Ile Ala Arg Ser Leu 770 775 780 Leu Val Phe Tyr Val Leu Val Asn Ser Ser Gln Thr Leu His Asn Lys 785 790 795 800 Met Phe Glu Ser Ile Leu Lys Ala Pro Val Leu Phe Phe Asp Arg Asn 805 810 815 Pro Ile Gly Arg Ile Leu Asn Arg Phe Ser Lys Asp Ile Gly His Leu 820 825 830 Asp Asp Leu Leu Pro Leu Thr Phe Leu Asp Phe Ile Gln Thr Leu Leu 835 840 845 Gln Val Val Gly Val Val Ser Val Ala Val Ala Val Ile Pro Trp Ile 850 855 860 Ala Ile Pro Leu Val Pro Leu Gly Ile Ile Phe Ile Phe Leu Arg Arg 865 870 875 880 Tyr Phe Leu Glu Thr Ser Arg Asp Val Lys Arg Leu Glu Ser Thr Thr 885 890 895 Arg Ser Pro Val Phe Ser His Leu Ser Ser Ser Leu Gln Gly Leu Trp 900 905 910 Thr Ile Arg Ala Tyr Lys Ala Glu Glu Arg Cys Gln Glu Leu Phe Asp 915 920 925 Ala His Gln Asp Leu His Ser Glu Ala Trp Phe Leu Phe Leu Thr Thr 930 935 940 Ser Arg Trp Phe Ala Val Arg Leu Asp Ala Ile Cys Ala Met Phe Val 945 950 955 960 Ile Ile Val Ala Phe Gly Ser Leu Ile Leu Ala Lys Thr Leu Asp Ala 965 970 975 Gly Gln Val Gly Leu Ala Leu Ser Tyr Ala Leu Thr Leu Met Gly Met 980 985 990 Phe Gln Trp Cys Val Arg Gln Ser Ala Glu Val Glu Asn Met Met Ile 995 1000 1005 Ser Val Glu Arg Val Ile Glu Tyr Thr Asp Leu Glu Lys Glu Ala Pro 1010 1015 1020 Trp Glu Tyr Gln Lys Arg Pro Pro Pro Ala Trp Pro His Glu Gly Val 1025 1030 1035 1040 Ile Ile Phe Asp Asn Val Asn Phe Met Tyr Ser Pro Gly Gly Pro Leu 1045 1050 1055 Val Leu Lys His Leu Thr Ala Leu Ile Lys Ser Gln Glu Lys Val Gly 1060 1065 1070 Ile Val Gly Arg Thr Gly Ala Gly Lys Ser Ser Leu Ile Ser Ala Leu 1075 1080 1085 Phe Arg Leu Ser Glu Pro Glu Gly Lys Ile Trp Ile Asp Lys Ile Leu 1090 1095 1100 Thr Thr Glu Ile Gly Leu His Asp Leu Arg Lys Lys Met Ser Ile Ile 1105 1110 1115 1120 Pro Gln Glu Pro Val Leu Phe Thr Gly Thr Met Arg Lys Asn Leu Asp 1125 1130 1135 Pro Phe Asn Glu His Thr Asp Glu Glu Leu Trp Asn Ala Leu Gln Glu 1140 1145 1150 Val Gln Leu Lys Glu Thr Ile Glu Asp Leu Pro Gly Lys Met Asp Thr 1155 1160 1165 Glu Leu Ala Glu Ser Gly Ser Asn Phe Ser Val Gly Gln Arg Gln Leu 1170 1175 1180 Val Cys Leu Ala Arg Ala Ile Leu Arg Lys Asn Gln Ile Leu Ile Ile 1185 1190 1195 1200 Asp Glu Ala Thr Ala Asn Val Asp Pro Arg Thr Asp Glu Leu Ile Gln 1205 1210 1215 Lys Lys Ile Arg Glu Lys Phe Ala His Cys Thr Val Leu Thr Ile Ala 1220 1225 1230 His Arg Leu Asn Thr Ile Ile Asp Ser Asp Lys Ile Met Val Leu Asp 1235 1240 1245 Ser Gly Arg Leu Lys Glu Tyr Asp Glu Pro Tyr Val Leu Leu Gln Asn 1250 1255 1260 Lys Glu Ser Leu Phe Tyr Lys Met Val Gln Gln Leu Gly Lys Ala Glu 1265 1270 1275 1280 Ala Ala Ala Leu Thr Glu Thr Ala Lys Gln Val Tyr Phe Lys Arg Asn 1285 1290 1295 Tyr Pro His Ile Gly His Thr Asp His Met Val Thr Asn Thr Ser Asn 1300 1305 1310 Gly Gln Pro Ser Thr Leu Thr Ile Phe Glu Thr Ala Leu 1315 1320 1325 <210> 13 <211> 1040 <212> PRT <213> Homo sapiens <400> 13 Met Gly Thr Ala Thr Arg Arg Lys Pro His Leu Leu Leu Val Ala Ala 1 5 10 15 Val Ala Leu Val Ser Ser Ser Ala Trp Ser Ser Ala Leu Gly Ser Gln 20 25 30 Thr Thr Phe Gly Pro Val Phe Glu Asp Gln Pro Leu Ser Val Leu Phe 35 40 45 Pro Glu Glu Ser Thr Glu Glu Gln Val Leu Leu Ala Cys Arg Ala Arg 50 55 60 Ala Ser Pro Pro Ala Thr Tyr Arg Trp Lys Met Asn Gly Thr Glu Met 65 70 75 80 Lys Leu Glu Pro Gly Ser Arg His Gln Leu Val Gly Gly Asn Leu Val 85 90 95 Ile Met Asn Pro Thr Lys Ala Gln Asp Ala Gly Val Tyr Gln Cys Leu 100 105 110 Ala Ser Asn Pro Val Gly Thr Val Val Ser Arg Glu Ala Ile Leu Arg 115 120 125 Phe Gly Phe Leu Gln Glu Phe Ser Lys Glu Glu Arg Asp Pro Val Lys 130 135 140 Ala His Glu Gly Trp Gly Val Met Leu Pro Cys Asn Pro Pro Ala His 145 150 155 160 Tyr Pro Gly Leu Ser Tyr Arg Trp Leu Leu Asn Glu Phe Pro Asn Phe 165 170 175 Ile Pro Thr Asp Gly Arg His Phe Val Ser Gln Thr Thr Gly Asn Leu 180 185 190 Tyr Ile Ala Arg Thr Asn Ala Ser Asp Leu Gly Asn Tyr Ser Cys Leu 195 200 205 Ala Thr Ser His Met Asp Phe Ser Thr Lys Ser Val Phe Ser Lys Phe 210 215 220 Ala Gln Leu Asn Leu Ala Ala Glu Asp Thr Arg Leu Phe Ala Pro Ser 225 230 235 240 Ile Lys Ala Arg Phe Pro Ala Glu Thr Tyr Ala Leu Val Gly Gln Gln 245 250 255 Val Thr Leu Glu Cys Phe Ala Phe Gly Asn Pro Val Pro Arg Ile Lys 260 265 270 Trp Arg Lys Val Asp Gly Ser Leu Ser Pro Gln Trp Thr Thr Ala Glu 275 280 285 Pro Thr Leu Gln Ile Pro Ser Val Ser Phe Glu Asp Glu Gly Thr Tyr 290 295 300 Glu Cys Glu Ala Glu Asn Ser Lys Gly Arg Asp Thr Val Gln Gly Arg 305 310 315 320 Ile Ile Val Gln Ala Gln Pro Glu Trp Leu Lys Val Ile Ser Asp Thr 325 330 335 Glu Ala Asp Ile Gly Ser Asn Leu Arg Trp Gly Cys Ala Ala Ala Gly 340 345 350 Lys Pro Arg Pro Thr Val Arg Trp Leu Arg Asn Gly Glu Pro Leu Ala 355 360 365 Ser Gln Asn Arg Val Glu Val Leu Ala Gly Asp Leu Arg Phe Ser Lys 370 375 380 Leu Ser Leu Glu Asp Ser Gly Met Tyr Gln Cys Val Ala Glu Asn Lys 385 390 395 400 His Gly Thr Ile Tyr Ala Ser Ala Glu Leu Ala Val Gln Ala Leu Ala 405 410 415 Pro Asp Phe Arg Leu Asn Pro Val Arg Arg Leu Ile Pro Ala Ala Arg 420 425 430 Gly Gly Glu Ile Leu Ile Pro Cys Gln Pro Arg Ala Ala Pro Lys Ala 435 440 445 Val Val Leu Trp Ser Lys Gly Thr Glu Ile Leu Val Asn Ser Ser Arg 450 455 460 Val Thr Val Thr Pro Asp Gly Thr Leu Ile Ile Arg Asn Ile Ser Arg 465 470 475 480 Ser Asp Glu Gly Lys Tyr Thr Cys Phe Ala Glu Asn Phe Met Gly Lys 485 490 495 Ala Asn Ser Thr Gly Ile Leu Ser Val Arg Asp Ala Thr Lys Ile Thr 500 505 510 Leu Ala Pro Ser Ser Ala Asp Ile Asn Leu Gly Asp Asn Leu Thr Leu 515 520 525 Gln Cys His Ala Ser His Asp Pro Thr Met Asp Leu Thr Phe Thr Trp 530 535 540 Thr Leu Asp Asp Phe Pro Ile Asp Phe Asp Lys Pro Gly Gly His Tyr 545 550 555 560 Arg Arg Thr Asn Val Lys Glu Thr Ile Gly Asp Leu Thr Ile Leu Asn 565 570 575 Ala Gln Leu Arg His Gly Gly Lys Tyr Thr Cys Met Ala Gln Thr Val 580 585 590 Val Asp Ser Ala Ser Lys Glu Ala Thr Val Leu Val Arg Gly Pro Pro 595 600 605 Gly Pro Pro Gly Gly Val Val Val Arg Asp Ile Gly Asp Thr Thr Ile 610 615 620 Gln Leu Ser Trp Ser Arg Gly Phe Asp Asn His Ser Pro Ile Ala Lys 625 630 635 640 Tyr Thr Leu Gln Ala Arg Thr Pro Pro Ala Gly Lys Trp Lys Gln Val 645 650 655 Arg Thr Asn Pro Ala Asn Ile Glu Gly Asn Ala Glu Thr Ala Gln Val 660 665 670 Leu Gly Leu Thr Pro Trp Met Asp Tyr Glu Phe Arg Val Ile Ala Ser 675 680 685 Asn Ile Leu Gly Thr Gly Glu Pro Ser Gly Pro Ser Ser Lys Ile Arg 690 695 700 Thr Arg Glu Ala Ala Pro Ser Val Ala Pro Ser Gly Leu Ser Gly Gly 705 710 715 720 Gly Gly Ala Pro Gly Glu Leu Ile Val Asn Trp Thr Pro Met Ser Arg 725 730 735 Glu Tyr Gln Asn Gly Asp Gly Phe Gly Tyr Leu Leu Ser Phe Arg Arg 740 745 750 Gln Gly Ser Thr His Trp Gln Thr Ala Arg Val Pro Gly Ala Asp Ala 755 760 765 Gln Tyr Phe Val Tyr Ser Asn Glu Ser Val Arg Pro Tyr Thr Pro Phe 770 775 780 Glu Val Lys Ile Arg Ser Tyr Asn Arg Arg Gly Asp Gly Pro Glu Ser 785 790 795 800 Leu Thr Ala Leu Val Tyr Ser Ala Glu Glu Glu Pro Arg Val Ala Pro 805 810 815 Thr Lys Val Trp Ala Lys Gly Val Ser Ser Ser Glu Met Asn Val Thr 820 825 830 Trp Glu Pro Val Gln Gln Asp Met Asn Gly Ile Leu Leu Gly Tyr Glu 835 840 845 Ile Arg Tyr Trp Lys Ala Gly Asp Lys Glu Ala Ala Ala Asp Arg Val 850 855 860 Arg Thr Ala Gly Leu Asp Thr Ser Ala Arg Val Ser Gly Leu His Pro 865 870 875 880 Asn Thr Lys Tyr His Val Thr Val Arg Ala Tyr Asn Arg Ala Gly Thr 885 890 895 Gly Pro Ala Ser Pro Ser Ala Asn Ala Thr Thr Met Lys Pro Pro Pro 900 905 910 Arg Arg Pro Pro Gly Asn Ile Ser Trp Thr Phe Ser Ser Ser Ser Ser Leu 915 920 925 Ser Ile Lys Trp Asp Pro Val Val Pro Phe Arg Asn Glu Ser Ala Val 930 935 940 Thr Gly Tyr Lys Met Leu Tyr Gln Asn Asp Leu His Leu Thr Pro Thr 945 950 955 960 Leu His Leu Thr Gly Lys Asn Trp Ile Glu Ile Pro Val Pro Glu Asp 965 970 975 Ile Gly His Ala Leu Val Gln Ile Arg Thr Thr Gly Pro Gly Gly Asp 980 985 990 Gly Ile Pro Ala Glu Val His Ile Val Arg Asn Gly Gly Thr Ser Met 995 1000 1005 Met Val Glu Asn Met Ala Val Arg Pro Ala Pro His Pro Gly Thr Val 1010 1015 1020 Ile Ser His Ser Val Ala Met Leu Ile Leu Ile Gly Ser Leu Glu Leu 1025 1030 1035 1040 <210> 14 <211> 870 <212> PRT <213> Homo sapiens <400> 14 Met Thr Ala Asp Lys Glu Lys Lys Arg Ser Ser Ser Glu Arg Arg Lys 1 5 10 15 Glu Lys Ser Arg Asp Ala Ala Arg Cys Arg Arg Ser Lys Glu Thr Glu 20 25 30 Val Phe Tyr Glu Leu Ala His Glu Leu Pro Leu Pro His Ser Val Ser 35 40 45 Ser His Leu Asp Lys Ala Ser Ile Met Arg Leu Ala Ile Ser Phe Leu 50 55 60 Arg Thr His Lys Leu Leu Ser Ser Val Cys Ser Glu Asn Glu Ser Glu 65 70 75 80 Ala Glu Ala Asp Gln Gln Met Asp Asn Leu Tyr Leu Lys Ala Leu Glu 85 90 95 Gly Phe Ile Ala Val Val Thr Gln Asp Gly Asp Met Ile Phe Leu Ser 100 105 110 Glu Asn Ile Ser Lys Phe Met Gly Leu Thr Gln Val Glu Leu Thr Gly 115 120 125 His Ser Ile Phe Asp Phe Thr His Pro Cys Asp His Glu Glu Ile Arg 130 135 140 Glu Asn Leu Ser Leu Lys Asn Gly Ser Gly Phe Gly Lys Lys Ser Lys 145 150 155 160 Asp Met Ser Thr Glu Arg Asp Phe Phe Met Arg Met Lys Cys Thr Val 165 170 175 Thr Asn Arg Gly Arg Thr Val Asn Leu Lys Ser Ala Thr Trp Lys Val 180 185 190 Leu His Cys Thr Gly Gln Val Lys Val Tyr Asn Asn Cys Pro Pro His 195 200 205 Asn Ser Leu Cys Gly Tyr Lys Glu Pro Leu Leu Ser Cys Leu Ile Ile 210 215 220 Met Cys Glu Pro Ile Gln His Pro Ser His Met Asp Ile Pro Leu Asp 225 230 235 240 Ser Lys Thr Phe Leu Ser Arg His Ser Met Asp Met Lys Phe Thr Tyr 245 250 255 Cys Asp Asp Arg Ile Thr Glu Leu Ile Gly Tyr His Pro Glu Glu Leu 260 265 270 Leu Gly Arg Ser Ala Tyr Glu Phe Tyr His Ala Leu Asp Ser Glu Asn 275 280 285 Met Thr Lys Ser His Gln Asn Leu Cys Thr Lys Gly Gln Val Val Ser 290 295 300 Gly Gly Tyr Arg Met Leu Ala Lys His Gly Gly Tyr Val Trp Leu Glu 305 310 315 320 Thr Gln Gly Thr Val Ile Tyr Asn Pro Arg Asn Leu Gln Pro Gln Cys 325 330 335 Ile Met Cys Val Asn Tyr Val Leu Ser Glu Ile Glu Lys Asn Asp Val 340 345 350 Val Phe Ser Met Asp Gln Thr Glu Ser Leu Phe Lys Pro His Leu Met 355 360 365 Ala Met Asn Ser Ile Phe Asp Ser Ser Gly Lys Gly Ala Val Ser Glu 370 375 380 Lys Ser Asn Phe Leu Phe Thr Lys Leu Lys Glu Glu Pro Glu Glu Leu 385 390 395 400 Ala Gln Leu Ala Pro Thr Pro Gly Asp Ala Ile Ile Ser Leu Asp Phe 405 410 415 Gly Asn Gln Asn Phe Glu Glu Ser Ser Ala Tyr Gly Lys Ala Ile Leu 420 425 430 Pro Pro Ser Gln Pro Trp Ala Thr Glu Leu Arg Ser His Ser Thr Gln 435 440 445 Ser Glu Ala Gly Ser Leu Pro Ala Phe Thr Val Pro Gln Ala Ala Ala 450 455 460 Pro Gly Ser Thr Thr Pro Ser Ala Thr Ser Ser Ser Ser Ser Ser Cys Ser 465 470 475 480 Thr Pro Asn Ser Pro Glu Asp Tyr Tyr Thr Ser Leu Asp Asn Asp Leu 485 490 495 Lys Ile Glu Val Ile Glu Lys Leu Phe Ala Met Asp Thr Glu Ala Lys 500 505 510 Asp Gln Cys Ser Thr Gln Thr Asp Phe Asn Glu Leu Asp Leu Glu Thr 515 520 525 Leu Ala Pro Tyr Ile Pro Met Asp Gly Glu Asp Phe Gln Leu Ser Pro 530 535 540 Ile Cys Pro Glu Glu Arg Leu Leu Ala Glu Asn Pro Gln Ser Thr Pro 545 550 555 560 Gln His Cys Phe Ser Ala Met Thr Asn Ile Phe Gln Pro Leu Ala Pro 565 570 575 Val Ala Pro His Ser Pro Phe Leu Leu Asp Lys Phe Gln Gln Gln Leu 580 585 590 Glu Ser Lys Lys Thr Glu Pro Glu His Arg Pro Met Ser Ser Ile Phe 595 600 605 Phe Asp Ala Gly Ser Lys Ala Ser Leu Pro Pro Cys Cys Gly Gln Ala 610 615 620 Ser Thr Pro Leu Ser Ser Met Gly Gly Arg Ser Asn Thr Gln Trp Pro 625 630 635 640 Pro Asp Pro Leu His Phe Gly Pro Thr Lys Trp Ala Val Gly Asp 645 650 655 Gln Arg Thr Glu Phe Leu Gly Ala Ala Pro Leu Gly Pro Pro Val Ser 660 665 670 Pro Pro His Val Ser Thr Phe Lys Thr Arg Ser Ala Lys Gly Phe Gly 675 680 685 Ala Arg Gly Pro Asp Val Leu Ser Pro Ala Met Val Ala Leu Ser Asn 690 695 700 Lys Leu Lys Leu Lys Arg Gln Leu Glu Tyr Glu Glu Gln Ala Phe Gln 705 710 715 720 Asp Leu Ser Gly Gly Asp Pro Pro Gly Gly Ser Thr Ser His Leu Met 725 730 735 Trp Lys Arg Met Lys Asn Leu Arg Gly Gly Ser Cys Pro Leu Met Pro 740 745 750 Asp Lys Pro Leu Ser Ala Asn Val Pro Asn Asp Lys Phe Thr Gln Asn 755 760 765 Pro Met Arg Gly Leu Gly His Pro Leu Arg His Leu Pro Leu Pro Gln 770 775 780 Pro Pro Ser Ala Ile Ser Pro Gly Glu Asn Ser Lys Ser Arg Phe Pro 785 790 795 800 Pro Gln Cys Tyr Ala Thr Gln Tyr Gln Asp Tyr Ser Leu Ser Ser Ala 805 810 815 His Lys Val Ser Gly Met Ala Ser Arg Leu Leu Gly Pro Ser Phe Glu 820 825 830 Ser Tyr Leu Leu Pro Glu Leu Thr Arg Tyr Asp Cys Glu Val Asn Val 835 840 845 Pro Val Leu Gly Ser Ser Thr Leu Leu Gln Gly Gly Asp Leu Leu Arg 850 855 860 Ala Leu Asp Gln Ala Thr 865 870 <210> 15 <211> 393 <212> PRT <213> Homo sapiens <400> 15 Met Thr Thr Tyr Ser Asp Lys Gly Ala Lys Pro Glu Arg Gly Arg Phe 1 5 10 15 Leu His Phe His Ser Val Thr Phe Trp Val Gly Asn Ala Lys Gln Ala 20 25 30 Thr Ser Phe Tyr Cys Ser Lys Met Gly Phe Glu Pro Leu Ala Tyr Arg 35 40 45 Gly Leu Glu Thr Gly Ser Arg Glu Val Val Ser His Val Ile Lys Gln 50 55 60 Gly Lys Ile Val Phe Val Leu Ser Ser Ala Leu Asn Pro Trp Asn Lys 65 70 75 80 Glu Met Gly Asp His Leu Val Lys His Gly Asp Gly Val Lys Asp Ile 85 90 95 Ala Phe Glu Val Glu Asp Cys Asp Tyr Ile Val Gln Lys Ala Arg Glu 100 105 110 Arg Gly Ala Lys Ile Met Arg Glu Pro Trp Val Glu Gln Asp Lys Phe 115 120 125 Gly Lys Val Lys Phe Ala Val Leu Gln Thr Tyr Gly Asp Thr Thr His 130 135 140 Thr Leu Val Glu Lys Met Asn Tyr Ile Gly Gln Phe Leu Pro Gly Tyr 145 150 155 160 Glu Ala Pro Ala Phe Met Asp Pro Leu Leu Pro Lys Leu Pro Lys Cys 165 170 175 Ser Leu Glu Met Ile Asp His Ile Val Gly Asn Gln Pro Asp Gln Glu 180 185 190 Met Val Ser Ala Ser Glu Trp Tyr Leu Lys Asn Leu Gln Phe His Arg 195 200 205 Phe Trp Ser Val Asp Asp Thr Gln Val His Thr Glu Tyr Ser Ser Leu 210 215 220 Arg Ser Ile Val Val Ala Asn Tyr Glu Glu Ser Ile Lys Met Pro Ile 225 230 235 240 Asn Glu Pro Ala Pro Gly Lys Lys Lys Ser Gln Ile Gln Glu Tyr Val 245 250 255 Asp Tyr Asn Gly Gly Ala Gly Val Gln His Ile Ala Leu Lys Thr Glu 260 265 270 Asp Ile Ile Thr Ala Ile Arg His Leu Arg Glu Arg Gly Leu Glu Phe 275 280 285 Leu Ser Val Pro Ser Thr Tyr Tyr Lys Gln Leu Arg Glu Lys Leu Lys 290 295 300 Thr Ala Lys Ile Lys Val Lys Glu Asn Ile Asp Ala Leu Glu Glu Leu 305 310 315 320 Lys Ile Leu Val Asp Tyr Asp Glu Lys Gly Tyr Leu Leu Gln Ile Phe 325 330 335 Thr Lys Pro Val Gln Asp Arg Pro Thr Leu Phe Leu Glu Val Ile Gln 340 345 350 Arg His Asn His Gln Gly Phe Gly Ala Gly Asn Phe Asn Ser Leu Phe 355 360 365 Lys Ala Phe Glu Glu Glu Gln Asn Leu Arg Gly Asn Leu Thr Asn Met 370 375 380 Glu Thr Asn Gly Val Val Pro Gly Met 385 390 <210> 16 <211> 1250 <212> PRT <213> Homo sapiens <400> 16 Met Ala Arg Gly Asp Ala Gly Arg Gly Arg Gly Leu Leu Ala Leu Thr 1 5 10 15 Phe Cys Leu Leu Ala Ala Arg Gly Glu Leu Leu Leu Pro Gln Glu Thr 20 25 30 Thr Val Glu Leu Ser Cys Gly Val Gly Pro Leu Gln Val Ile Leu Gly 35 40 45 Pro Glu Gln Ala Ala Val Leu Asn Cys Ser Leu Gly Ala Ala Ala Ala 50 55 60 Gly Pro Pro Thr Arg Val Thr Trp Ser Lys Asp Gly Asp Thr Leu Leu 65 70 75 80 Glu His Asp His Leu His Leu Leu Pro Asn Gly Ser Leu Trp Leu Ser 85 90 95 Gln Pro Leu Ala Pro Asn Gly Ser Asp Glu Ser Val Pro Glu Ala Val 100 105 110 Gly Val Ile Glu Gly Asn Tyr Ser Cys Leu Ala His Gly Pro Leu Gly 115 120 125 Val Leu Ala Ser Gln Thr Ala Val Val Lys Leu Ala Thr Leu Ala Asp 130 135 140 Phe Ser Leu His Pro Glu Ser Gln Thr Val Glu Glu Asn Gly Thr Ala 145 150 155 160 Arg Phe Glu Cys His Ile Glu Gly Leu Pro Ala Pro Ile Ile Thr Trp 165 170 175 Glu Lys Asp Gln Val Thr Leu Pro Glu Glu Pro Arg Leu Ile Val Leu 180 185 190 Pro Asn Gly Val Leu Gln Ile Leu Asp Val Gln Glu Ser Asp Ala Gly 195 200 205 Pro Tyr Arg Cys Val Ala Thr Asn Ser Ala Arg Gln His Phe Ser Gln 210 215 220 Glu Ala Leu Leu Ser Val Ala His Arg Gly Ser Leu Ala Ser Thr Arg 225 230 235 240 Gly Gln Asp Val Val Ile Val Ala Ala Pro Glu Asn Thr Thr Val Val 245 250 255 Ser Gly Gln Ser Val Val Met Glu Cys Val Ala Ser Ala Asp Pro Thr 260 265 270 Pro Phe Val Ser Trp Val Arg Gln Asp Gly Lys Pro Ile Ser Thr Asp 275 280 285 Val Ile Val Leu Gly Arg Thr Asn Leu Leu Ile Ala Asn Ala Gln Pro 290 295 300 Trp His Ser Gly Val Tyr Val Cys Arg Ala Asn Lys Pro Arg Thr Arg 305 310 315 320 Asp Phe Ala Thr Ala Ala Ala Glu Leu Arg Val Leu Ala Ala Pro Ala 325 330 335 Ile Thr Gln Ala Pro Glu Ala Leu Ser Arg Thr Arg Ala Ser Thr Ala 340 345 350 Arg Phe Val Cys Arg Ala Ser Gly Glu Pro Arg Pro Ala Leu Arg Trp 355 360 365 Leu His Asn Gly Ala Pro Leu Arg Pro Asn Gly Arg Val Lys Val Gln 370 375 380 Gly Gly Gly Gly Ser Leu Val Ile Thr Gln Ile Gly Leu Gln Asp Ala 385 390 395 400 Gly Tyr Tyr Gln Cys Val Ala Glu Asn Ser Ala Gly Met Ala Cys Ala 405 410 415 Ala Ala Ser Leu Ala Val Val Val Arg Glu Gly Leu Pro Ser Ala Pro 420 425 430 Thr Arg Val Thr Ala Thr Pro Leu Ser Ser Ser Ala Val Leu Val Ala 435 440 445 Trp Glu Arg Pro Glu Met His Ser Glu Gln Ile Ile Gly Phe Ser Leu 450 455 460 His Tyr Gln Lys Ala Arg Gly Met Asp Asn Val Glu Tyr Gln Phe Ala 465 470 475 480 Val Asn Asn Asp Thr Thr Glu Leu Gln Val Arg Asp Leu Glu Pro Asn 485 490 495 Thr Asp Tyr Glu Phe Tyr Val Val Ala Tyr Ser Gln Leu Gly Ala Ser 500 505 510 Arg Thr Ser Thr Pro Ala Leu Val His Thr Leu Asp Asp Val Pro Ser 515 520 525 Ala Ala Pro Gln Leu Ser Leu Ser Ser Pro Asn Pro Ser Asp Ile Arg 530 535 540 Val Ala Trp Leu Pro Leu Pro Pro Ser Leu Ser Asn Gly Gln Val Val 545 550 555 560 Lys Tyr Lys Ile Glu Tyr Gly Leu Gly Lys Glu Asp Gln Ile Phe Ser 565 570 575 Thr Glu Val Arg Gly Asn Glu Thr Gln Leu Met Leu Asn Ser Leu Gln 580 585 590 Pro Asn Lys Val Tyr Arg Val Arg Ile Ser Ala Gly Thr Ala Ala Gly 595 600 605 Phe Gly Ala Pro Ser Gln Trp Met His His Arg Thr Pro Ser Met His 610 615 620 Asn Gln Ser His Val Pro Phe Ala Pro Ala Glu Leu Lys Val Gln Ala 625 630 635 640 Lys Met Glu Ser Leu Val Val Ser Trp Gln Pro Pro His Pro Thr 645 650 655 Gln Ile Ser Gly Tyr Lys Leu Tyr Trp Arg Glu Val Gly Ala Glu Glu 660 665 670 Glu Ala Asn Gly Asp Arg Leu Pro Gly Gly Arg Gly Asp Gln Ala Trp 675 680 685 Asp Val Gly Pro Val Arg Leu Lys Lys Lys Val Lys Gln Tyr Glu Leu 690 695 700 Thr Gln Leu Val Pro Gly Arg Leu Tyr Glu Val Lys Leu Val Ala Phe 705 710 715 720 Asn Lys His Glu Asp Gly Tyr Ala Ala Val Trp Lys Gly Lys Thr Glu 725 730 735 Lys Ala Pro Ala Pro Asp Met Pro Ile Gln Arg Gly Pro Pro Leu Pro 740 745 750 Pro Ala His Val His Ala Glu Ser Asn Ser Ser Thr Ser Ile Trp Leu 755 760 765 Arg Trp Lys Lys Pro Asp Phe Thr Thr Val Lys Ile Val Asn Tyr Thr 770 775 780 Val Arg Phe Ser Pro Trp Gly Leu Arg Asn Ala Ser Leu Val Thr Tyr 785 790 795 800 Tyr Thr Ser Ser Gly Glu Asp Ile Leu Ile Gly Gly Leu Lys Pro Phe 805 810 815 Thr Lys Tyr Glu Phe Ala Val Gln Ser His Gly Val Asp Met Asp Gly 820 825 830 Pro Phe Gly Ser Val Val Glu Arg Ser Thr Leu Pro Asp Arg Pro Ser 835 840 845 Thr Pro Pro Ser Asp Leu Arg Leu Ser Pro Leu Thr Pro Ser Thr Val 850 855 860 Arg Leu His Trp Cys Pro Pro Thr Glu Pro Asn Gly Glu Ile Val Glu 865 870 875 880 Tyr Leu Ile Leu Tyr Ser Ser Asn His Thr Gln Pro Glu His Gln Trp 885 890 895 Thr Leu Leu Thr Thr Gln Gly Asn Ile Phe Ser Ala Glu Val His Gly 900 905 910 Leu Glu Ser Asp Thr Arg Tyr Phe Phe Lys Met Gly Ala Arg Thr Glu 915 920 925 Val Gly Pro Gly Pro Phe Ser Arg Leu Gln Asp Val Ile Thr Leu Gln 930 935 940 Glu Lys Leu Ser Asp Ser Leu Asp Met His Ser Val Thr Gly Ile Ile 945 950 955 960 Val Gly Val Cys Leu Gly Leu Leu Cys Leu Leu Ala Cys Met Cys Ala 965 970 975 Gly Leu Arg Arg Ser Pro His Arg Glu Ser Leu Pro Gly Leu Ser Ser 980 985 990 Thr Ala Thr Pro Gly Asn Pro Ala Leu Tyr Ser Arg Ala Arg Leu Gly 995 1000 1005 Pro Pro Ser Pro Pro Ala Ala His Glu Leu Glu Ser Leu Val His Pro 1010 1015 1020 His Pro Gln Asp Trp Ser Pro Pro Pro Ser Asp Val Glu Asp Arg Ala 1025 1030 1035 1040 Glu Val His Ser Leu Met Gly Gly Gly Val Ser Glu Gly Arg Ser His 1045 1050 1055 Ser Lys Arg Lys Ile Ser Trp Ala Gln Pro Ser Gly Leu Ser Trp Ala 1060 1065 1070 Gly Ser Trp Ala Gly Cys Glu Leu Pro Gln Ala Gly Pro Arg Pro Ala 1075 1080 1085 Leu Thr Arg Ala Leu Leu Pro Pro Ala Gly Thr Gly Gln Thr Leu Leu 1090 1095 1100 Leu Gln Ala Leu Val Tyr Asp Ala Ile Lys Gly Asn Gly Arg Lys Lys 1105 1110 1115 1120 Ser Pro Pro Ala Cys Arg Asn Gln Val Glu Ala Glu Val Ile Val His 1125 1130 1135 Ser Asp Phe Ser Ala Ser Asn Gly Asn Pro Asp Leu His Leu Gln Asp 1140 1145 1150 Leu Glu Pro Glu Asp Pro Leu Pro Pro Glu Ala Pro Asp Leu Ile Ser 1155 1160 1165 Gly Val Gly Asp Pro Gly Gln Gly Ala Ala Trp Leu Asp Arg Glu Leu 1170 1175 1180 Gly Gly Cys Glu Leu Ala Ala Pro Gly Pro Asp Arg Leu Thr Cys Leu 1185 1190 1195 1200 Pro Glu Ala Ala Ser Ala Ser Cys Ser Tyr Pro Asp Leu Gln Pro Gly 1205 1210 1215 Glu Val Leu Glu Glu Thr Pro Gly Asp Ser Cys Gln Leu Lys Ser Pro 1220 1225 1230 Cys Pro Leu Gly Ala Ser Pro Gly Leu Pro Arg Ser Pro Val Ser Ser 1235 1240 1245 Ser Ala 1250 <210> 17 <211> 612 <212> PRT <213> Homo sapiens <400> 17 Met Glu Leu Ala Met Asp Asn Ser Tyr Ala Phe Asn Gln Arg Ser Thr 1 5 10 15 Cys Asn Gly Ile Pro Ser Glu Lys Lys Asn Asn Phe Leu Val Ser Glu 20 25 30 Asp His Gly Gln Lys Ile Leu Ser Val Leu Gln Asn Phe Arg Glu Gln 35 40 45 Asn Val Phe Tyr Asp Phe Lys Ile Ile Met Lys Asp Glu Ile Ile Pro 50 55 60 Cys His Arg Cys Val Leu Ala Ala Cys Ser Asp Phe Phe Arg Ala Met 65 70 75 80 Phe Glu Val Asn Met Lys Glu Arg Asp Asp Gly Ser Val Thr Ile Thr 85 90 95 Asn Leu Ser Ser Lys Ala Val Lys Ala Phe Leu Asp Tyr Ala Tyr Thr 100 105 110 Gly Lys Thr Lys Ile Thr Asp Asp Asn Val Glu Met Phe Phe Gln Leu 115 120 125 Ser Ser Phe Leu Gln Val Ser Phe Leu Ser Lys Ala Cys Ser Asp Phe 130 135 140 Leu Ile Lys Ser Ile Asn Leu Val Asn Cys Leu Gln Leu Leu Ser Ile 145 150 155 160 Ser Asp Ser Tyr Gly Ser Thr Ser Leu Phe Asp His Ala Leu His Phe 165 170 175 Val Gln His His Phe Ser Leu Leu Phe Lys Ser Ser Asp Phe Leu Glu 180 185 190 Met Asn Phe Gly Val Leu Gln Lys Cys Leu Glu Ser Asp Glu Leu Asn 195 200 205 Val Pro Glu Glu Glu Met Val Leu Lys Val Val Leu Ser Trp Thr Lys 210 215 220 His Asn Leu Glu Ser Arg Gln Lys Tyr Leu Pro His Leu Ile Glu Lys 225 230 235 240 Val Arg Leu His Gln Leu Ser Glu Glu Thr Leu Gln Asp Cys Leu Phe 245 250 255 Asn Glu Glu Ser Leu Leu Lys Ser Thr Asn Cys Phe Asp Ile Ile Met 260 265 270 Asp Ala Ile Lys Cys Val Gln Gly Ser Gly Gly Leu Phe Pro Asp Ala 275 280 285 Arg Pro Ser Thr Thr Glu Lys Tyr Ile Phe Ile His Lys Thr Glu Glu 290 295 300 Asn Gly Glu Asn Gln Tyr Thr Phe Cys Tyr Asn Ile Lys Ser Asp Ser 305 310 315 320 Trp Lys Ile Leu Pro Gln Ser His Leu Ile Asp Leu Pro Gly Ser Ser 325 330 335 Leu Ser Ser Tyr Gly Glu Lys Ile Phe Leu Thr Gly Gly Cys Lys Gly 340 345 350 Lys Cys Cys Arg Thr Val Arg Leu His Ile Ala Glu Ser Tyr His Asp 355 360 365 Ala Thr Asp Gln Thr Trp Cys Tyr Cys Pro Val Lys Asn Asp Phe Phe 370 375 380 Leu Val Ser Thr Met Lys Thr Pro Arg Thr Met His Thr Ser Val Met 385 390 395 400 Ala Leu Asp Arg Leu Phe Val Ile Gly Gly Lys Thr Arg Gly Ser Arg 405 410 415 Asp Ile Lys Ser Leu Leu Asp Val Glu Ser Tyr Asn Pro Leu Ser Lys 420 425 430 Glu Trp Ile Ser Val Ser Pro Leu Pro Arg Gly Ile Tyr Tyr Pro Glu 435 440 445 Ala Ser Thr Cys Gln Asn Val Ile Tyr Val Leu Gly Ser Glu Val Glu 450 455 460 Ile Thr Asp Ala Phe Asn Pro Ser Leu Asp Cys Phe Phe Lys Tyr Asn 465 470 475 480 Ala Thr Thr Asp Gln Trp Ser Glu Leu Val Ala Glu Phe Gly Gln Phe 485 490 495 Phe His Ala Thr Leu Ile Lys Ala Val Pro Val Asn Cys Thr Leu Tyr 500 505 510 Ile Cys Asp Leu Ser Thr Tyr Lys Val Tyr Ser Phe Cys Pro Asp Thr 515 520 525 Cys Val Trp Lys Gly Glu Gly Ser Phe Glu Cys Ala Gly Phe Asn Ala 530 535 540 Gly Ala Ile Gly Ile Glu Asp Lys Ile Tyr Ile Leu Gly Gly Asp Tyr 545 550 555 560 Ala Pro Asp Glu Ile Thr Asp Glu Val Gln Val Tyr His Ser Asn Arg 565 570 575 Ser Glu Trp Glu Glu Val Ser Pro Met Pro Arg Ala Leu Thr Glu Phe 580 585 590 Tyr Cys Gln Val Ile Gln Phe Asn Lys Tyr Arg Asp Pro Trp Phe Ser 595 600 605 Asn Leu Cys Ala 610 <210> 18 <211> 767 <212> PRT <213> Homo sapiens <400> 18 Met Ser His Ala Val Thr Ile Glu Glu Pro Gln Ala Gln Pro Gln Val 1 5 10 15 Ser Gln Thr Arg Tyr Arg Glu Arg Ser Arg Ala Gly Ser His Ile Ser 20 25 30 Ser Asn Arg Ala Tyr Asp Phe Leu Tyr Asp Pro Leu Phe Ile Val Ser 35 40 45 Ser Glu Lys Asp His Thr Gln Ala Asn Ile Gln Ala Thr Leu Ile Arg 50 55 60 Ser Arg Leu Arg Lys Val Pro Arg Phe Lys Thr Met Phe Ser Asn Leu 65 70 75 80 Ile His Tyr Pro Arg Tyr Ser Leu Tyr Trp Ser Lys Ser Asp Pro Val 85 90 95 Pro Pro Phe Ile Ser Arg Glu Trp Lys Gly His Lys Glu Lys His Arg 100 105 110 Glu Ala Leu Arg Gln Leu Thr Thr Thr Asp Ala Ser Phe Gln Met Pro 115 120 125 Lys Glu Val Tyr Glu Asp Pro Glu Val Thr Gly Lys Asn Arg Tyr Lys 130 135 140 Tyr Phe Glu Arg Pro Phe Leu Pro Phe Phe Gln Gln Met Pro Phe Asn 145 150 155 160 Val Val Tyr Ala Val Ser Lys Ala Glu Pro Tyr Thr Phe Pro Pro Thr 165 170 175 Ser Thr Lys His Leu Ser Ile Pro Ser Lys Ser Thr Val Gly Thr Gln 180 185 190 Thr Asp Tyr Arg Asp Ala Asp Val Gln Thr Asp Pro Tyr Ser Ala Glu 195 200 205 Tyr Val Val Cys Gln Asp Ser Ile Pro Glu Leu Leu Thr Leu Ala Thr 210 215 220 Leu Thr Trp Gly Arg Gly Leu Pro Ala Gly Gln Ala Glu Val Glu Met 225 230 235 240 Ile Glu Arg Ala Arg Glu Lys Arg Ala Trp Glu Ala Ser Leu Pro Ala 245 250 255 Leu Ser Asp Thr Ser Gln Phe Glu Lys Arg Arg Lys Met Met Asn Glu 260 265 270 Met Glu Arg Lys Glu Trp Ala Phe Arg Glu Gln Glu Ile Glu Lys Leu 275 280 285 Gln Glu Ile Arg Leu Glu Val Leu Lys Glu Leu Leu Arg Lys Arg Glu 290 295 300 Glu Asn Gln Asn Glu Val Asn Met Lys His Leu Asn Ala Arg Trp Ser 305 310 315 320 Lys Leu Gln Glu Gly Lys Glu Ala Lys Met Ala Lys Ile Gln Arg Thr 325 330 335 His Val Ser Thr Ile Arg Lys Leu Val Gly Lys Arg Lys Asn Ile Glu 340 345 350 Gly Lys Leu Glu Arg Arg Asn Ile Ile Lys Asp Tyr Ser Asp Tyr Ala 355 360 365 Ser Gln Val Tyr Gly Pro Leu Ser Arg Leu Gly Cys Phe Pro Asp Asn 370 375 380 Asn Ser Glu Asp Phe Val Val Lys Asn Tyr Tyr Leu Asn Thr Tyr Glu 385 390 395 400 Gly Leu Val Glu Leu Glu Ser Cys Leu Pro Asp Phe Val Thr Gln Pro 405 410 415 Gln Ile Arg Ala Pro Lys Pro Lys Val Ile Thr Thr Lys Ala Gly Phe 420 425 430 Leu Lys Arg Ala Ala Arg Leu Asp Tyr Glu Leu Ala Glu Val His Lys 435 440 445 Ala Leu Leu Asp Lys Lys Asn Lys Val Leu Glu Val Lys Lys Pro Pro 450 455 460 Arg Phe Leu Gln Arg Asn Pro Ile Pro Gln Pro Arg Leu Pro Thr Pro 465 470 475 480 Thr Leu Glu Met Thr Ser Asn Glu Glu Glu Glu Met Glu Met Ala Val 485 490 495 Ile Tyr Leu Gln Lys Leu Leu Arg Gly Arg Val Val Gln Asn Met Met 500 505 510 Phe Glu Gly Lys Glu Lys Arg Leu Glu Leu Ile Gln Glu Leu Arg Thr 515 520 525 Cys His Ala Leu Gln Glu Asp Glu Lys Leu Val Lys Lys Ala Glu Lys 530 535 540 Gln Val Thr Leu Ala Leu Gln Arg Gln Arg Asn Leu His Glu His Lys 545 550 555 560 Val Ser Leu Val Glu Asn His Leu Ala Gly Leu Glu Gly Arg Ala Leu 565 570 575 Ala Asp Met Phe Asp Phe Leu Ser Lys Glu Leu Val Arg Leu Gln Glu 580 585 590 Glu Arg Arg Ile His Ala Phe Val Met Leu Ala Glu Arg Gln Arg Arg 595 600 605 Val Arg Glu Ala Glu Glu Ser Gly Arg Arg Gln Val Glu Lys Gln Arg 610 615 620 Leu Arg Glu Glu Asp Glu Ile Phe Lys Glu Val Val Lys Val His His 625 630 635 640 Ser Thr Ile Ser Ser Tyr Leu Glu Asp Ile Ile Leu Asn Thr Glu Ala 645 650 655 Asn Thr Ala Glu Glu Gln Ala Arg Ala Glu Ile Glu Lys Met Ala Glu 660 665 670 Lys Ile Asn Asp Ile Ala Tyr Glu Met Glu Ser Arg Arg Thr Tyr Leu 675 680 685 Gln Ser Glu Glu Ile Val Ala Glu Leu Val Tyr Ser Phe Leu Ile Pro 690 695 700 Glu Val Gln Lys Tyr Phe Val Lys Glu Lys Val Arg Asn Ala Gln Arg 705 710 715 720 Lys His Ile Leu Ala Ala His Gln Ile Ile His Ser Tyr Thr Glu Ser 725 730 735 Met Val Gln Lys Lys Leu Thr Glu Gly Glu Gln Asp Glu Ala Ser Asn 740 745 750 Ala Ala Met Leu Leu Glu Lys Glu Thr Gln Asn Glu Asn Asn Ser 755 760 765 <210> 19 <211> 134 <212> PRT <213> Homo sapiens <400> 19 Met Thr Arg Asp Gln Asn Gly Thr Trp Glu Met Glu Ser Asn Glu Asn 1 5 10 15 Phe Glu Gly Tyr Met Lys Ala Leu Asp Ile Asp Phe Ala Thr Arg Lys 20 25 30 Ile Ala Val Arg Leu Thr Gln Thr Lys Val Ile Asp Gln Asp Gly Asp 35 40 45 Asn Phe Lys Thr Lys Thr Thr Ser Thr Phe Arg Asn Tyr Asp Val Asp 50 55 60 Phe Thr Val Gly Val Glu Phe Asp Glu Tyr Thr Lys Ser Leu Asp Asn 65 70 75 80 Arg His Val Lys Ala Leu Val Thr Trp Glu Gly Asp Val Leu Val Cys 85 90 95 Val Gln Lys Gly Glu Lys Glu Asn Arg Gly Trp Lys Gln Trp Ile Glu 100 105 110 Gly Asp Lys Leu Tyr Leu Glu Leu Thr Cys Gly Asp Gln Val Cys Arg 115 120 125 Gln Val Phe Lys Lys Lys 130 <210> 20 <211> 285 <212> PRT <213> Homo sapiens <400> 20 Met Ser Asp Asp Phe Leu Trp Phe Glu Gly Ile Ala Phe Pro Thr Met 120 124 129 134 Gly Phe Arg Ser Glu Thr Leu Arg Lys Val Arg Asp Glu Phe Val Ile 139 144 149 Arg Asp Glu Asp Val Ile Ile Leu Thr Tyr Pro Lys Ser Gly Thr Asn 154 159 164 Trp Leu Ala Glu Ile Leu Cys Leu Met His Ser Lys Gly Asp Ala Lys 169 174 179 Trp Ile Gln Ser Val Pro Ile Trp Glu Arg Ser Pro Trp Val Glu Ser 184 189 194 199 Glu Ile Gly Tyr Thr Ala Leu Ser Glu Thr Glu Ser Pro Arg Leu Phe 204 209 214 Ser Ser His Leu Pro Ile Gln Leu Phe Pro Lys Ser Phe Phe Ser Ser Ser 219 224 229 Lys Ala Lys Val Ile Tyr Leu Met Arg Asn Pro Arg Asp Val Leu Val 234 239 244 Ser Gly Tyr Phe Phe Trp Lys Asn Met Lys Phe Ile Lys Lys Pro Lys 249 254 259 Ser Trp Glu Glu Tyr Phe Glu Trp Phe Cys Gln Gly Thr Val Leu Tyr 264 269 274 279 Gly Ser Trp Phe Asp His Ile His Gly Trp Met Pro Met Arg Glu Glu 284 289 294 Lys Asn Phe Leu Leu Leu Ser Tyr Glu Glu Leu Lys Gln Asp Thr Gly 299 304 309 Arg Thr Ile Glu Lys Ile Cys Gln Phe Leu Gly Lys Thr Leu Glu Pro 314 319 324 Glu Glu Leu Asn Leu Ile Leu Lys Asn Ser Ser Phe Gln Ser Met Lys 329 334 339 Glu Asn Lys Met Ser Asn Tyr Ser Leu Leu Ser Val Asp Tyr Val Val 344 349 354 359 Asp Lys Ala Gln Leu Leu Arg Lys Gly Val Ser Gly Asp Trp Lys Asn 364 369 374 His Phe Thr Val Ala Gln Ala Glu Asp Phe Asp Lys Leu Phe Gln Glu 379 384 389 Lys Met Ala Asp Leu Pro Arg Glu Leu Phe Pro Trp Glu 394 399 404 <210> 21 <211> 1059 <212> PRT <213> Homo sapiens <400> 21 Met Glu Pro Thr Val Ala Asp Val His Leu Val Pro Arg Thr Thr Lys 1 5 10 15 Glu Val Pro Ala Leu Asp Ala Ala Cys Cys Arg Ala Ala Ser Ile Gly 20 25 30 Val Val Ala Thr Ser Leu Val Val Leu Thr Leu Gly Val Leu Leu Ala 35 40 45 Phe Leu Ser Thr Gln Gly Phe His Val Asp His Thr Ala Glu Leu Arg 50 55 60 Gly Ile Arg Trp Thr Ser Ser Leu Arg Arg Glu Thr Ser Asp Tyr His 65 70 75 80 Arg Thr Leu Thr Pro Thr Leu Glu Ala Leu Leu His Phe Leu Leu Arg 85 90 95 Pro Leu Gln Thr Leu Ser Leu Gly Leu Glu Glu Glu Leu Leu Gln Arg 100 105 110 Gly Ile Arg Ala Arg Leu Arg Glu His Gly Ile Ser Leu Ala Ala Tyr 115 120 125 Gly Thr Ile Val Ser Ala Glu Leu Thr Gly Arg His Lys Gly Pro Leu 130 135 140 Ala Glu Arg Asp Phe Lys Ser Gly Arg Cys Pro Gly Asn Ser Phe Ser 145 150 155 160 Cys Gly Asn Ser Gln Cys Val Thr Lys Val Asn Pro Glu Cys Asp Asp 165 170 175 Gln Glu Asp Cys Ser Asp Gly Ser Asp Glu Ala His Cys Glu Cys Gly 180 185 190 Leu Gln Pro Ala Trp Arg Met Ala Gly Arg Ile Val Gly Gly Met Glu 195 200 205 Ala Ser Pro Gly Glu Phe Pro Trp Gln Ala Ser Leu Arg Glu Asn Lys 210 215 220 Glu His Phe Cys Gly Ala Ala Ile Ile Asn Ala Arg Trp Leu Val Ser 225 230 235 240 Ala Ala His Cys Phe Asn Glu Phe Gln Asp Pro Thr Lys Trp Val Ala 245 250 255 Tyr Val Gly Ala Thr Tyr Leu Ser Gly Ser Glu Ala Ser Thr Val Arg 260 265 270 Ala Gln Val Val Gln Ile Val Lys His Pro Leu Tyr Asn Ala Asp Thr 275 280 285 Ala Asp Phe Asp Val Ala Val Leu Glu Leu Thr Ser Pro Leu Pro Phe 290 295 300 Gly Arg His Ile Gln Pro Val Cys Leu Pro Ala Ala Thr His Ile Phe 305 310 315 320 Pro Pro Ser Lys Lys Cys Leu Ile Ser Gly Trp Gly Tyr Leu Lys Glu 325 330 335 Asp Phe Leu Val Lys Pro Glu Val Leu Gln Lys Ala Thr Val Glu Leu 340 345 350 Leu Asp Gln Ala Leu Cys Ala Ser Leu Tyr Gly His Ser Leu Thr Asp 355 360 365 Arg Met Val Cys Ala Gly Tyr Leu Asp Gly Lys Val Asp Ser Cys Gln 370 375 380 Gly Asp Ser Gly Gly Pro Leu Val Cys Glu Glu Pro Ser Gly Arg Phe 385 390 395 400 Phe Leu Ala Gly Ile Val Ser Trp Gly Ile Gly Cys Ala Glu Ala Arg 405 410 415 Arg Pro Gly Val Tyr Ala Arg Val Thr Arg Leu Arg Asp Trp Ile Leu 420 425 430 Glu Ala Thr Thr Lys Ala Ser Met Pro Leu Ala Pro Thr Met Ala Pro 435 440 445 Ala Pro Ala Ala Pro Ser Thr Ala Trp Pro Thr Ser Pro Glu Ser Pro 450 455 460 Val Val Ser Thr Pro Thr Lys Ser Met Gln Ala Leu Ser Thr Val Pro 465 470 475 480 Leu Asp Trp Val Thr Val Pro Lys Leu Gln Glu Cys Gly Ala Arg Pro 485 490 495 Ala Met Glu Lys Pro Thr Arg Val Val Gly Gly Phe Gly Ala Ala Ser 500 505 510 Gly Glu Val Pro Trp Gln Val Ser Leu Lys Glu Gly Ser Arg His Phe 515 520 525 Cys Gly Ala Thr Val Val Gly Asp Arg Trp Leu Leu Ser Ala Ala His 530 535 540 Cys Phe Asn His Thr Lys Val Glu Gln Val Arg Ala His Leu Gly Thr 545 550 555 560 Ala Ser Leu Leu Gly Leu Gly Gly Ser Pro Val Lys Ile Gly Leu Arg 565 570 575 Arg Val Val Leu His Pro Leu Tyr Asn Pro Gly Ile Leu Asp Phe Asp 580 585 590 Leu Ala Val Leu Glu Leu Ala Ser Pro Leu Ala Phe Asn Lys Tyr Ile 595 600 605 Gln Pro Val Cys Leu Pro Leu Ala Ile Gln Lys Phe Pro Val Gly Arg 610 615 620 Lys Cys Met Ile Ser Gly Trp Gly Asn Thr Gln Glu Gly Asn Ala Thr 625 630 635 640 Lys Pro Glu Leu Leu Gln Lys Ala Ser Val Gly Ile Ile Asp Gln Lys 645 650 655 Thr Cys Ser Val Leu Tyr Asn Phe Ser Leu Thr Asp Arg Met Ile Cys 660 665 670 Ala Gly Phe Leu Glu Gly Lys Val Asp Ser Cys Gln Gly Asp Ser Gly 675 680 685 Gly Pro Leu Ala Cys Glu Glu Ala Pro Gly Val Phe Tyr Leu Ala Gly 690 695 700 Ile Val Ser Trp Gly Ile Gly Cys Ala Gln Val Lys Lys Pro Gly Val 705 710 715 720 Tyr Thr Arg Ile Thr Arg Leu Lys Gly Trp Ile Leu Glu Ile Met Ser 725 730 735 Ser Gln Pro Leu Pro Met Ser Pro Pro Ser Thr Thr Arg Met Leu Ala 740 745 750 Thr Thr Ser Pro Arg Thr Thr Ala Gly Leu Thr Val Pro Gly Ala Thr 755 760 765 Pro Ser Arg Pro Thr Pro Gly Ala Ala Ser Arg Val Thr Gly Gln Pro 770 775 780 Ala Asn Ser Thr Leu Ser Ala Val Ser Thr Thr Ala Arg Gly Gln Thr 785 790 795 800 Pro Phe Pro Asp Ala Pro Glu Ala Thr Thr His Thr Gln Leu Pro Asp 805 810 815 Cys Gly Leu Ala Pro Ala Ala Leu Thr Arg Ile Val Gly Gly Ser Ala 820 825 830 Ala Gly Arg Gly Glu Trp Pro Trp Gln Val Ser Leu Trp Leu Arg Arg 835 840 845 Arg Glu His Arg Cys Gly Ala Val Leu Val Ala Glu Arg Trp Leu Leu 850 855 860 Ser Ala Ala His Cys Phe Asp Val Tyr Gly Asp Pro Lys Gln Trp Ala 865 870 875 880 Ala Phe Leu Gly Thr Pro Phe Leu Ser Gly Ala Glu Gly Gln Leu Glu 885 890 895 Arg Val Ala Arg Ile Tyr Lys His Pro Phe Tyr Asn Leu Tyr Thr Leu 900 905 910 Asp Tyr Asp Val Ala Leu Leu Glu Leu Ala Gly Pro Val Arg Arg Ser 915 920 925 Arg Leu Val Arg Pro Ile Cys Leu Pro Glu Pro Ala Pro Arg Pro Pro 930 935 940 Asp Gly Thr Arg Cys Val Ile Thr Gly Trp Gly Ser Val Arg Glu Gly 945 950 955 960 Gly Ser Met Ala Arg Gln Leu Gln Lys Ala Ala Val Arg Leu Leu Ser 965 970 975 Glu Gln Thr Cys Arg Arg Phe Tyr Pro Val Gln Ile Ser Ser Arg Met 980 985 990 Leu Cys Ala Gly Phe Pro Gln Gly Gly Val Asp Ser Cys Ser Gly Asp 995 1000 1005 Ala Gly Gly Pro Leu Ala Cys Arg Glu Pro Ser Gly Arg Trp Val Leu 1010 1015 1020 Thr Gly Val Thr Ser Trp Gly Tyr Gly Cys Gly Arg Pro His Phe Pro 1025 1030 1035 1040 Gly Val Tyr Thr Arg Val Ala Ala Val Arg Gly Trp Ile Gly Gln His 1045 1050 1055 Ile Gln Glu <210> 22 <211> 527 <212> PRT <213> Homo sapiens <400> 22 Met Ile Leu Ser Ser Tyr Asn Thr Ile Gln Ser Val Phe Cys Cys Cys 1 5 10 15 Cys Cys Cys Ser Val Gln Lys Arg Gln Met Arg Thr Gln Ile Ser Leu 20 25 30 Ser Thr Asp Glu Glu Leu Pro Glu Lys Tyr Thr Gln Arg Arg Arg Pro 35 40 45 Trp Leu Ser Gln Leu Ser Asn Lys Lys Gln Ser Asn Thr Gly Arg Val 50 55 60 Gln Pro Ser Lys Arg Lys Pro Leu Pro Pro Leu Pro Pro Ser Glu Val 65 70 75 80 Ala Glu Glu Lys Ile Gln Val Lys Ala Leu Tyr Asp Phe Leu Pro Arg 85 90 95 Glu Pro Cys Asn Leu Ala Leu Arg Arg Ala Glu Glu Tyr Leu Ile Leu 100 105 110 Glu Lys Tyr Asn Pro His Trp Trp Lys Ala Arg Asp Arg Leu Gly Asn 115 120 125 Glu Gly Leu Ile Pro Ser Asn Tyr Val Thr Glu Asn Lys Ile Thr Asn 130 135 140 Leu Glu Ile Tyr Glu Trp Tyr His Arg Asn Ile Thr Arg Asn Gln Ala 145 150 155 160 Glu His Leu Leu Arg Gln Glu Ser Lys Glu Gly Ala Phe Ile Val Arg 165 170 175 Asp Ser Arg His Leu Gly Ser Tyr Thr Ile Ser Val Phe Met Gly Ala 180 185 190 Arg Arg Ser Thr Glu Ala Ala Ile Lys His Tyr Gln Ile Lys Lys Asn 195 200 205 Asp Ser Gly Gln Trp Tyr Val Ala Glu Arg His Ala Phe Gln Ser Ile 210 215 220 Pro Glu Leu Ile Trp Tyr His Gln His Asn Ala Ala Gly Leu Met Thr 225 230 235 240 Arg Leu Arg Tyr Pro Val Gly Leu Met Gly Ser Cys Leu Pro Ala Thr 245 250 255 Ala Gly Phe Ser Tyr Glu Lys Trp Glu Ile Asp Pro Ser Glu Leu Ala 260 265 270 Phe Ile Lys Glu Ile Gly Ser Gly Gln Phe Gly Val Val His Leu Gly 275 280 285 Glu Trp Arg Ser His Ile Gln Val Ala Ile Lys Ala Ile Asn Glu Gly 290 295 300 Ser Met Ser Glu Glu Asp Phe Ile Glu Glu Ala Lys Val Met Met Lys 305 310 315 320 Leu Ser His Ser Lys Leu Val Gln Leu Tyr Gly Val Cys Ile Gln Arg 325 330 335 Lys Pro Leu Tyr Ile Val Thr Glu Phe Met Glu Asn Gly Cys Leu Leu 340 345 350 Asn Tyr Leu Arg Glu Asn Lys Gly Lys Leu Arg Lys Glu Met Leu Leu 355 360 365 Ser Val Cys Gln Asp Ile Cys Glu Gly Met Glu Tyr Leu Glu Arg Asn 370 375 380 Gly Tyr Ile His Arg Asp Leu Ala Ala Arg Asn Cys Leu Val Ser Ser 385 390 395 400 Thr Cys Ile Val Lys Ile Ser Asp Phe Gly Met Thr Arg Tyr Val Leu 405 410 415 Asp Asp Glu Tyr Val Ser Ser Phe Gly Ala Lys Phe Pro Ile Lys Trp 420 425 430 Ser Pro Pro Glu Val Phe Leu Phe Asn Lys Tyr Ser Ser Lys Ser Asp 435 440 445 Val Trp Ser Phe Gly Val Leu Met Trp Glu Val Phe Thr Glu Gly Lys 450 455 460 Met Pro Phe Glu Asn Lys Ser Asn Leu Gln Val Val Glu Ala Ile Ser 465 470 475 480 Glu Gly Phe Arg Leu Tyr Arg Pro His Leu Ala Pro Met Ser Ile Tyr 485 490 495 Glu Val Met Tyr Ser Cys Trp His Glu Lys Pro Glu Gly Arg Pro Thr 500 505 510 Phe Ala Glu Leu Leu Arg Ala Val Thr Glu Ile Ala Glu Thr Trp 515 520 525

Claims (10)

BTBD10 gene mutation, GRIA2 gene mutation, GUCY1A2 gene mutation, ITGA3 gene mutation, MED1 gene mutation, MTUS2 gene mutation, PIK3C2A gene mutation, QARS gene mutation, SALL1 gene mutation, SIN3A gene mutation and A composition for prognostic diagnosis of bladder cancer according to whether recurrence, comprising a reagent capable of detecting a recurrence-specific marker of a bladder cancer patient comprising at least one selected from the group consisting of a mutation of the SLC45A1 gene. The method according to claim 1,
The reagent is a composition comprising one or more selected from the group consisting of primers, probes, aptamers and antibodies. The method according to claim 1,
The relapse-specific marker is a mutation in the ABCC4 gene, mutation in the CNTN2 gene, mutation in the EPAS1 gene, mutation in the HPD gene, mutation in the IGDCC4 gene, mutation in the KBTBD3 gene, mutation in the MAATS1 gene, mutation in the RBP2 gene, mutation in the SULT2A1 gene , A composition further comprising at least one selected from the group consisting of a mutation of the TMPRSS9 gene and a mutation of the TXK gene. BTBD10 gene mutation, GRIA2 gene mutation, GUCY1A2 gene mutation, ITGA3 gene mutation, MED1 gene mutation, MTUS2 gene mutation, PIK3C2A gene mutation, QARS gene mutation, SALL1 gene mutation, SIN3A gene mutation and A kit for diagnosing the prognosis of bladder cancer according to whether recurrence, comprising a reagent capable of detecting a recurrence-specific marker of a bladder cancer patient comprising at least one selected from the group consisting of a mutation of the SLC45A1 gene. 5. The method according to claim 4,
The reagent is a kit comprising at least one selected from the group consisting of primers, probes, aptamers and antibodies. 5. The method according to claim 4,
The relapse-specific marker is a mutation in the ABCC4 gene, mutation in the CNTN2 gene, mutation in the EPAS1 gene, mutation in the HPD gene, mutation in the IGDCC4 gene, mutation in the KBTBD3 gene, mutation in the MAATS1 gene, mutation in the RBP2 gene, mutation in the SULT2A1 gene , A kit further comprising at least one selected from the group consisting of a mutation of the TMPRSS9 gene and a mutation of the TXK gene. preparing sample DNA from a sample of a bladder cancer patient;
Using the composition for prognostic diagnosis of any one of claims 1 to 3 or the kit for prognostic diagnosis of bladder cancer of any one of claims 4 to 6 for the sample DNA, confirming the presence or absence of a recurrence-specific marker; including; A method of providing information necessary for prognostic diagnosis of bladder cancer patients. 8. The method of claim 7,
The method further comprising the step of amplifying the sample DNA prepared from the bladder cancer patient sample. 8. The method of claim 7,
The method further comprising; determining that the bladder cancer patient whose recurrence-specific marker is confirmed has a higher survival rate than that of a person whose recurrence-specific marker is not identified. 8. The method of claim 7,
The method further comprising; determining that the bladder cancer patient for which the recurrence-specific marker is confirmed has a lower recurrence rate of bladder cancer than the person for which the recurrence-specific marker is not identified.

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