KR20220099686A - Metastic interval-specific markers for diagnosing prognosis and determining treatment strategies in metastatic solid cancer patients - Google Patents

Abstract

The present invention relates to a marker for diagnosing difference in treatment effect or prognosis of solid cancer according to the metastasis period of metastatic solid cancer patients. Since mutations in the gene of the present invention are correlated with the survival rate or recurrence rate of solid cancer patients in a specific metastasis period, respectively, the mutated gene of the present invention can be used for predicting the difference in treatment effect of metastatic solid cancer or the prognosis of metastatic solid cancer patients based on the metastasis period as a marker.

Description

Metastatic interval-specific markers for diagnosing prognosis and determining treatment strategies in metastatic solid cancer patients}

The present invention provides information necessary for prognosis diagnosis and treatment strategy determination of solid cancer by using a metastasis period-specific marker for prognosis diagnosis of a patient with metastatic solid cancer, a kit for prognosis diagnosis of a solid cancer patient including the same, and a prognostic diagnostic marker for a solid cancer patient. it's about how

Cancer is a disease in which the cell cycle is not regulated and continues to divide. There are lung cancer, stomach cancer, breast cancer, colorectal cancer, etc. The specific cause of its occurrence is not yet known, but according to what is known so far, normal cell genes or cancer It is known that mutations occur in repressor genes. Based on the statistical data on the cause of death in Korea, these cancers have continued to occupy the top position since the related statistics were compiled in 1983, accounting for 27.5% of deaths in 2019, and 8546 patients in 2020 with cancer. It is expected to die as a result of this, and it is recognized as one of the greatest threats to modern people.

These cancers can be largely divided into blood cancers and solid cancers. Solid cancers are cancers that start in a specific organ, grow and then metastasize. Representatively, there are gastric cancer, lung cancer, colon cancer, and breast cancer. As malignant ones, there are leukemia, multiple myeloma, and malignant lymphoma. Gastric cancer, colorectal cancer, lung cancer, and thyroid cancer, which are types of solid cancer, consistently occupy the 1st to 4th places among the causes of cancer in Korea. If complete resection is possible through resection, chemotherapy is performed after resection. However, due to the nature of cancer, which is a mutated normal cell, the side effects of treatment are large and many patients suffer from sequelae.

If cancer is diagnosed early, the patient's mortality rate is significantly lowered. For example, the survival rate after 5 years for patients with stage 1 and 2 colorectal cancer reaches 90%, but for patients with stage 4 colorectal cancer where metastasis has started, 5 years After that, the survival rate drops to 10%. Therefore, early diagnosis is very important for cancer treatment, and metastatic cancer shares major mutations found in primary cancer, but often new mutations are additionally generated during metastasis or treatment. Although there are many documents disclosing markers (Patent Publication No. 10-2017-0041693), markers that can measure the prognosis of patients with metastatic solid cancer, in particular, the association with the survival rate and metastasis period of patients found in patients with solid cancer have yet to be confirmed. Research has not been done.

In order to solve the above problems, the present inventors confirmed that the occurrence of specific mutations increases according to the metastasis period in patients with metastatic solid cancer, and the survival rate of each mutation for metastatic solid cancer was analyzed using TCGA patient data and MSKCC sample data. After synthesis, through three feature selections (Information Gain, Chi-Square, MRMR), a marker was developed that can predict the prognosis of patients with solid cancer and help determine treatment strategies.

Accordingly, the present invention provides a marker composition for predicting the treatment effect or prognosis diagnosis according to the metastasis period of a solid cancer patient, comprising a mutation of a gene encoding one or more selected from the group consisting of CREBBP, ESR1, GATA3, H3F3B and MYD88 aim to

In addition, a composition for predicting treatment effect or prognosis diagnosis according to the metastasis period of a solid cancer patient, comprising an agent capable of detecting a mutation in a gene encoding one or more selected from the group consisting of CREBBP, ESR1, GATA3, H3F3B and MYD88 provide for a different purpose.

Another object of the present invention is to provide a kit for diagnosing a therapeutic effect or prognosis according to the metastasis period of a solid cancer patient, comprising the composition.

In addition, the present invention comprises the steps of preparing a sample DNA from a sample of a solid cancer patient; amplifying the sample DNA using the kit; and confirming the presence or absence of a metastasis period-specific marker from the amplification result. Another object of the present invention is to provide a method for providing information necessary for prognostic diagnosis of solid cancer according to the metastasis period of a solid cancer patient.

However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.

In order to achieve the above object, the present invention includes a mutation in a gene encoding one or more selected from the group consisting of CREBBP, ESR1, GATA3, H3F3B and MYD88, for predicting treatment effect or prognosis diagnosis according to the metastasis period of a solid cancer patient A marker composition is provided.

In addition, the present invention includes an agent capable of detecting a mutation of one or more genes encoding one or more selected from the group consisting of CREBBP, ESR1, GATA3, H3F3B and MYD88. A diagnostic composition is provided.

In one embodiment of the present invention, the mutation of the gene encoding CREBBP may be one or more selected from the group consisting of the following mutations encoded by SEQ ID NO: 1.

Y2189S, Q1756E, S2394F, L829F, S977L, A259T, R1328M, G587R, R672L, T345I, Y1622H, D1480N, P988S, P1096A, R351H, G689R, A2265V, Q662H, R1446C, R1446H, W1472R W Y Y, R1446H, W1472R R1446S, L1499Q, D1435N, R1446P, Y1450N, Y1482C, W1502R, Y1482N, Y1482D, L1499R, W1502C, W1472G, W1502L, I1431S, R1446C, I1431N, Y1503N, V1802M, T396K1778L, R1782V, E5503N, V1802M, T396K1778L, R1782V R1664C, T1260M, T950M, C1408Y, R424Q, R625H, R1081H, R601Q, P248L, M1798I, S1072F, P949L, A1824T, R1682H, R1428C, A206V, Y1167C, A2144V, V1650I, A2591, S136M, R1427W16341, T872, V E1243D, F1439L, R1319Q, R714C, E1012K, R1347W, D1481G, D1273N, A1944P, K1809R, E1247K, P2038L, G706R, P766L, P928S, R1800Q, V1371F, R714H, S945L, S1392Q, S945L, S32557T, R669W, R32557T R1602H, R519K, C1240Y, N645K, P107L, Y1973H, N2141K, S554F, R742L, Q963H, T862M, G21D, A698V, A533T, G2010E, A1510V, P907S, R1851H, Q2292R, Q11249H, K1498Q, N530S, K1498Q, N530S R1866C, P2285H, A1398V, M2192I, T1932M, Q1698L, G1699D, E1020G, N522S, P1889L, H2178Y, P2011S, I1455N, S2065N, K1269N, Q1928H, A259S, R2353W, Y1828C, N797K, P496L, R1378L, S791T, G1404S, Q1941L, L1451211S, Q1941L, L1451211R, S2065N, L1451211R, S2065N, K1269N, Q1928H, A259S V992L, I678M, G252C, H1470L, Q1113H, Q102R, D2433G, E1099K, T1210A, L869F, T537P, V460F, E2404K, A787V, M1021I, P552L, L833V, E637K, P2331S, D1156M, T2066T, R1964C, A190 S767Y, E1459Q, E1452K, N374I, Q1879E, G2162R, E1400Q, F1540S, S893W, E1501K, H1351D, S479I, H1485Y, D1276H, Q2299K, E1626Q, T320I, Q1152E, S2377L, K1271T, R1433H, L1271T, R1433H, K1271T, R, A2419V, Y1125H, S1207F, E1088K, R1317K, V2149M, S139N, P975S, G1305D, R624C, T4668S, P1953S, S247F, S2361F, T1242S, V1429M, L33F, D1543V, S566F, R1341P, P2383L, S237704 L2198Q, S554F, P2352L, P2415L, G219V, P1489T, QP1257HS, P1488L, E548K, D1309N, V1371D, E1400K, E1576D, A1739V, Q610H, L161M, W1545L, C1199F, H2384R, G786P, H2384R, E5281963D A924T, L1181R, F22L, V1818M, P432S, Q21 03K, V1704F, E371Q, D1420A, P2331L, R2195K, P1110L, V824M, D599N, G268R, P2187L, P2155S, S2345F, E996K, G591S, A2046V, Q2324K, M2391I, V1429A, G2132V, P1429A, G2132V P248S, P308S, S1030F, P957A, S646N, R1985L, G1418V, M481V, P543L, P2311L, A2170T, A924V, E1715K, D1263N, P1997L, P1951L, R1173G, P1991L, H17E12Y, S232V2L, H17E12Y2, L232V21374 M1625N, P1208S, H1738N, M1981I, Q1863R, L679F, W1745C, G2236E, G1753V, A1093V, V2056M, A476T, H1413P, V1722E, A924S, R1866L, R1926W, F1632V, K1870P, C398Y, G1870N, C398Y at least one missense mutation selected from the group consisting of S121I, G1411R, N1350I, T1332P, P1488T, D1480H and I1483S;

G572*, Q771*, Q497*, R1360*, R1173*, Q1073*, Q1796*, R1498*, R1103*, R1341*, Q1756*, Q887*, Q1856*, S985*, E349*, R1672*, Q1928* , Y1230*, S1065*, Q2235*, Y1726*, R440*, Y659*, E1243*, Q719*, E1205*, R1392*, R386*, L243*, Q540*, R424*, Q517*, E1000*, Q1148 *, S547*, Q357*, R370*, E1626*, S381*, Q2103*, S331*, Q1852*, Y1828*, K68*, Q963*, Q356*, R2004*, E1559*, Q203*, Q919*, at least one nonsense mutation selected from the group consisting of K1051*, Q1041*, Q1941*, Y1460*, S1030_K1033delins* and W1158*;

I1084Sfs*15, P1946Hfs*30, F1523Sfs*27, H2384Tfs*12, T1574Pfs*61, S801Qfs*29, L524Wfs*6, Q232Rfs*12, P1423Lfs*36, S1065*, P928Rfs*2316, L516F , S893Pfs*27, S1382Yfs*2, L243*, H408Ifs*26, C1444Hfs*6, K1505Rfs*45, E1054Dfs*4, G1815Pfs*149, E72Afs*10, V2012Sfs*28, N2181Kfs*5, E371Kfs*53, E371Kfs*53 7, E1061Rfs*4, K1051Rfs*5, V1057*, L1692Rfs*50, C1178Afs*72, G587Kfs*19, C1311*, M784Ifs*17, T163Afs*13, I1493Yfs*57, E594Dfs*11, C1783Afs*16, and I1783Afs*16 at least one frame shift delete mutation selected from the group consisting of 61;

At least one frame shift selected from the group consisting of L1346Ffs*8, I1084Nfs*3, Q1209Tfs*25, P1947Tfs*19, S1172Qfs*7, P2077Afs*264, H397Afs*30, S1737Rfs*8, G77Afs*9 and S1598Kfs*19. frame shift insert mutation;

M2115_G2120dup, an inframe insert mutation;

at least one inframe delete mutation selected from the group consisting of S1680del K1588del and Q2216del;

X1203_splice, X1305_splice, X406_splice, X1021_splice, X1427_splice, X961_splice, X1465_splice, X1084_splice, X29_splice, X705_splice, X1378_splice, X406_splice, X1305_splice, X1576_splice, X266_splice, X525_splice 및 X406_splice X1465_splice로 이루어진 군으로부터 선택되는 적어도 하나의 적어도 하나의 스플라이스(splice ) mutations; and

CREBBP-CRAMP1L fusion, CREBP-NARFL fusion, TRAP1-CREBBP fusion, CREBBP-intragenic, CREBBP-TRAP1 fusion, CREBBP-TIGD7 fusion, TSG1-CREBBP fusion, CREBBP-SRRM2 fusion, CREBBP-TBL3 fusion and CREBBP-DNASE1 fusion consisting of at least one fusion mutation selected from the group.

In another embodiment of the present invention, the mutation of the gene encoding ESR1 may be one or more selected from the group consisting of the following mutations encoded by SEQ ID NO:2.

S554N, D538G, N290K, Y537S, D538G, S433P, G77D, P38L, Y537C, Y537N, D538G, E380Q, L536Q, L536R, Y537S, S463P, L536H, L536P, Y537D, S463P, V2153I, R463P, V V392I, D218N, Q159L, R37L, R243C, R394H, R477Q, R28H, R243H, A361V, E56K, E330K, L370F, H488Y, N519S, T585M, T228A, Q506H, R259Q, M109T, A350E, R269H, S576R, A269H, S576R D564Y, A307P, L410S, Y54C, K206T, L26M, G57C, C237Y, P113L, Q314K, R158C, R157Q, E203V, S338R, D369Y, A65V, D258Y, K32Q, A361E, A361T, R269C, G344D, P333T, R548H, V4 A207T, P25T, D374Y, N532K, S432L, A546D, E542G, V534E, G442R, V418E, F461V, L466Q, G442R, S329Y, Y80H, G160D, M421V, K252N, L540Q, L403R, R277S, E385D, T224I, G L117Q, M437I, G57S, G284E, D564N, N304H, H398P, R193G, K48N, P324S, A593V, A288T, T4A, R211S, R260K, L15V, K4349R, P325S, R363K, E470K, P147Q, V478I and R18349C at least one missense mutation;

at least one nonsense mutation selected from the group consisting of Y60*, C245*, E444*, R256* and K401*;

at least one frame shift delete mutation selected from the group consisting of L536Qfs*2, P99Hfs*10, I326Yfs*17, P99Hfs*10, G96Vfs*13 and *594fs*;

at least one frame shift insert mutation selected from the group consisting of L100Tfs*57, G521Rfs*18 and E275Gfs*5;

at least one inframe insert mutation selected from the group consisting of D538_L539insHD and Q500dup;

at least one inframe delete mutation selected from the group consisting of V422del and Y328_S329del; and

At least one fusion mutation selected from the group consisting of TACR1-ESR1 fusion, ESR1-NCOA3 fusion and ESR1-C6orf97 fusion.

In another embodiment of the present invention, the mutation of the gene encoding GATA3 may be one or more selected from the group consisting of the following mutations encoded by SEQ ID NO:3.

N331I, S175W, Y229H, C266S, M293K, R364S, R364G, R364T, R298W, P421L, M356V, G248R, E359K, T420M, S118F, T418M, S407L, A146T, S137L, G100S, P223L, G128W, S4 L347R, R366Q, R305L, P148L, S142L, S402F, P158L, P425I, R9H, H281R, V132I, S369Y, P148T, K387N, G342W, T279M, L347I, S172L, L114I, S213L, A286T, P163Q, G241F, R311S, P148T K358N, K292E, P98T, S82R, G232R, S82I, G143E, C287F, R275W, R9C, S93F, M356I, V337D, S121F, C183R, G278D, Q296K, L190P, S370R, A173T, L130H, S175L, S372F, P134S, S372F, P134S, S397Y G99S, S243Y, A310T, Q362R, N285K, D6H, A207D, P111S, S389I, G55C, S238R, W328C, T215I, H13R, L428Q, S139F, P424S, P111H, T108I, P299L, S230N, A441D, T71M, D335E, T335M at least one missense mutation selected from the group consisting of A176G, P135T and P95H;

at least one nonsense mutation selected from the group consisting of Q73*, R366*, R390*, K377* and S381*;

E359Afs*44, S407Afs*99, S237Afs*28, V378Cfs*26, P135Rfs*60, D335Pfs*16, P408Lfs*98, R329Gfs*17, G246Afs*19, L396Qfs*109, H123Pfs*69, A394436Pfs*110, A394436Pfs* 39, P408Qfs*97, T418Afs*86, P432Tfs*74, G443Vfs*32, P408Qfs*97, M438Wfs*37, T355Qfs*97, F430Sfs*38, G431Tfs*41, T355*, L416Pfs*83, S437Rfs*38, L396RfsHfs At least one frame shift delete selected from the group consisting of *107, S390Rfs*112, A441Pfs*34, P424Rfs*51, K387Rfs*17, C320Wfs*18, R330Mfs*20, N331Gfs*17 and C284Afs*10. ) mutations;

A441Hfs*44, D335Gfs*17, R330Efs*22, H434Pfs*42, S426Yfs*50, P408Afs*99, D335Gfs*17, P408Afs*99, G431Wfs*76, H434Pfs*73, D335Gfs*81, S426AIf 99, S436Lfs*71, G334Wfs*18, C320Lfs*32, S237Qfs*66, S237Qfs*66, S401Vfs*106, S413Qfs*94, P435Tfs*41, M422Dfs*85, V47Gfs*6, *444Lfs*63, A441Rfs*66 , N331Efs*21, S401Ffs*106, S426Afs*82, G314Rfs*38, H405Efs*103, N319Efs*33, T315Kfs*37, R330Nfs*24, H434Tfs*42, R69Qfs*234, C338Lfs*14, R330E4 *90, M356Nfs*15, T440Sfs*68, A332Cfs*20, T332Dfs*30, Y344Sfs*12, N333Kfs*19, G443Pfs*34, P419Afs*88, F430Lfs*77, S402Pfs*3, P435Rfs*42, M422Dfs*85 , S404Hfs*107, M442Hfs*65, N351Kfs*20, V337Gfs*21, H411Pfs*96, D335Vfs*35, T332Rfs*34, I361Rfs*11 and A313Sfs*39. shift insert) mutation;

an inframe insert mutation that is T221delinsPACCELLYVPYVL;

at least one inframe delete mutation selected from the group consisting of K358del, Y345del and M356_K387del;

at least one splice mutation selected from the group consisting of X349_splice and X350_splice; and

At least one fusion mutation selected from the group consisting of GATA3-intragenic and LOC100128811-GATA3 fusion.

In one embodiment of the present invention, the mutation of the gene encoding H3F3B may be one or more selected from the group consisting of the following mutations encoded by SEQ ID NO: 4.

at least one missense mutation selected from the group consisting of E106K, V47G, D78N, F105L, D107N, E106K, G13R, K5M, R3G, E98K, S32C, Q69K, R18L, A25V, R9S, Q6P, I78T and Q6H;

at least one nonsense mutation selected from the group consisting of E60*, E98* and R50*;

at least one frame shift delete mutation selected from the group consisting of R135Sfs*12, F105Kfs*33 and A2Pfs*35;

Q94Afs*4 frame shift insert mutation; and

A splice mutation that is X37_splice.

In one embodiment of the present invention, the mutation of the gene encoding MYD88 may be one or more selected from the group consisting of the following mutations encoded by SEQ ID NO: 5.

K275T, L265P, E139K, S243N, S219C, R301C, R5C, A13V, D184N, M67V, V27A, D288N, P19S, E70K, R301H, S296C, T84A, Y240C, P292T, I130M, T61I, G96D, Q262E, P83S, P11L, P83S at least one missense mutation selected from the group consisting of P9L, R41P, R94H and K271T;

at least one nonsense mutation selected from the group consisting of Q159*, Q189* and E172*;

a frame shift delete mutation that is R101Afs*19;

a splice mutation that is X228_splice; and

At least one fusion mutation selected from the group consisting of MYD88-ACAA1 fusion, MYD88-CTDSPL fusion, OXSR1-MYD88 fusion and MYD88-VILL fusion.

Since the mutation of at least one gene selected from the gene group consisting of the mutant genes, CREBBP, ESR1, GATA3, H3F3B and MYD88, which are the mutant genes discovered in the present invention, is correlated with the metastasis period of solid cancer patients, solid cancer It is possible to predict the difference in the treatment effect and survival rate of solid cancer according to the metastasis period of the patient.

However, the effect of the present invention is not limited to the above effect, and it should be understood to include all effects that can be inferred from the configuration of the invention described in the detailed description or claims of the present invention.

1 is a metastatic period-specific mutant gene of 63 ( FIGS. 1a to 1c ) identified through comparative analysis between transition period groups I, II, III and IV.
2 is a metastasis period-specific mutant gene of 90 ( FIGS. 2a to 2e ) identified through comparative analysis between transition period groups I and II + III+ IV.
FIG. 3 is a metastatic period-specific mutant gene of 33 ( FIGS. 3a to 3b ) identified through comparative analysis between transition period groups I + II and III + IV.
4 to 87 are graphs of the total survival rate or disease-free survival rate of a patient with solid cancer having a mutation in the gene (red) and a patient with solid cancer without a mutation in the gene (blue) for each gene specific to the metastasis period.

Prostate adenocarcinoma (PRAD) reported to The Cancer Genome Atlas (TCGA) in order to discover a metastasis period-specific marker for differential diagnosis, treatment strategy determination, or prognosis of solid cancer based on the difference in metastasis period of solid cancer patients. Machine learning using data was implemented. As a result, metastasis period-specific mutant genes for 157 solid cancers were found, and as a result of selecting genes that overlap with the data of MSKCC (provided by 10945 samples), five solid cancer metastasis period-specific markers (CREBBP, ESR1, GATA3, H3F3B) were selected. and MYD88) were discovered.

Hereinafter, the present invention will be described in detail.

1. Metastasis period-specific mutant gene in solid cancer patients

One aspect of the present invention is from the group consisting of CREBBP (CREB Binding Protein), ESR1 (Estrogen Receptor 1), GATA3 (GATA Binding Protein 3), H3F3B (H3.3 Histone B) and MYD88 (MYD88 Innate Immune Signal Transduction Adapter). To provide a marker composition for predicting treatment effect or prognosis diagnosis according to the metastasis period of a solid cancer patient, comprising a mutation of a gene encoding one or more selected.

Gene bank accession numbers of the genes are, respectively, CREBBP (Gene bank accession number: NM_004380), ESR1 (Gene bank accession number: NM_000125), GATA3 (Gene bank accession number: NM_001002295), H3F3B (Gene bank accession number: NM_005324), MYD88 (Gene bank accession number: NM_001172567).

In the present invention, the mutation of the gene encoding CREBBP may be one or more selected from the group consisting of the following mutations encoded by SEQ ID NO: 1.

Y2189S, Q1756E, S2394F, L829F, S977L, A259T, R1328M, G587R, R672L, T345I, Y1622H, D1480N, P988S, P1096A, R351H, G689R, A2265V, Q662H, R1446C, R1446H, W1472R W Y Y, R1446H, W1472R R1446S, L1499Q, D1435N, R1446P, Y1450N, Y1482C, W1502R, Y1482N, Y1482D, L1499R, W1502C, W1472G, W1502L, I1431S, R1446C, I1431N, Y1503N, V1802M, T396K1778L, R1782V, E5503N, V1802M, T396K1778L, R1782V R1664C, T1260M, T950M, C1408Y, R424Q, R625H, R1081H, R601Q, P248L, M1798I, S1072F, P949L, A1824T, R1682H, R1428C, A206V, Y1167C, A2144V, V1650I, A2591, S136M, R1427W16341, T872, V E1243D, F1439L, R1319Q, R714C, E1012K, R1347W, D1481G, D1273N, A1944P, K1809R, E1247K, P2038L, G706R, P766L, P928S, R1800Q, V1371F, R714H, S945L, S1392Q, S945L, S32557T, R669W, R32557T R1602H, R519K, C1240Y, N645K, P107L, Y1973H, N2141K, S554F, R742L, Q963H, T862M, G21D, A698V, A533T, G2010E, A1510V, P907S, R1851H, Q2292R, Q11249H, K1498Q, N530S, K1498Q, N530S R1866C, P2285H, A1398V, M2192I, T1932M, Q1698L, G1699D, E1020G, N522S, P1889L, H2178Y, P2011S, I1455N, S2065N, K1269N, Q1928H, A259S, R2353W, Y1828C, N797K, P496L, R1378L, S791T, G1404S, Q1941L, L1451211S, Q1941L, L1451211R, S2065N, L1451211R, S2065N, K1269N, Q1928H, A259S V992L, I678M, G252C, H1470L, Q1113H, Q102R, D2433G, E1099K, T1210A, L869F, T537P, V460F, E2404K, A787V, M1021I, P552L, L833V, E637K, P2331S, D1156M, T2066T, R1964C, A190 S767Y, E1459Q, E1452K, N374I, Q1879E, G2162R, E1400Q, F1540S, S893W, E1501K, H1351D, S479I, H1485Y, D1276H, Q2299K, E1626Q, T320I, Q1152E, S2377L, K1271T, R1433H, L1271T, R1433H, K1271T, R, A2419V, Y1125H, S1207F, E1088K, R1317K, V2149M, S139N, P975S, G1305D, R624C, T4668S, P1953S, S247F, S2361F, T1242S, V1429M, L33F, D1543V, S566F, R1341P, P2383L, S237704 L2198Q, S554F, P2352L, P2415L, G219V, P1489T, QP1257HS, P1488L, E548K, D1309N, V1371D, E1400K, E1576D, A1739V, Q610H, L161M, W1545L, C1199F, H2384R, G786P, H2384R, E5281963D A924T, L1181R, F22L, V1818M, P432S, Q21 03K, V1704F, E371Q, D1420A, P2331L, R2195K, P1110L, V824M, D599N, G268R, P2187L, P2155S, S2345F, E996K, G591S, A2046V, Q2324K, M2391I, V1429A, G2132V, P1429A, G2132V P248S, P308S, S1030F, P957A, S646N, R1985L, G1418V, M481V, P543L, P2311L, A2170T, A924V, E1715K, D1263N, P1997L, P1951L, R1173G, P1991L, H17E12Y, S232V2L, H17E12Y2, L232V21374 M1625N, P1208S, H1738N, M1981I, Q1863R, L679F, W1745C, G2236E, G1753V, A1093V, V2056M, A476T, H1413P, V1722E, A924S, R1866L, R1926W, F1632V, K1870P, C398Y, G1870N, C398Y at least one missense mutation selected from the group consisting of S121I, G1411R, N1350I, T1332P, P1488T, D1480H and I1483S;

G572*, Q771*, Q497*, R1360*, R1173*, Q1073*, Q1796*, R1498*, R1103*, R1341*, Q1756*, Q887*, Q1856*, S985*, E349*, R1672*, Q1928* , Y1230*, S1065*, Q2235*, Y1726*, R440*, Y659*, E1243*, Q719*, E1205*, R1392*, R386*, L243*, Q540*, R424*, Q517*, E1000*, Q1148 *, S547*, Q357*, R370*, E1626*, S381*, Q2103*, S331*, Q1852*, Y1828*, K68*, Q963*, Q356*, R2004*, E1559*, Q203*, Q919*, at least one nonsense mutation selected from the group consisting of K1051*, Q1041*, Q1941*, Y1460*, S1030_K1033delins* and W1158*;

I1084Sfs*15, P1946Hfs*30, F1523Sfs*27, H2384Tfs*12, T1574Pfs*61, S801Qfs*29, L524Wfs*6, Q232Rfs*12, P1423Lfs*36, S1065*, P928Rfs*2316, L516F , S893Pfs*27, S1382Yfs*2, L243*, H408Ifs*26, C1444Hfs*6, K1505Rfs*45, E1054Dfs*4, G1815Pfs*149, E72Afs*10, V2012Sfs*28, N2181Kfs*5, E371Kfs*53, E371Kfs*53 7, E1061Rfs*4, K1051Rfs*5, V1057*, L1692Rfs*50, C1178Afs*72, G587Kfs*19, C1311*, M784Ifs*17, T163Afs*13, I1493Yfs*57, E594Dfs*11, C1783Afs*16, and I1783Afs*16 at least one frame shift delete mutation selected from the group consisting of 61;

At least one frame shift selected from the group consisting of L1346Ffs*8, I1084Nfs*3, Q1209Tfs*25, P1947Tfs*19, S1172Qfs*7, P2077Afs*264, H397Afs*30, S1737Rfs*8, G77Afs*9 and S1598Kfs*19. frame shift insert mutation;

M2115_G2120dup in-frame insert mutation;

at least one inframe delete mutation selected from the group consisting of S1680del K1588del and Q2216del;

X1203_splice, X1305_splice, X406_splice, X1021_splice, X1427_splice, X961_splice, X1465_splice, X1084_splice, X29_splice, X705_splice, X1378_splice, X406_splice, X1305_splice, X1576_splice, X266_splice, X525_splice 및 X406_splice X1465_splice로 이루어진 군으로부터 선택되는 적어도 하나의 적어도 하나의 스플라이스(splice ) mutations; and

CREBBP-CRAMP1L fusion, CREBP-NARFL fusion, TRAP1-CREBBP fusion, CREBBP-intragenic, CREBBP-TRAP1 fusion, CREBBP-TIGD7 fusion, TSG1-CREBBP fusion, CREBBP-SRRM2 fusion, CREBBP-TBL3 fusion and CREBBP-DNASE1 fusion consisting of at least one fusion mutation selected from the group.

In the present invention, the mutation of the gene encoding ESR1 may be one or more selected from the group consisting of the following mutations in the amino acid sequence encoded by SEQ ID NO: 2.

S554N, D538G, N290K, Y537S, D538G, S433P, G77D, P38L, Y537C, Y537N, D538G, E380Q, L536Q, L536R, Y537S, S463P, L536H, L536P, Y537D, S463P, V2153I, R463P, V V392I, D218N, Q159L, R37L, R243C, R394H, R477Q, R28H, R243H, A361V, E56K, E330K, L370F, H488Y, N519S, T585M, T228A, Q506H, R259Q, M109T, A350E, R269H, S576R, A269H, S576R D564Y, A307P, L410S, Y54C, K206T, L26M, G57C, C237Y, P113L, Q314K, R158C, R157Q, E203V, S338R, D369Y, A65V, D258Y, K32Q, A361E, A361T, R269C, G344D, P333T, R548H, V4 A207T, P25T, D374Y, N532K, S432L, A546D, E542G, V534E, G442R, V418E, F461V, L466Q, G442R, S329Y, Y80H, G160D, M421V, K252N, L540Q, L403R, R277S, E385D, T224I, G L117Q, M437I, G57S, G284E, D564N, N304H, H398P, R193G, K48N, P324S, A593V, A288T, T4A, R211S, R260K, L15V, K4349R, P325S, R363K, E470K, P147Q, V478I and R18349C at least one missense mutation;

at least one nonsense mutation selected from the group consisting of Y60*, C245*, E444*, R256* and K401*;

at least one frame shift delete mutation selected from the group consisting of L536Qfs*2, P99Hfs*10, I326Yfs*17, P99Hfs*10, G96Vfs*13 and *594fs*;

at least one frame shift insert mutation selected from the group consisting of L100Tfs*57, G521Rfs*18 and E275Gfs*5;

at least one inframe insert mutation selected from the group consisting of D538_L539insHD and Q500dup;

at least one inframe delete mutation selected from the group consisting of V422del and Y328_S329del; and

At least one fusion mutation selected from the group consisting of TACR1-ESR1 fusion, ESR1-NCOA3 fusion and ESR1-C6orf97 fusion.

In the present invention, the mutation of the gene encoding GATA3 may be one or more selected from the group consisting of the following mutations in the amino acid sequence encoded by SEQ ID NO: 3.

N331I, S175W, Y229H, C266S, M293K, R364S, R364G, R364T, R298W, P421L, M356V, G248R, E359K, T420M, S118F, T418M, S407L, A146T, S137L, G100S, P223L, G128W, S4 L347R, R366Q, R305L, P148L, S142L, S402F, P158L, P425I, R9H, H281R, V132I, S369Y, P148T, K387N, G342W, T279M, L347I, S172L, L114I, S213L, A286T, P163Q, G241F, R311S, P148T K358N, K292E, P98T, S82R, G232R, S82I, G143E, C287F, R275W, R9C, S93F, M356I, V337D, S121F, C183R, G278D, Q296K, L190P, S370R, A173T, L130H, S175L, S372F, P134S, S372F, P134S, S397Y G99S, S243Y, A310T, Q362R, N285K, D6H, A207D, P111S, S389I, G55C, S238R, W328C, T215I, H13R, L428Q, S139F, P424S, P111H, T108I, P299L, S230N, A441D, T71M, D335E, T335M at least one missense mutation selected from the group consisting of A176G, P135T and P95H;

at least one nonsense mutation selected from the group consisting of Q73*, R366*, R390*, K377* and S381*;

E359Afs*44, S407Afs*99, S237Afs*28, V378Cfs*26, P135Rfs*60, D335Pfs*16, P408Lfs*98, R329Gfs*17, G246Afs*19, L396Qfs*109, H123Pfs*69, A394436Pfs*110, A394436Pfs* 39, P408Qfs*97, T418Afs*86, P432Tfs*74, G443Vfs*32, P408Qfs*97, M438Wfs*37, T355Qfs*97, F430Sfs*38, G431Tfs*41, T355*, L416Pfs*83, S437Rfs*38, L396RfsHfs At least one frame shift delete selected from the group consisting of *107, S390Rfs*112, A441Pfs*34, P424Rfs*51, K387Rfs*17, C320Wfs*18, R330Mfs*20, N331Gfs*17 and C284Afs*10. ) mutations;

A441Hfs*44, D335Gfs*17, R330Efs*22, H434Pfs*42, S426Yfs*50, P408Afs*99, D335Gfs*17, P408Afs*99, G431Wfs*76, H434Pfs*73, D335Gfs*81, S426AIf 99, S436Lfs*71, G334Wfs*18, C320Lfs*32, S237Qfs*66, S237Qfs*66, S401Vfs*106, S413Qfs*94, P435Tfs*41, M422Dfs*85, V47Gfs*6, *444Lfs*63, A441Rfs*66 , N331Efs*21, S401Ffs*106, S426Afs*82, G314Rfs*38, H405Efs*103, N319Efs*33, T315Kfs*37, R330Nfs*24, H434Tfs*42, R69Qfs*234, C338Lfs*14, R330E4 *90, M356Nfs*15, T440Sfs*68, A332Cfs*20, T332Dfs*30, Y344Sfs*12, N333Kfs*19, G443Pfs*34, P419Afs*88, F430Lfs*77, S402Pfs*3, P435Rfs*42, M422Dfs*85 , S404Hfs*107, M442Hfs*65, N351Kfs*20, V337Gfs*21, H411Pfs*96, D335Vfs*35, T332Rfs*34, I361Rfs*11 and A313Sfs*39. shift insert) mutation;

an inframe insert mutation that is T221delinsPACCELLYVPYVL;

at least one inframe delete mutation selected from the group consisting of K358del, Y345del and M356_K387del;

at least one splice mutation selected from the group consisting of X349_splice and X350_splice; and

At least one fusion mutation selected from the group consisting of GATA3-intragenic and LOC100128811-GATA3 fusion.

In the present invention, the mutation of the gene encoding H3F3B may be one or more selected from the group consisting of the following mutations in the amino acid sequence encoded by SEQ ID NO: 4.

at least one missense mutation selected from the group consisting of E106K, V47G, D78N, F105L, D107N, E106K, G13R, K5M, R3G, E98K, S32C, Q69K, R18L, A25V, R9S, Q6P, I78T and Q6H;

at least one nonsense mutation selected from the group consisting of E60*, E98* and R50*;

at least one frame shift delete mutation selected from the group consisting of R135Sfs*12, F105Kfs*33 and A2Pfs*35;

Q94Afs*4, a frame shift insert mutation; and

A splice mutation that is X37_splice.

In the present invention, the mutation of the gene encoding MYD88 may be one or more selected from the group consisting of the following mutations in the amino acid sequence encoded by SEQ ID NO: 5.

K275T, L265P, E139K, S243N, S219C, R301C, R5C, A13V, D184N, M67V, V27A, D288N, P19S, E70K, R301H, S296C, T84A, Y240C, P292T, I130M, T61I, G96D, Q262E, P83S, P11L, P83S at least one missense mutation selected from the group consisting of P9L, R41P, R94H and K271T;

at least one nonsense mutation selected from the group consisting of Q159*, Q189* and E172*;

a frame shift delete mutation that is R101Afs*19;

a splice mutation that is X228_splice; and

At least one fusion mutation selected from the group consisting of MYD88-ACAA1 fusion, MYD88-CTDSPL fusion, OXSR1-MYD88 fusion and MYD88-VILL fusion.

In the present invention, the solid cancer is bladder cancer, colon cancer, stomach cancer, lung cancer, lung adenocarcinoma, breast invasive ductal carcinoma (Breast invasive ductal carcinoma) , Colon adenocarcinoma, Prostate adenocarcinoma, Bladder urothelial carcinoma, Lung squamous cell carcinoma, Cutaneous melanoma, Cancer of unknown origin of unknown primary), Pancreatic adenocarcinoma, Glioblastoma multiforme, Colorectal adenocarcinoma, High grade serous ovarian cancer, Stomach adenocarcinoma, renal cell carcinoma ( Renal clear cell carcinoma), esophageal adenocarcinoma, testicular cancer, or intrahepatic cholangiocarcinoma.

In the present invention, the metastasis period-specific marker of a solid cancer patient can be used to predict the risk of metastasis over time after the onset of cancer, and can be used for predicting the prognosis (survival) of a patient with metastasis. have.

In addition, the present invention includes an agent capable of detecting a mutation of one or more genes encoding one or more selected from the group consisting of CREBBP, ESR1, GATA3, H3F3B and MYD88. A diagnostic composition is provided.

A composition for predicting treatment effect or prognosis diagnosis according to the metastasis period of a solid cancer patient, comprising an agent capable of detecting a mutation in a gene encoding one or more selected from the group consisting of CREBBP, ESR1, GATA3, H3F3B and MYD88.

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, but is not limited to, all known cancers and neoplastic conditions, whether characterized as malignant, benign, soft or solid, and cancers of all stages and grades, including pre- and post-metastatic cancers. Bladder cancer, colon cancer, stomach cancer, lung cancer, lung adenocarcinoma, breast invasive ductal carcinoma, colon adenocarcinoma, Prostate adenocarcinoma, Bladder urothelial carcinoma, Lung squamous cell carcinoma, Cutaneous melanoma, Cancer of unknown primary, Pancreatic ductal adenocarcinoma Pancreatic adenocarcinoma, Glioblastoma multiforme, Colorectal adenocarcinoma, High grade serous ovarian cancer, Stomach adenocarcinoma, Renal clear cell carcinoma, esophageal cancer Esophageal adenocarcinoma), testicular cancer, and intrahepatic cholangiocarcinoma.

In the present invention, the term 'gene' and its variants include DNA fragments involved in the production of polypeptide chains; 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).

In the present invention, the term 'metastasis period' refers to the time point at which metastasis occurs in metastatic solid cancer.

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 ) mutations, in-frame mutations (or in-frame mutations), splice mutations, splice_region mutations, nonstop mutations, nonstart mutations and fusions ) may have at least one mutation selected from the group consisting of mutations. The frame shift mutation may be at least one of a frame shift insert (FS ins) mutation and a frame shift delete mutation (FS del), and the in-frame mutation is an in-frame insertion (in-frame) mutation. It may be at least one of a frame insertion, IF ins) mutation and an in-frame delete (IF del) mutation.

In the present invention, the term 'missense mutation' refers to a mutation in which one base in a DNA base sequence is substituted with another base to change the codon of an amino acid to another codon.

In the present invention, the term 'nonsense mutation' refers to a mutation in which a part of a specific nucleotide sequence of a gene is converted to a stop codon, so that protein synthesis is no longer made.

In the present invention, the term 'frame shift insertion' refers to a mutation that occurs when one or more nucleotides are added to DNA to shift the decoding frame of the genetic code.

In the present invention, the term 'frame shift deletion' refers to a mutation in which one or more nucleotides are deleted in DNA and the reading frame of the genetic code is shifted and shifted.

In the present invention, the term 'in-frame insertion' refers to a mutation in which a specific nucleotide sequence of a gene has been inserted, but the remaining amino acids except for the amino acid by the inserted nucleotide sequence are not changed.

In the present invention, the term 'in-frame deletion' refers to a mutation in which a specific nucleotide sequence of a gene is deleted, but the remaining amino acids except for the amino acid caused by the deleted nucleotide sequence are not changed.

In the present invention, the term 'splice site mutation' refers to a gene mutation in which a nucleotide at a specific position of a gene is substituted.

In the present invention, the term 'non-start mutation' refers to a gene mutation in which the start codon is lost due to base substitution or frame shift.

As used herein, the term 'non-stop mutation' refers to a gene mutation in which a stop codon is lost due to base substitution or frame shift.

In the present invention, the term 'fusion mutation' refers to a gene mutation in which a structural abnormality occurs through structural rearrangement (translocation, inversion, deletion, and insertion) or non-structural rearrangement (over-translation, etc.) of specific genes.

The term "X#Y" in reference to mutations 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 "G1717V" with respect to a BAZ2B polypeptide indicates that glycine is present at amino acid number 1717 of the wild-type BAZ2B sequence and that glycine has been replaced by valine in the mutant BAZ2B sequence.

The term "*" in reference to mutations in a polypeptide sequence is readily recognized in the art where "*" may be used to indicate translation stop codons in the one and three amino acid codes, e.g., nonsense mutations * indicates that the amino acid synthesis at the corresponding amino acid position is terminated.

The term "_" with respect to a mutation in a polypeptide sequence is readily recognized in the art, where "_" indicates a range, for example, when A200_C240 is used, the alanine of the 200 amino acid sequence of the polypeptide. ) to the cysteine located at the 240 amino acid sequence.

The term "del" in reference to a mutation in a polypeptide sequence is readily recognized in the art where "del" denotes a deletion, e.g., when used as V7del, the 7th position in a particular sequence, the valine , and when used as V76_S79del, it means a mutation in which a deletion from valine located at position 76 to serine located at position 79 in a specific sequence occurs.

The term "ins" with respect to a mutation in a polypeptide sequence is art-recognized as self-evident in the art where "ins" denotes an insertion, e.g., when used as V76_S77insV, from valine at position 76 to 77 in a particular sequence. It means a mutation in which valine is inserted between the serine located at the berth.

The term "dup" in reference to a mutation in a polypeptide sequence is art-recognized as is self-evident in the art, where "dup" denotes a deletion, e.g., when used as V7dup, the 7th position of the sequence is Valine. This duplicate represents a sequence having two valines, and when V76_S79dup is used, the sequence of the same sequence from valine located at position 76 to serine located at position 79 in a specific sequence refers to a mutation in which replication has occurred.

The term "fs" with respect to mutations in a polypeptide sequence is art-recognized as self-evident in the art where "fs" stands for a frame shift, e.g. when used as V97SfsTer23 or V97Sfs*23, the 97th position in a particular sequence It indicates that the valine located at position is changed to serine and there is a termination codon (Termination, Ter) at position 23 (120th amino acid sequence) after it, and when V76_S79*? , means a mutation in which a new stop codon does not appear.

The term "fusion" in reference to a mutation in a polypeptide sequence is self-recognized in the art where "fusion" refers to the fusion of genes, eg BCR, which is known to cause chronic myeloid leukemia. -ABl fusion refers to a fusion mutation in which the BCR and ABL genes are fused by translocation. The fusion method is not limited thereto, but may be fused through structural rearrangement (translocation, inversion, deletion and insertion) or non-structural rearrangement (overtranslation, etc.).

Next generation sequencing (NGS), RT-PCR, direct nucleic acid sequencing, and microarray can be used as an analysis method for diagnosing the prognosis of solid cancer using the mutation of the gene, and the gene of the present invention Any method that can confirm the existence 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 mutation 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. - an RNA comprising a single-stranded region, or a hybrid comprising DNA and RNA, which may be single-stranded or more typically double-stranded or may comprise single- and double-stranded regions

contains molecules. 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 to provide a kit for predicting treatment effect or prognosis diagnosis according to the metastasis period of a solid cancer patient, comprising the composition.

The kit of the present invention prepared as described above is very economical because it saves time and money compared to the existing general gene mutation search 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 examined quickly and simply through next generation sequencing (NGS). In the case of testing mutations by existing analysis methods such as SSCP, cloning, direct sequencing, and RFLP (Restriction Fragment Length Polymorphism), 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 existing method, the average cost of reagents is less than half per experiment, so even greater cost savings can be expected when considering the researcher's labor costs.

2. Method of providing information necessary for prognosis diagnosis of solid cancer using metastatic period-specific mutant gene

Another aspect of the present invention comprises the steps of preparing a sample DNA from a sample of a solid cancer patient with a known time point (metastasis period) at which metastasis occurred; amplifying the sample DNA using the kit; confirming the presence or absence of a metastasis period-specific marker from the amplification result; treating a solid cancer patient for which a metastasis period-specific marker has been identified, or treating a solid cancer treatment candidate by any method; And when any solid cancer treatment candidate material or any treatment method improves or treats solid cancer, adopting it as a treatment candidate or treatment method suitable for a solid cancer patient whose metastasis period-specific marker has been identified; metastasis of solid cancer patients, including Provided is a method for providing information necessary to determine a difference in cancer treatment effect over time.

In one embodiment of the present invention, the method may be a mutation of a gene encoding one selected from the group consisting of CREBBP, ESR1, GATA3, H3F3B and MYD88, which are the metastasis period-specific markers.

In another embodiment of the present invention, the metastasis period group I-specific metastasis period-specific marker among metastatic solid cancer patients may be a mutation in genes encoding ESR1, GATA3 and MYD88.

In another embodiment of the present invention, the metastasis period group II-specific metastasis period-specific marker among metastatic solid cancer patients may be a mutation in a gene encoding H3F3B.

In another embodiment of the present invention, the metastasis period group III-specific metastasis period-specific marker among metastatic solid cancer patients may be a mutation in genes encoding CREBBP, ESR1 and GATA3.

Another aspect of the present invention comprises the steps of preparing a sample DNA from a sample of a solid cancer patient; amplifying the sample DNA using the kit; and confirming the presence or absence of a metastasis period-specific marker from the amplification result.

For the description of the kit for prognostic diagnosis of solid cancer, refer to '1. Since it is the same as described in 'Metastatic period-specific mutant gene in solid cancer patients', a detailed description will be omitted.

Any of the therapeutic candidate substances may be a therapeutic agent commonly used for the treatment of solid cancer or a novel substance whose therapeutic effect on solid cancer is unknown, but is not limited thereto. By treating any of the above candidate therapeutic substances to a solid cancer patient having a recurrence-specific marker and then confirming the therapeutic effect, it can be determined whether the therapeutic candidate substance is effective in a specific patient group. If there is a treatment effect for solid cancer, the treatment effect can be predicted to be high when applied to a patient group having the same metastasis period-specific marker, so it can provide useful information for determining a treatment strategy. In addition, if a therapeutic effect does not appear when any treatment candidate is used, treatment strategy can be designed efficiently because unnecessary treatment is not required by not proceeding with treatment for the patient group having the same recurrence-specific marker. have.

Any solid cancer treatment method is also applicable instead of any of the above treatment candidates, and by confirming the therapeutic effect in a patient group having a specific metastasis period-specific marker, it can be determined whether to apply to a patient group having the same metastasis period-specific marker. . When confirming the therapeutic effect in a patient group having a metastasis period-specific marker, any treatment candidate substance and any solid cancer treatment method may be combined.

As used herein, the term 'sample' includes any biological sample obtained from a patient. Samples include whole blood, plasma, serum, red blood cells, white blood cells (eg peripheral blood mononuclear cells), ductal fluid, ascites, pleural efflux, nipple aspirate, lymphatic fluid (eg, disseminated tumors of lymph nodes). cells), bone marrow aspirate, saliva, urine, feces (i.e. feces), sputum, bronchial lavage fluid, tears, microneedle aspirate (e.g. harvested by random mammary microneedle aspiration), any other bodily fluid, tissue A sample (eg tumor tissue) such as a tumor biopsy (eg puncture biopsy) or lymph node (eg sentinel lymph node biopsy), a tissue sample (eg tumor tissue), eg surgical resection of a tumor and cell extracts thereof.

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 'subject' includes subjects other than humans diagnosed or suspected of having solid cancer.

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

As used herein, the term 'overall survival' includes a clinical endpoint describing a patient who is alive for a finite time after being diagnosed with or treated for a disease, such as cancer, and the survival rate with or without cancer recurrence. means possibility.

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).

In the present invention, by analyzing the presence of a mutation in the gene of the present invention in a sample of a solid cancer patient, it is possible to determine what prognosis an individual having the target sample has for cancer. This method can also be achieved by comparing the total survival or disease-free survival of subjects 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 who has no history of metastasis, recurrence, death, etc. after cancer has developed.

A sample of an individual suspected of having cancer refers to a sample of an individual or tissue in which cancer or tumor has already occurred or is expected to occur, and is a target sample for diagnosing the prognosis.

The method of providing information necessary for prognostic diagnosis of solid cancer according to the metastasis period of the solid cancer patient can predict the total survival rate or disease-free survival rate of the solid cancer patient. For example, in the method, a mutation is identified in a gene encoding CREBBP, ESR1, GATA3, H3F3B and MYD88, and in the case of a solid cancer patient, the survival rate of the solid cancer patient is lower than the survival rate of a person in which the mutation is not identified in the gene. or, determining that the recurrence rate of solid cancer of the solid cancer patient is higher than that of solid cancer of a person whose mutation is not confirmed in the gene; may further include.

As such, using the mutations of the present invention for CREBBP, ESR1, GATA3, H3F3B and MYD88, the content that there is a difference in gene mutation according to the onset and metastasis period of cancer, particularly solid cancer, has not yet been revealed. In addition, it has not yet been revealed that the prognosis for solid cancer can be diagnosed in a specific metastasis period using the mutation of the present invention. 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 mutations in the above genes can be used as diagnostic markers for predicting the difference in the treatment effect of solid cancer according to the metastasis period of the solid cancer patient or diagnosing the prognosis of the solid cancer patient.

The method for providing information necessary for predicting the difference in the treatment effect of solid cancer according to the metastasis period of the solid cancer patient of the present invention is to diagnose the genetic mutation of the solid cancer based on the metastasis period, increase the survival rate of the solid cancer patient, or reduce the recurrence rate It can be used to lower Through the method for prognostic diagnosis of solid cancer of the present invention, it is possible to predict the therapeutic effect of solid cancer, or the survival or recurrence rate of solid cancer patients, using information on gene mutations according to the onset and metastasis period of solid cancer. It can provide information not only in the discovery of therapeutic agents, but also in the selection of therapies, so that it is possible to efficiently design a therapeutic strategy for solid cancer.

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

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

[Example]

Example 1. Securing genetic information and clinical information

To determine whether the genes of the present invention (CREBBP, ESR1, GATA3, H3F3B and MYD88, hereinafter also referred to as 'candidate genes') can be utilized as solid cancer markers according to the metastasis period, The Cancer Genome Atlas (TCGA) Data on the gender, metastatic interval, and age of 500 patients with metastatic solid cancer for whom both genetic and clinical information were secured were obtained and used for analysis. Table 1 below shows data on the sex and metastasis period (time of metastasis) of solid cancer patients. The above candidate genes are genes that have been mutated in patients with solid cancer depending on the metastasis period.

Sum Number of patients (persons) ratio(%) gender Male 259 51.8 Female 241 48.2 transition period ≤12 144 28.8 13-36 150 30 37-120 137 27.4 ≥121 69 13.8 age ≤50 140 28 51 to 60 132 26.4 61-70 165 33 ≥71 63 12.6 total number of patients 500 people

Example 2. Confirmation of utility as a metastasis period-specific marker

Of the 500 patients with TCGA-reported solid cancer, 4 groups were group I (12 months or less), group II (13-36 months), group III (37-120 months), and group IV (121 months or longer) classified according to metastasis period. classified as shown in Table 2 below.

Comparison between groups in the transition period test set type Detail note test set 1 Transition period Ⅰ vs Ⅱ vs Ⅲ vs Ⅳ Comparative analysis of metastasis period (less than 12 months vs 13-36 months vs 37-120 months vs 121 months or more) test set 2 Transition period Ⅰ vs Ⅱ + Ⅲ + Ⅳ Comparative analysis of patients under 12 months vs. over 13 months test set 3 Transition period Ⅰ + Ⅱ vs Ⅲ + Ⅳ Comparative analysis of patients under 36 months vs. over 37 months test set 4 Transition period Ⅰ + Ⅱ + Ⅲ vs Ⅳ Comparative analysis of patients under 120 months vs. over 121 months Results of comparative analysis between groups in the transition period test set type Transition period-specific genes Transition period Ⅰ A2M, ADAMTSL5, ARL2BP, B4GALT3, BHLHE22, C11orf54, C8orf34, CCDC14, CCNJL, CD109, CERCAM, CFAP57, CLEC4G, CPO, CTNNBL1, DCAF13, DNAH1, DNAH9, ENG, ESR1, GDA, GLI4, GMPPA3, FGG, GATA3, FGG, HNRNPA0, HOXC10, ICAM5, IL6ST, ITGB3, KCNK2, KRTAP5-2, LAMC3, LILRB4, MMP16, MRPS9, MYD88, MYH7B, NIPAL3, NUP58, OR4D10, P4HB, PCDHA12, PNPT1, PPP1R15A RL PPP1R15A RL PPP1R15 RNF6, SCML4, STAT4, STK38L, TGM4, TIE1, TMEM229A, TMPRSS13, UNKL, VPS37D, ZBTB17, ZC3H3, ZNF730, ZNF783 Transition period Ⅱ A2M, ADAMTSL2, ADAMTSL5, ADCK5, ADRA2C, AHCY, AIMP2, ALKBH3, AQP11, ARMC10, ASPHD2, C11orf87, C14orf28, C20orf144, C2orf68, CCDC152, CCTSO CCT5, CDKL1, CEP85, CERCAM, DC CLPSCY4G, CERCAM DNAH1, ENO3, EPS15, ETV7, FAM131B, FAM113A, FAM221A, FAM227B, FBXO32, FEZF1, GJC3, GLCCI1, GPC1, GPR87, GPR88, GREB1, GRN, GYS2, H3F3B, HOXD12, HPGDS, IERHS5 KAZALD1, KCNK9, KIAA1524, KRT17, KRT39, LAS1L, MAT1A, MBOAT7, MED16, MFSD6, MRM2, NEDD1, NNMT, NUP58, OR1L8, OR1N2, OR2PTAK1, OR5H15, OR5L1, PARREVB, POUPLK, POUPL, N SAG, SLC43A1, SPDYA, STXBP2, SYTL1, TBL1X, TIE1, TMEM229A, TMPRSS113, TRAPPC5, TTC22, UNC5A, UNC5D, VRK3, ZNF730 transition period Ⅲ AAK1, ANO9, ASPDH, B4GALT3, BHLHE22, CCNJL, CR1, CREBBP, DNAH9, ESR1, FXR1, FZD1, GATA3, GDA, GLI4, GMPPA, HIST2H2BE, HNRNPA0, IGF2R, LILRB4, ORLRRIQ104, METTL13, MXI4D104, METTL13, SCNN1D, STAT4, STK38L, TMEM117, TMEM229A, UBD, UNKL, ZC3H3 Transition period IV NA

2-1. Comparative analysis between each group (test set 1 - transition period I vs Ⅱ vs Ⅲ vs Ⅳ)

In Table 2, for each of the four metastatic period groups divided by group, the association between the occurrence of mutations in candidate genes and the metastatic period of metastatic solid cancer patients was confirmed. A P-value of less than 0.05 was considered as statistically significant and excavated as a metastasis period-specific marker. Tables 3 to 6 below show information on candidate genes related to test set 1.

gene mutation
number Mutation (%) Saito
band Mutation type transition period group Fisher (p-value) cut missense in-frame Etc I II III IV A2M 17 3.40 12p13.31 6 11 0 0 0 10 7 0 0.0009143 ADAMTSL5 5 1.00 19p13.3 2 3 0 0 5 0 0 0 0.004852 ARL2BP 2 0.40 16q13 One One 0 0 0 0 0 2 0.01881 B4GALT3 4 0.80 1q23.3 One 3 0 0 0 0 4 0 0.01457 BHLHE22 4 0.80 8q12.3 0 2 2 0 0 0 4 0 0.01457 C11orf54 2 0.40 11q21 0 2 0 0 0 0 0 2 0.01881 C8orf34 6 1.20 8q13.2 0 6 0 0 0 6 0 0 0.003098 CCDC14 5 1.00 3q21.1 2 3 0 0 2 0 0 3 0.008878 CCNJL 4 0.80 5q33.3 0 4 0 0 0 0 One 3 0.003126 CD109 10 2.00 6q13 2 8 0 0 One 5 0 4 0.008275 CERCAM 7 1.40 9q34.11 One 6 0 0 6 0 One 0 0.01549 CFAP57 7 1.40 1p34.2 0 7 0 0 0 4 0 3 0.006001 CLEC4G 4 0.80 19p13.2 2 2 0 0 4 0 0 0 0.02125 CPO 5 1.00 2q33.3 2 3 0 0 5 0 0 0 0.004852 CTNNBL1 5 1.00 20q11.23 0 4 One 0 2 0 0 3 0.008878 DCAF13 9 1.80 8q22.3 2 7 0 0 0 7 2 0 0.01143 DDIT3 4 0.80 12q13.3 0 2 0 2 0 One One 2 0.133 DNAH1 30 6.00 3p21.1 5 25 0 0 17 3 7 3 0.004847 DNAH9 45 9.00 17p12 9 36 0 0 16 23 6 0 0.00008715 DNAJC4 One 0.20 11q13.1 0 One 0 0 0 0 0 One 0.138

gene mutation
number Mutation (%) Saito
band Mutation type transition period group Fisher (p-value) cut missense in-frame Etc I II III IV ENG 5 1.00 9q34.11 0 5 0 0 0 5 0 0 0.01349 ESR1 20 4.00 6q25.1-q25.2 3 17 0 0 3 0 6 11 0.00000117 FGG 2 0.40 4q32.1 2 0 0 0 0 0 0 2 0.01881 GATA3 8 1.60 10p14 4 4 0 0 0 One 3 4 0.007805 GDA 7 1.40 9q21.13 0 7 0 0 0 0 6 One 0.002415 GLI4 4 0.80 8q24.3 0 4 0 0 0 0 4 0 0.01457 GMPPA 4 0.80 2q35 0 4 0 0 0 0 4 0 0.01457 HNRNPA0 5 1.00 5q31.2 One 3 One 0 0 0 5 0 0.002967 HOXC10 5 1.00 12q13.13 One 4 0 0 One 0 0 4 0.0009958 ICAM5 7 1.40 19p13.2 2 5 0 0 4 0 0 3 0.004623 IL6ST 6 1.20 5q11.2 One 5 0 0 0 6 0 0 0.003098 ITGB3 11 2.20 17q21.32 One 10 0 0 One 8 2 0 0.03013 KCNK2 3 0.60 1q41 0 3 0 0 0 0 0 3 0.00253 KRTAP5-2 6 1.20 11p15.5 0 0 6 0 0 One One 4 0.004752 LAMC3 10 2.00 9q34.12 0 10 0 0 0 9 One 0 0.0007316 LILRB4 14 2.80 19q13.42 One 13 0 0 3 10 One 0 0.008855 MMP16 11 2.20 8q21.3 3 8 0 0 0 8 One 2 0.004511 MRPS9 2 0.40 2q12.1 0 2 0 0 0 0 0 2 0.01881 MYD88 2 0.40 3p22.2 One One 0 0 0 0 0 2 0.01881 MYH7B 10 2.00 20q11.22 One 8 One 0 7 3 0 0 0.01497

gene mutation
number Mutation (%) Saito
band Mutation type transition period group Fisher (p-value) cut missense in-frame Etc I II III IV NIPAL3 4 0.80 1p36.11 One 3 0 0 0 0 4 0 0.01457 NUP58 5 1.00 13q12.13 3 2 0 0 5 0 0 0 0.004852 OR4D10 12 2.40 11q12.1 2 10 0 0 2 0 6 4 0.005695 P4HB 4 0.80 17q25.3 4 0 0 0 0 0 One 3 0.003126 PCDHA12 13 2.60 5q31.3 0 13 0 0 5 8 0 0 0.007654 PIM1 2 0.40 6p21.2 0 2 0 0 0 0 2 0 0.09348 PNPT1 7 1.40 2p16.1 2 5 0 0 6 One 0 0 0.01661 PPP1R15A 6 1.20 19q13.33 2 4 0 0 0 3 0 3 0.01049 PPP1R9A 8 1.60 7q21.3 2 6 0 0 0 7 0 One 0.002929 PRKCD 4 0.80 3p21.1 One 3 0 0 0 0 4 0 0.01457 PROZ 2 0.40 13q34 0 2 0 0 0 0 2 0 0.09348 RIPPLY2 2 0.40 6q14.2 0 2 0 0 0 0 0 2 0.01881 RLN1 4 0.80 9p24.1 One 3 0 0 0 0 4 0 0.01457 RNF6 6 1.20 13q12.13 2 4 0 0 2 0 0 4 0.001431 RSPH6A 7 1.40 19q13.32 One 6 0 0 2 5 0 0 0.1003 SCML4 4 0.80 6q21 0 4 0 0 0 0 4 0 0.01457 STAT4 8 1.60 2q32.2-q32.3 One 7 0 0 One 0 3 4 0.007212 STK38L 8 1.60 12p11.23 2 6 0 0 0 One 3 4 0.007805 TGM4 7 1.40 3p21.31 2 5 0 0 0 6 0 One 0.005287 TIE1 7 1.40 1p34.2 0 7 0 0 6 One 0 0 0.01661

gene mutation
number Mutation (%) Saito
band Mutation type transition period group Fisher (p-value) cut missense in-frame Etc I II III IV TMEM229A 8 1.60 7q31.32 0 3 5 0 8 0 0 0 0.0001948 TMPRSS13 12 2.40 11q23.3 0 10 2 0 9 2 One 0 0.008759 UNKL 6 1.20 16p13.3 3 3 0 0 0 0 3 3 0.006681 VPS37D 2 0.40 7q11.23 0 2 0 0 0 0 0 2 0.01881 ZBTB17 6 1.20 1p36.13 One 5 0 0 0 6 0 0 0.003098 ZC3H3 8 1.60 8q24.3 0 7 One 0 One 0 3 4 0.007212 ZNF730 7 1.40 19p12 One 6 0 0 6 0 One 0 0.01549 ZNF783 4 0.80 7q36.1 One 3 0 0 0 4 0 0 0.02912

As a result of the analysis, in each transition period group, there were genes with a P-value of 0.05 or more when compared with other groups, even if they had a mutation, while genes with a mutation and a P-value of less than 0.05 were identified. Mutant genes with a P-value of less than 0.05 compared to other groups were correlated with a specific transition period compared to other groups, so they were defined as transition period-specific genes. indicated.

2-2. Comparative analysis before and after 12 months (test set 2 - transition period group Ⅰ vs Ⅱ+ III + Ⅳ)

Among the four metastasis period groups divided by group in Table 2, for the group with less than 12 months (I) and more than 13 months (II+III+IV), the association between the occurrence of mutations in candidate genes and the metastasis period of solid cancer patients was confirmed. A P-value of less than 0.05 was considered as statistically significant and excavated as a metastasis period-specific marker. Information on candidate genes related to test set 2 is shown in Tables 7 to 11 below.

gene mutation
number Mutation (%) Saito
band Mutation type transition period group Fisher's exact (P-Value) cut missense in-frame Etc I II+ III+IV Ⅱ+ III+IV (%) A2M 17 3.4 12p13.31 6 11 0 0 0 17 100.0 0.005 ADAMTSL2 3 0.6 9q34.2 One 2 0 0 3 0 0.0 0.025 ADAMTSL5 5 1.0 19p13.3 2 3 0 0 5 0 0.0 0.002 ADCK5 3 0.6 8q24.3 0 3 0 0 3 0 0.0 0.025 ADRA2C 3 0.6 4p16.3 0 2 One 0 3 0 0.0 0.025 AHCY 4 0.8 20q11.22 0 4 0 0 4 0 0.0 0.007 AIMP2 5 1.0 7p22.1 One 4 0 0 5 0 0.0 0.002 ALKBH3 3 0.6 11p11.2 One 2 0 0 3 0 0.0 0.025 AQP11 3 0.6 11q14.1 0 2 0 One 3 0 0.0 0.025 ARMC10 3 0.6 7q22.1 0 3 0 0 3 0 0.0 0.025 ASPHD2 3 0.6 22q12.1 0 3 0 0 3 0 0.0 0.025 AXIN1 5 1.0 16p13.3 0 3 0 2 3 2 40.0 0.15 C11orf87 3 0.6 11q22.3 0 3 0 0 3 0 0.0 0.025 C14orf28 3 0.6 14q21.2 2 One 0 0 3 0 0.0 0.025 C20orf144 3 0.6 20q11.22 0 3 0 0 3 0 0.0 0.025 C2orf68 3 0.6 2p11.2 One 2 0 0 3 0 0.0 0.025 CCDC152 3 0.6 5p12 2 One 0 0 3 0 0.0 0.025 CCT5 6 1.2 5p15.2 3 3 0 0 5 One 16.7 0.01 CDKL1 3 0.6 14q21.3 One 2 0 0 3 0 0.0 0.025 CEP85 3 0.6 1p36.11 One 2 0 0 3 0 0.0 0.025

gene mutation
number Mutation (%) Saito
band Mutation type transition period group Fisher's exact (P-Value) cut missense in-frame Etc I II+ III+IV Ⅱ+ III+(IV%) CERCAM 7 1.4 9q34.11 One 6 0 0 6 One 14.3 0.003 CLEC4G 4 0.8 19p13.2 2 2 0 0 4 0 0.0 0.007 COX11 2 0.4 17q22 0 2 0 0 2 0 0.0 0.084 CPO 5 1.0 2q33.3 2 3 0 0 5 0 0.0 0.002 CTSO 3 0.6 4q32.1 0 3 0 0 3 0 0.0 0.025 CYP26C1 3 0.6 10q23.33 2 One 0 0 3 0 0.0 0.025 DCPS 4 0.8 11q24.2 0 3 0 One 4 0 0.0 0.007 DNAH1 30 6.0 3p21.1 5 25 0 0 17 13 43.3 0.003 DUSP13 2 0.4 10q22.2 0 2 0 0 2 0 0.0 0.084 ENO3 3 0.6 17p13.2 2 One 0 0 3 0 0.0 0.025 EPS15 3 0.6 1p32.3 0 3 0 0 3 0 0.0 0.025 ERFE 2 0.4 2q37.3 0 2 0 0 2 0 0.0 0.084 ETV7 3 0.6 6p21.31 0 3 0 0 3 0 0.0 0.025 FAM131B 4 0.8 7q34 One 3 0 0 4 0 0.0 0.007 FAM133A 3 0.6 Xq21.32 2 One 0 0 3 0 0.0 0.025 FAM221A 3 0.6 7p15.3 One 2 0 0 3 0 0.0 0.025 FAM227B 3 0.6 15q21.2 0 3 0 0 3 0 0.0 0.025 FANCC 2 0.4 9q22.32 0 2 0 0 2 0 0.0 0.084 FBXO32 3 0.6 8q24.13 0 3 0 0 3 0 0.0 0.025 FEZF1 4 0.8 7q31.32 0 4 0 0 4 0 0.0 0.007

gene mutation
number Mutation (%) Saito
band Mutation type transition period group Fisher's exact (P-Value) cut missense in-frame Etc I II+ III+IV Ⅱ+ III+IV (%) FUS 5 1.0 16p11.2 2 One 0 2 3 2 40.0 0.15 GJC3 3 0.6 7q22.1 0 3 0 0 3 0 0.0 0.025 GLCCI1 3 0.6 7p21.3 One 2 0 0 3 0 0.0 0.025 GPC1 3 0.6 2q37.3 0 3 0 0 3 0 0.0 0.025 GPR87 3 0.6 3q25.1 0 3 0 0 3 0 0.0 0.025 GPR88 3 0.6 1p21.2 0 3 0 0 3 0 0.0 0.025 GREB1 26 5.2 2p25.1 2 22 One One 15 11 42.3 0.003 GRN 4 0.8 17q21.31 One 3 0 0 4 0 0.0 0.007 GYS2 3 0.6 12p12.1 One 2 0 0 3 0 0.0 0.025 H3F3B 4 0.8 17q25.1 0 4 0 0 4 0 0.0 0.007 HOXD12 3 0.6 2q31.1 0 3 0 0 3 0 0.0 0.025 HPGDS 6 1.2 4q22.3 3 3 0 0 5 One 16.7 0.01 HSPA12B 3 0.6 20p13 0 3 0 0 3 0 0.0 0.025 IER5L 3 0.6 9q34.11 One 2 0 0 3 0 0.0 0.025 IL22 3 0.6 12q15 One 2 0 0 3 0 0.0 0.025 INTS6L 3 0.6 Xq26.3 0 3 0 0 3 0 0.0 0.025 KAZALD1 3 0.6 10q24.31 0 3 0 0 3 0 0.0 0.025 KCNK9 3 0.6 8q24.3 0 3 0 0 3 0 0.0 0.025 KIAA1524 6 1.2 3q13.13 One 5 0 0 5 One 16.7 0.01 KRT17 5 1.0 17q21.2 2 3 0 0 5 0 0.0 0.002

gene mutation
number Mutation (%) Saito
band Mutation type transition period group Fisher's exact (P-Value) cut missense in-frame Etc I II+ III+IV Ⅱ+ III+IV (%) KRT39 3 0.6 17q21.2 0 3 0 0 3 0 0.0 0.025 LAS1L 3 0.6 Xq12 0 2 One 0 3 0 0.0 0.025 MAT1A 3 0.6 10q22.3 One 2 0 0 3 0 0.0 0.025 MBOAT7 3 0.6 19q13.42 0 3 0 0 3 0 0.0 0.025 MED16 7 1.4 19p13.3 One 6 0 0 6 One 14.3 0.003 MFSD6 4 0.8 2q32.2 0 4 0 0 4 0 0.0 0.007 MRM2 3 0.6 7p22.3 0 3 0 0 3 0 0.0 0.025 NEDD1 6 1.2 12q23.1 2 4 0 0 5 One 16.7 0.01 NNMT 4 0.8 11q23.2 2 2 0 0 4 0 0.0 0.007 NUBP2 2 0.4 16p13.3 0 2 0 0 2 0 0.0 0.084 NUP58 5 1.0 13q12.13 3 2 0 0 5 0 0.0 0.002 OR1L8 3 0.6 9q33.2 0 3 0 0 3 0 0.0 0.025 OR1N2 3 0.6 9q33.2 0 3 0 0 3 0 0.0 0.025 OR2AK2 4 0.8 1q44 0 4 0 0 4 0 0.0 0.007 OR5H15 4 0.8 3q11.2 2 2 0 0 4 0 0.0 0.007 OR5L1 3 0.6 11q12.1 One 2 0 0 3 0 0.0 0.025 PARVB 3 0.6 22q13.31 One 2 0 0 3 0 0.0 0.025 PLEKHO2 3 0.6 15q22.31 One 2 0 0 3 0 0.0 0.025 PNPT1 7 1.4 2p16.1 2 5 0 0 6 One 14.3 0.003 POU4F1 3 0.6 13q31.1 0 2 One 0 3 0 0.0 0.025

gene mutation
number Mutation (%) Saito
band Mutation type transition period group Fisher's exact (P-Value) cut missense in-frame Etc I Ⅱ+ III +IV Ⅱ+III+IV(%) PPM1H 6 1.2 12q14.1-q14.2 One 5 0 0 5 One 16.7 0.01 PREPL 4 0.8 2p21 0 4 0 0 4 0 0.0 0.007 SAG 4 0.8 2q37.1 One 3 0 0 4 0 0.0 0.007 SLC43A1 3 0.6 11q12.1 0 3 0 0 3 0 0.0 0.025 SPDYA 4 0.8 2p23.2 One 3 0 0 4 0 0.0 0.007 STXBP2 8 1.6 19p13.2 One 7 0 0 7 One 12.5 0.001 SYTL1 6 1.2 1p36.11 One 5 0 0 5 One 16.7 0.01 TBL1X 4 0.8 Xp22.31-p22.2 0 4 0 0 4 0 0.0 0.007 TIE1 7 1.4 1p34.2 0 7 0 0 6 One 14.3 0.003 TMEM229A 8 1.6 7q31.32 0 3 5 0 8 0 0.0 0.000056 TMPRSS13 12 2.4 11q23.3 0 10 2 0 9 3 25.0 0.001 TRAPPC5 4 0.8 19p13.2 0 4 0 0 4 0 0.0 0.007 TTC22 4 0.8 1p32.3 0 4 0 0 4 0 0.0 0.007 UNC5A 4 0.8 5q35.2 0 4 0 0 4 0 0.0 0.007 UNC5D 12 2.4 8p12 One 10 One 0 0 12 100.0 0.024 VRK3 5 1.0 19q13.33 0 5 0 0 4 One 20.0 0.028 ZNF730 7 1.4 19p12 One 6 0 0 6 One 14.3 0.003

As a result of the analysis, in each transition period group, there were genes with a P-value of 0.05 or more when compared with other groups, even if they had a mutation, while genes with a mutation and a P-value of less than 0.05 were identified. Mutant genes with a P-value of less than 0.05 compared to other groups were correlated with a specific transition period group compared to other groups, so they were defined as transition period-specific genes. The results of analyzing the association of

2-3. Comparative analysis before and after 36 months (test set 3 - transition period group I + II vs III + IV)

Among the four metastasis period groups divided by group in Table 2, for the group with less than 36 months (I + II) and longer than 37 months (III + IV), the association between the occurrence of mutations in candidate genes and the metastasis period of solid cancer patients was confirmed. A P-value of less than 0.05 was considered as statistically significant and excavated as a metastasis period-specific marker. Information on candidate genes related to test set 3 is shown in Tables 12 to 15 below.

gene mutation
number Mutation (%) Saito
band Mutation type transition period group Fisher's exact (P-Value) cut missense in-frame Etc Ⅰ+Ⅱ III+IV III+IV(%) AAK1 4 0.8 2p13.3 0 4 0 0 0 4 100.0 0.03 ABCC9 15 3.0 12p12.1 One 14 0 0 7 8 53.3 0.428 ADGRF5 11 2.2 6p12.3 2 9 0 0 5 6 54.5 0.278 ANO9 4 0.8 11p15.5 0 4 0 0 0 4 100.0 0.03 ASPDH 4 0.8 19q13.33 One 3 0 0 0 4 100.0 0.03 B4GALT3 4 0.8 1q23.3 One 3 0 0 0 4 100.0 0.03 BHLHE22 4 0.8 8q12.3 0 2 2 0 0 4 100.0 0.03 CCNJL 4 0.8 5q33.3 0 4 0 0 0 4 100.0 0.03 CDH22 13 2.6 20q13.12 0 13 0 0 6 7 53.8 0.63 COL4A3 12 2.4 2q36.3 0 12 0 0 6 6 50.0 0.371 CR1 9 1.8 1q32.2 0 9 0 0 2 7 77.8 0.039 CREBBP 27 5.4 16p13.3 4 18 2 3 11 16 59.3 0.05 DNAH9 45 9.0 17p12 9 36 0 0 16 29 64.4 0.004 ELFN2 11 2.2 22q13.1 0 11 0 0 5 6 54.5 0.278 EMILIN3 8 1.6 20q12 One 7 0 0 2 6 75.0 0.073 ESR1 20 4.0 6q25.1-q25.2 3 17 0 0 3 17 85.0 0.000113 FLI1 3 0.6 11q24.3 0 3 0 0 0 3 100.0 0.71 FMNL3 8 1.6 12q13.12 One 7 0 0 4 4 50.0 0.723 FXR1 6 1.2 3q26.33 One 4 0 One One 5 83.3 0.048 FZD1 5 1.0 7q21.13 0 3 2 0 0 5 100.0 0.012

gene mutation
number Mutation (%) Saito
band Mutation type transition period group Fisher's exact (P-Value) cut missense in-frame Etc Ⅰ+Ⅱ III+IV III+IV(%) GATA3 8 1.6 10p14 4 4 0 0 0 8 100.0 0.001 GDA 7 1.4 9q21.13 0 7 0 0 0 7 100.0 0.002 GLI4 4 0.8 8q24.3 0 4 0 0 0 4 100.0 0.03 GMPPA 4 0.8 2q35 0 4 0 0 0 4 100.0 0.03 GRM5 9 1.8 11q14.2-q14.3 2 7 0 0 5 4 44.4 0.549 GUCY2F 9 1.8 Xq22.3-q23 2 7 0 0 3 6 66.7 0.117 HEATR3 8 1.6 16q12.1 0 8 0 0 4 4 50.0 0.723 HIST2H2BE 4 0.8 1q21.2 0 4 0 0 0 4 100.0 0.03 HNRNPA0 5 1.0 5q31.2 One 3 One 0 0 5 100.0 0.012 IGF2R 9 1.8 6q25.3 3 6 0 0 One 8 88.9 0.005 KCNA4 10 2.0 11p14.1 3 7 0 0 6 4 40.0 0.604 KCND2 10 2.0 7q31.31 One 9 0 0 5 5 50.0 0.401 KCNJ4 9 1.8 22q13.1 2 7 0 0 5 4 44.4 0.549 LILRB4 14 2.8 19q13.42 One 13 0 0 3 11 78.6 0.011 LRRIQ4 5 1.0 3q26.2 One 4 0 0 0 5 100.0 0.012 MAGEL2 9 1.8 15q11.2 One 8 0 0 5 4 44.4 0.549 MAP3K6 9 1.8 1p36.11 2 7 0 0 5 4 44.4 0.549 METTL13 5 1.0 1q24.3 2 2 One 0 0 5 100.0 0.012 MICAL3 11 2.2 22q11.21 2 8 One 0 7 4 36.4 0.502 MXI1 4 0.8 10q25.2 2 2 0 0 0 4 100.0 0.03

gene mutation
number Mutation (%) Saito
band Mutation type transition period group Fisher's exact (P-Value) cut missense in-frame Etc Ⅰ+Ⅱ III +IV III+IV(%) MYH7B 10 2.0 20q11.22 One 8 One 0 7 3 30.0 0.356 MYO3A 25 5.0 10p12.1 2 23 0 0 9 16 64.0 0.361 NUP133 5 1.0 1q42.13 2 3 0 0 0 5 100.0 0.012 OPRM1 8 1.6 6q25.2 One 7 0 0 6 2 25.0 0.294 OR4D10 12 2.4 11q12.1 2 10 0 0 2 10 83.3 0.005 PAX1 8 1.6 20p11.22 One 7 0 0 5 3 37.5 0.568 PCDHA12 13 2.6 5q31.3 0 13 0 0 5 8 61.5 0.119 PCDHGA10 10 2.0 5q31.3 0 10 0 0 6 4 40.0 0.604 PHLDB2 9 1.8 3q13.2 2 7 0 0 3 6 66.7 0.117 SCNN1D 5 1.0 1p36.33 One 4 0 0 0 5 100.0 0.012 STAT4 8 1.6 2q32.2-q32.3 One 7 0 0 One 7 87.5 0.011 STK38L 8 1.6 12p11.23 2 6 0 0 0 8 100.0 0.001 SYBU 8 1.6 8q23.2 One 7 0 0 3 5 62.5 0.197 TEX13A 8 1.6 Xq22.3 One 7 0 0 2 6 75.0 0.073 TFF3 3 0.6 21q22.3 One 2 0 0 0 3 100.0 0.71 TMEM117 4 0.8 12q12 One 3 0 0 0 4 100.0 0.03 TMEM229A 8 1.6 7q31.32 0 3 5 0 8 0 0.0 0.024 TMPRSS13 12 2.4 11q23.3 0 10 2 0 9 3 25.0 0.376 TNRC6C 11 2.2 17q25.3 2 9 0 0 7 4 36.4 0.502 TSPAN10 5 1.0 17q25.3 One 4 0 0 3 2 40.0 0.662

gene mutation
number Mutation (%) Saito
band Mutation type transition period group Fisher's exact (P-Value) cut missense in-frame Etc Ⅰ+Ⅱ III+IV III+IV(%) UBD 4 0.8 6p22.1 One 3 0 0 0 4 100.0 0.03 UNKL 6 1.2 16p13.3 3 3 0 0 0 6 100.0 0.005 ZC3H3 8 1.6 8q24.3 0 7 One 0 One 7 87.5 0.011 ZFYVE28 10 2.0 4p16.3 2 8 0 0 4 6 60.0 0.191 ZNF41 7 1.4 Xp11.3 One 6 0 0 2 5 71.4 0.111 ZNF496 8 1.6 1q44 2 6 0 0 5 3 37.5 0.568 ZNF667 11 2.2 19q13.43 3 7 One 0 6 5 45.5 0.503 ZNF71 9 1.8 19q13.43 0 9 0 0 5 4 44.4 0.549

As a result of the analysis, in each transition period group, there were genes with a P-value of 0.05 or more when compared with other groups, even if they had a mutation, while genes with a mutation and a P-value of less than 0.05 were identified. Mutant genes with a P-value of less than 0.05 compared to other groups were correlated with a specific transition period group compared to other groups, so they were designated as transition period-specific genes. showed the results of analyzing the association of , and information on marker mutations in metastatic solid cancer patients specific to metastatic period before and after 36 months was confirmed through data provided by MSKCC.

2-4. Comparative analysis before and after 120 months (test set 4 - transition period group I + II + III vs IV)

Among the four metastasis period groups divided by group in Table 2, for the group with less than 120 months (I + II + III) and more than 121 months (IV), the association between the occurrence of mutations in candidate genes and the metastasis period of solid cancer patients was confirmed. A P-value of less than 0.05 was considered as statistically significant and excavated as a metastasis period-specific marker. Tables 16 and 17 below show information of candidate genes related to test set 4.

gene mutation
number Mutation (%) Saito
band Mutation type transition period group Fisher's exact (P-Value) cut missense in-frame Etc I+II+III IV IV (%) ASB1 2 0.4 2q37.3 0 2 0 0 2 0 0.0 0.744 CCPG1 4 0.8 15q21.3 0 4 0 0 4 0 0.0 0.554 EPX 2 0.4 17q22 0 2 0 0 2 0 0.0 0.744 ETFDH 3 0.6 4q32.1 One 2 0 0 3 0 0.0 0.147 FLVCR2 One 0.2 14q24.3 0 One 0 0 One 0 0.0 0.862 HYAL1 2 0.4 3p21.31 0 2 0 0 2 0 0.0 0.744 IDH3B One 0.2 20p13 0 One 0 0 One 0 0.0 0.862 KRTAP19-4 2 0.4 21q22.11 0 2 0 0 2 0 0.0 0.744 LCE4A 2 0.4 1q21.3 One 0 One 0 2 0 0.0 0.744 LIN7A 2 0.4 12q21.31 One One 0 0 One One 50.0 0.26 LINS1 4 0.8 15q26.3 0 4 0 0 4 0 0.0 0.554 LRRTM2 2 0.4 5q31.2 0 2 0 0 2 0 0.0 0.744 MRPS22 2 0.4 3q23 0 2 0 0 One One 50.0 0.26 ORMDL3 2 0.4 17q21.1 One One 0 0 2 0 0.0 0.744 PGLS 2 0.4 19p13.11 One One 0 0 One One 50.0 0.26 PLK5 2 0.4 19p13.3 One 0 One 0 2 0 0.0 0.744 PNKP 2 0.4 19q13.33 0 2 0 0 2 0 0.0 0.744 RAI14 5 1.0 5p13.2 2 3 0 0 5 0 0.0 0.478 REG3A 2 0.4 2p12 0 2 0 0 2 0 0.0 0.744 RIMS3 2 0.4 1p34.2 0 2 0 0 One One 50.0 0.26

gene mutation
number Mutation (%) Saito
band Mutation type transition period group Fisher's exact (P-Value) cut missense in-frame Etc I+II+III IV IV (%) RNF139 4 0.8 8q24.13 One 2 0 One 2 2 50.0 0.097 RNF19A 2 0.4 8q22.2 0 2 0 0 One One 50.0 0.26 RPS2 2 0.4 16p13.3 0 2 0 0 2 0 0.0 0.744 SAFB 2 0.4 19p13.3 One One 0 0 One One 50.0 0.26 SPRR3 2 0.4 1q21.3 0 2 0 0 2 0 0.0 0.744 TM9SF4 2 0.4 20q11.21 0 2 0 0 2 0 0.0 0.744 TRAPPC13 2 0.4 5q12.3 0 2 0 0 2 0 0.0 0.744 VWA1 4 0.8 1p36.33 2 2 0 0 4 0 0.0 0.554 YWHAG 2 0.4 7q11.23 One One 0 0 2 0 0.0 0.744 ZBTB12 2 0.4 6p21.33 0 2 0 0 One One 50.0 0.26 ZNF92 2 0.4 7q11.21 0 2 0 0 One One 50.0 0.26

As a result of the analysis, in each transition period group, there were genes with a P-value of 0.05 or more when compared with other groups, even if they had a mutation, while genes with a mutation and a P-value of less than 0.05 were identified. Mutant genes with a P-value of less than 0.05 compared to other groups were correlated with a specific metastatic period group compared to other groups, so they were metastasis period-specific genes. Since there was no marker indicating a significant p-value, a marker specific for the corresponding period could not be discovered.

2-5. Derivation of specific genes for each metastasis period group

Based on the analysis results of Examples 2-2 to 2-4, specific mutation markers for each transition period group were derived.

From the above results, A2M, ADAMTSL5, ARL2BP, B4GALT3, BHLHE22, C11orf54, C8orf34, CCDC14, CCNJL, CD109, CERCAM, CFAP57, CLEC4G, CPO, CTNNBL1, DCAF13, DNAH1, DNAH9, FGG, GSRATA3, GLI4, GMPPA, HNRNPA0, HOXC10, ICAM5, IL6ST, ITGB3, KCNK2, KRTAP5-2, LAMC3, LILRB4, MMP16, MRPS9, MYD88, MYH7B, NIPAL3, NUP58, OR4D10, P4HB, PCDHA12, PNPP1RPT1, PPP1R It was confirmed that mutations in RIPPLY2, RLN1, RNF6, SCML4, STAT4, STK38L, TGM4, TIE1, TMEM229A, TMPRSS13, UNKL, VPS37D, ZBTB17, ZC3H3, ZNF730 and ZNF783 can be used as metastatic group I-specific markers, Among these markers, as a result of reselecting markers that can be analyzed in detail related to survival in accordance with the data provided by MSKCC (10945 samples), ESR1, GATA3, and MYD88 were finally selected as metastatic period group I-specific markers.

From the above results, A2M, ADAMTSL2, ADAMTSL5, ADCK5, ADRA2C, AHCY, AIMP2, ALKBH3, AQP11, ARMC10, ASPHD2, C11orf87, C14orf28, C20orf144, C2orf68, CCDC152, CCT5, CDKL1, CEP85, CERSO, CEP85, CYP26C1, DCPS, DNAH1, ENO3, EPS15, ETV7, FAM131B, FAM113A, FAM221A, FAM227B, FBXO32, FEZF1, GJC3, GLCCI1, GPC1, GPR87, GPR88, GREB1, GRN, GYS2, H3F3B, HOX D12, HPGDS IL22, INTS6L, KAZALD1, KCNK9, KIAA1524, KRT17, KRT39, LAS1L, MAT1A, MBOAT7, MED16, MFSD6, MRM2, NEDD1, NNMT, NUP58, OR1L8, OR1N2, OR2AK2, OR5H15, ORVB, PLEKHO, OR5H15, ORV5LOU Mutations of PPM1H, PREPL, SAG, SLC43A1, SPDYA, STXBP2, SYTL1, TBL1X, TIE1, TMEM229A, TMPRSS113, TRAPPC5, TTC22, UNC5A, UNC5D, VRK3 and ZNF730 can be used as metastatic group II-specific markers. Among these markers, as a result of reselecting markers that can be analyzed in detail related to survival in accordance with the data (10945 samples) provided by MSKCC, H3F3B was finally selected as a metastasis period group II-specific marker.

From the above results, AAK1, ANO9, ASPDH, B4GALT3, BHLHE22, CCNJL, CR1, CREBBP, DNAH9, ESR1, FXR1, FZD1, GATA3, GDA, GLI4, GMPPA, HIST2H2BERI, HNRNPA0, IGF2R, LILRB4, It was confirmed that mutations in NUP133, OR4D10, SCNN1D, STAT4, STK38L, TMEM117, TMEM229A, UBD, UNKL and ZC3H3 can be used as metastatic group III-specific markers. Among these markers, data provided by MSKCC (sample 10945) As a result of reselecting the markers that can be analyzed in detail in relation to survival rate, CREBBP, ESR1, and GATA3 were finally selected as metastatic period group III-specific markers.

However, from the above results, a significant marker for the metastasis period group IV could not be identified, so a marker specific to the metastasis period group IV could not be selected.

Example 3. Confirmation of utility as survival-specific markers of metastasis-related genes

When mutations occurred in the candidate genes selected in Example 1 in metastatic solid cancer patients, the correlation between the markers of the present invention and survival rates was checked for 17 major solid cancers to determine the effect on survival. The overall OS and DFS for each cancer type of CREBBP, ESR1, GATA3, H3F3B and MYD88 are shown in Table 18 below, and the OS and DFS of each gene are shown in Table 19 (CREBBP), Table 20 (ESR1), Table 21 (GATA3), Table 22 (H3F3B) and Table 23 (MYD88) are shown.

NO MSKCC 10945 OS DFS number of mutation data One Lung adenocarcinoma 0.0918 0.723 2322 2 Breast invasive ductal carcinoma 0.064 0.319 6563 3 Colon adenocarcinoma 3.50E-03 0.231 135 4 Prostate adenocarcinoma 3.52E-04 1.08E-03 4588 5 Bladder urothelial carcinoma 2.97E-03 0.287 1756 6 Lung squamous cell carcinoma 0.298 0.167 841 7 Cutaneous melanoma 0.0589 0.311 1420 8 Cancer of unknown primary 0.0582 0.703 17285 9 Pancreatic adenocarcinoma 0.234 0.407 920 10 Glioblastoma multiforme 0.29 0.617 1118 11 Colorectal adenocarcinoma 0.358 0.266 3278 12 High-grade serous ovarian cancer 0.976 0.454 1155 13 Stomach adenocarcinoma 0.68 0.347 1278 14 Renal clear cell carcinoma 0.275 0.196 1596 15 Esophageal adenocarcinoma 0.147 0.0349 518 16 Testis (Testicular cancer) 0.9740e-5 0.0664 480 17 Intrahepatic cholangiocarcinoma 0.244 NA 103

NO MSKCC 10945 OS DFS number of mutation data One Lung adenocarcinoma 0.482 0.509 2322 2 Breast invasive ductal carcinoma 0.0897 0.557 6563 3 Colon adenocarcinoma 0.0284 0.13 135 4 Prostate adenocarcinoma 9.44E-05 0.0111 4588 5 Bladder urothelial carcinoma 1.20E-03 0.953 1756 6 Lung squamous cell carcinoma 0.818 0.901 841 7 Cutaneous melanoma 0.565 0.919 1420 8 Cancer of unknown primary 0.0655 0.412 17285 9 Pancreatic adenocarcinoma 0.629 0.144 920 10 Glioblastoma multiforme 0.629 0.144 1118 11 Colorectal adenocarcinoma 0.301 0.446 3278 12 High-grade serous ovarian cancer 0.612 0.592 1155 13 Stomach adenocarcinoma 0.0917 0.555 1278 14 Renal clear cell carcinoma 0.252 0.352 1596 15 Esophageal adenocarcinoma 6.99E-03 0.0223 518 16 Testis (Testicular cancer) 1.038e-4 0.172 480 17 Intrahepatic cholangiocarcinoma 0.0155 0.243 103

NO MSKCC 10945 OS DFS number of mutation data One Lung adenocarcinoma 0.569 0.473 2322 2 Breast invasive ductal carcinoma 3.58E-03 0.318 6563 3 Colon adenocarcinoma 7.41E-04 0.64 135 4 Prostate adenocarcinoma 0.404 0.733 4588 5 Bladder urothelial carcinoma 0.0875 0.905 1756 6 Lung squamous cell carcinoma 0.698 0.0108 841 7 Cutaneous melanoma 0.688 0.329 1420 8 Cancer of unknown primary 0.891 0.799 17285 9 Pancreatic adenocarcinoma 0.782 0.823 920 10 Glioblastoma multiforme 0.782 0.823 1118 11 Colorectal adenocarcinoma 0.694 0.0768 3278 12 High-grade serous ovarian cancer 0.802 0.818 1155 13 Stomach adenocarcinoma 0.854 0.756 1278 14 Renal clear cell carcinoma 0.167 0.472 1596 15 Esophageal adenocarcinoma 0.937 0.506 518 16 Testis (Testicular cancer) 0.870 0.471 480 17 Intrahepatic cholangiocarcinoma 0.973 0.653 103

NO MSKCC 10945 OS DFS number of mutation data One Lung adenocarcinoma 0.0148 0.929 2322 2 Breast invasive ductal carcinoma 6.52E-06 8.03E-03 6563 3 Colon adenocarcinoma 0.634 0.0733 135 4 Prostate adenocarcinoma 0.105 1.60E-03 4588 5 Bladder urothelial carcinoma 0.0429 0.185 1756 6 Lung squamous cell carcinoma 0.821 5.34E-03 841 7 Cutaneous melanoma 0.141 0.334 1420 8 Cancer of unknown primary 0.0121 NA 17285 9 Pancreatic adenocarcinoma 0.447 0.11 920 10 Glioblastoma multiforme 0.447 0.11 1118 11 Colorectal adenocarcinoma 0.819 0.962 3278 12 High-grade serous ovarian cancer 0.351 0.454 1155 13 Stomach adenocarcinoma 0.0471 0.156 1278 14 Renal clear cell carcinoma 0.917 0.345 1596 15 Esophageal adenocarcinoma 0.0329 3.57E-03 518 16 Testis (Testicular cancer) 0.816 0.335 480 17 Intrahepatic cholangiocarcinoma 0.0778 0.0969 103

NO MSKCC 10945 OS DFS number of mutation data One Lung adenocarcinoma 0.469 0.415 2322 2 Breast invasive ductal carcinoma 0.443 0.667 6563 3 Colon adenocarcinoma 0.773 0.794 135 4 Prostate adenocarcinoma 0.081 0.0294 4588 5 Bladder urothelial carcinoma 0.972 0.422 1756 6 Lung squamous cell carcinoma 0.978 0.924 841 7 Cutaneous melanoma 1.16E-03 0.0399 1420 8 Cancer of unknown primary 0.247 NA 17285 9 Pancreatic adenocarcinoma 0.103 NA 920 10 Glioblastoma multiforme 0.103 NA 1118 11 Colorectal adenocarcinoma 0.255 0.368 3278 12 High-grade serous ovarian cancer 0.671 0.233 1155 13 Stomach adenocarcinoma 0.528 0.0361 1278 14 Renal clear cell carcinoma NA NA 1596 15 Esophageal adenocarcinoma 0.157 0.496 518 16 Testis (Testicular cancer) NA NA 480 17 Intrahepatic cholangiocarcinoma 0.149 0.497 103

NO MSKCC 10945 OS DFS number of mutation data One Lung adenocarcinoma 0.0693 0.275 2322 2 Breast invasive ductal carcinoma 0.734 0.655 6563 3 Colon adenocarcinoma NA NA 135 4 Prostate adenocarcinoma 0.0178 0.558 4588 5 Bladder urothelial carcinoma 0.081 0.847 1756 6 Lung squamous cell carcinoma 0.663 0.628 841 7 Cutaneous melanoma 0.165 0.763 1420 8 Cancer of unknown primary 0.119 NA 17285 9 Pancreatic adenocarcinoma 0.112 0.119 920 10 Glioblastoma multiforme 0.112 0.119 1118 11 Colorectal adenocarcinoma 0.778 0.552 3278 12 High-grade serous ovarian cancer 0.541 0.0391 1155 13 Stomach adenocarcinoma 0.46 0.271 1278 14 Renal clear cell carcinoma 0.0481 0.948 1596 15 Esophageal adenocarcinoma 0.471 0.943 518 16 Testis (Testicular cancer) 0.870 2.54e-7 480 17 Intrahepatic cholangiocarcinoma 0.599 0.697 103

Based on the clinical information obtained in Example 1 of metastatic solid cancer of each candidate gene, the overall survival kaplan-meier estimate and the disease free survival kaplan-meier estimate were calculated by the Kaplan Meier survival assay (Spss 21). saved In the total survival period, death was defined as an event, and in the disease-free survival period, recurrence of solid cancer was determined as an event. In order to determine whether the occurrence of mutations in each of the above genes is correlated with the death or recurrence of solid cancer in patients with metastatic solid cancer, based on the event time of each group obtained by the Kaplan Meier survival assay. The association between mutagenesis and total survival and the association between mutagenesis and disease-free survival were confirmed by log rank test, and a P-value of less than 0.05 was considered statistically significant. The experimental group was 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 median disease-free survival period (median months desease free) means a value located at the center when the survival period of patients in the relevant group is listed. The slope in the survival curve by the Kaplan Meier survival assay is determined by the duration of survival.

The present inventors have identified 17 representative metastatic solid cancer types (Lung adenocarcinoma, Breast invasive ductal carcinoma), Colon adenocarcinoma, Prostate adenocarcinoma, and Bladder urothelial carcinoma. , Lung squamous cell carcinoma, Cutaneous melanoma, Cancer of unknown primary, Pancreatic adenocarcinoma, Glioblastoma multiforme, Colorectal adenocarcinoma), High grade serous ovarian cancer, Stomach adenocarcinoma, Renal clear cell carcinoma, Esophageal adenocarcinoma, Testicular cancer and Intrahepatic cholangiocarcinoma ) in metastatic solid cancer patients, mutations in each of the candidate genes were derived using 10945 samples provided by MSKCC. ESR1 mutations are shown in Tables 50 to 63 below, GATA3 mutations are shown in Tables 64 to 78 below, H3F3B mutations are shown in Tables 79 and 80 below, and mutations in MYD88 are It is shown in Tables 81 to 83 below.

[Table 24]

[Table 25]

[Table 26]

[Table 27]

[Table 28]

[Table 29]

[Table 30]

[Table 31]

[Table 32]

[Table 33]

[Table 34]

[Table 35]

[Table 36]

[Table 37]

[Table 38]

[Table 39]

[Table 40]

[Table 41]

[Table 42]

[Table 43]

[Table 44]

[Table 45]

[Table 46]

[Table 47]

[Table 48]

[Table 49]

[Table 50]

[Table 51]

[Table 52]

[Table 53]

[Table 54]

[Table 55]

[Table 56]

[Table 57]

[Table 58]

[Table 59]

[Table 60]

[Table 61]

[Table 62]

[Table 63]

[Table 64]

[Table 65]

[Table 66]

[Table 67]

[Table 68]

[Table 69]

[Table 70]

[Table 71]

[Table 72]

[Table 73]

[Table 74]

[Table 75]

[Table 76]

[Table 77]

[Table 78]

[Table 79]

[Table 80]

[Table 81]

[Table 82]

[Table 83]

In order to determine whether the occurrence of the derived mutation and the survival rate of metastatic solid cancer patients is correlated (null hypothesis), the prognosis of 500 solid cancer patients obtained in Example 1 was analyzed, and the total survival rate and disease-free survival rate were confirmed. .

As a result of the analysis, as shown in FIGS. 4 to 88, the null hypothesis that mutations in genes encoding CREBBP, ESR1, GATA3, H3F3B, and MYD88, which are metastasis period-specific markers of the present invention, are associated with the survival rate of patients with metastatic solid cancer Since the probability of being correct is more than 99.5%, that is, the probability that the null hypothesis is incorrect is less than 0.5%, it can be seen that there is a correlation between the occurrence of mutations in the above genes and the survival rate of patients with metastatic solid cancer.

As a result of confirming the overall survival rate for 17 metastatic solid cancers, Fig. 4 (CREBBP, ESR1, GATA3, H3F3B and MYD88), Fig. 5 (CREBBP), Fig. 6 (ESR1), Fig. 7 (GATA3), Fig. 8 (H3F3B) and FIG. 9 (MYD88).

In addition, when a mutation occurs in the age-specific marker of the present invention in each carcinoma, the survival rate and disease-free survival rate were specifically confirmed.

In lung adenocarcinoma, one of the metastatic solid cancers, mutations in the CREBBP, ESR1, GATA3, H3F3B and MYD88 genes are shown in red, and the case in which no mutation occurs is shown in blue. Total survival rate graph (Overall Survival, left) and disease-free survival rate graph (Disease/Progression-free, right) is shown in FIG. 10 .

In lung adenocarcinoma, one of metastatic solid cancers, the case where the CREBBP gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. -free, right) is shown in FIG. 11 .

In lung adenocarcinoma, one of metastatic solid cancers, the case where the ESR1 gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. -free, right) is shown in FIG. 12 .

In lung adenocarcinoma, one of metastatic solid cancers, the case where the GATA3 gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. -free, right) is shown in FIG. 13 .

In lung adenocarcinoma, one of metastatic solid cancers, the case where the H3F3B gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. -free, right) is shown in FIG. 14 .

In lung adenocarcinoma, one of metastatic solid cancers, the case in which the MYD88 gene is mutated is shown in red and the case in which no mutation occurs is shown in blue. -free, right) is shown in FIG. 15 .

In breast invasive ductal carcinoma, one of metastatic solid cancers, the case of mutations in the CREBBP, ESR1, GATA3, H3F3B and MYD88 genes is shown in red, and the case where no mutation occurs is shown in blue. Survival, left) and disease-free survival rate graph (Disease/Progression-free, right) are shown in FIG. 16 .

In breast invasive ductal carcinoma, one of metastatic solid cancers, the case where the CREBBP gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. Overall survival graph (Overall Survival, left) and disease-free survival graph (Disease/Progression-free, right) is shown in FIG. 17 .

In breast invasive ductal carcinoma, one of metastatic solid cancers, the case in which the ESR1 gene is mutated is shown in red and the case in which no mutation occurs is shown in blue. Overall survival graph (Overall Survival, left) and disease-free survival graph (Disease/Progression-free, right) is shown in FIG. 18 .

In breast invasive ductal carcinoma, one of metastatic solid cancers, the case of mutation in the GATA3 gene is shown in red, and the case in which no mutation occurs is shown in blue. Overall survival graph (Overall Survival, left) and disease-free survival graph (Disease/Progression-free, right) is shown in FIG. 19 .

In breast invasive ductal carcinoma, one of metastatic solid cancers, the case of mutation in the H3F3B gene is shown in red and the case in which no mutation occurs is shown in blue. Overall survival graph (Overall Survival, left) and disease-free survival graph (Disease/Progression-free, right) is shown in FIG. 20 .

In breast invasive ductal carcinoma, one of metastatic solid cancers, the case where the MYD88 gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. Overall survival graph (Overall Survival, left) and disease-free survival graph (Disease/Progression-free, right) is shown in FIG. 21 .

In colon adenocarcinoma, one of metastatic solid cancers, mutations in the CREBBP, ESR1, GATA3, H3F3B, and MYD88 genes are shown in red and non-mutations are shown in blue. Overall survival rate graph (Overall Survival, left) and disease-free survival rate graph (Disease/Progression-free, right) is shown in FIG. 22 .

In colon adenocarcinoma, one of metastatic solid cancers, the case where the CREBBP gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. -free, right) is shown in FIG. 23 .

In colon adenocarcinoma, one of metastatic solid cancers, the case where the ESR1 gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. -free, right) is shown in FIG. 24 .

In colon adenocarcinoma, one of metastatic solid cancers, the case where the GATA3 gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. -free, right) is shown in FIG. 25 .

In colon adenocarcinoma, one of the metastatic solid cancers, the case in which the H3F3B gene is mutated is shown in red and the case in which no mutation occurs is shown in blue. -free, right) is shown in FIG. 26 .

In colon adenocarcinoma, one of the metastatic solid cancers, the case where the MYD88 gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. -free, right) is shown in FIG. 27 .

In prostate adenocarcinoma, one of the metastatic solid cancers, the case of mutations in the CREBBP, ESR1, GATA3, H3F3B and MYD88 genes is shown in red, and the case in which no mutation occurs is shown in blue. Total survival rate graph (Overall Survival, left) and disease-free survival rate graph (Disease/Progression-free, right) is shown in FIG. 28 .

In prostate adenocarcinoma, one of metastatic solid cancers, the case where the CREBBP gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. -free, right) is shown in FIG. 29 .

In prostate adenocarcinoma, one of metastatic solid cancers, the case in which the ESR1 gene is mutated is shown in red, and the case in which no mutation occurs is shown in blue. -free, right) is shown in FIG. 30 .

In prostate adenocarcinoma, one of metastatic solid cancers, the case of mutation in the GATA3 gene is shown in red, and the case in which no mutation occurs is shown in blue. -free, right) is shown in FIG. 31 .

In prostate adenocarcinoma, one of metastatic solid cancers, the case in which the H3F3B gene is mutated is shown in red, and the case in which no mutation occurs is shown in blue. -free, right) is shown in FIG. 32 .

In prostate adenocarcinoma, one of metastatic solid cancers, the case in which the MYD88 gene is mutated is shown in red, and the case in which no mutation occurs is shown in blue. -free, right) is shown in FIG. 33 .

In the case of mutations in the CREBBP, ESR1, GATA3, H3F3B, and MYD88 genes in Bladder urothelial carcinoma, one of the metastatic solid cancers, the case of mutations is shown in red, and the case of no mutation is shown in blue. , left) and a graph of disease-free survival rate (Disease/Progression-free, right) are shown in FIG. 34 .

In the case of mutation in the CREBBP gene in Bladder urothelial carcinoma, one of the metastatic solid cancers, the case where the CREBBP gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. Disease/Progression-free, right) is shown in FIG. 35 .

In Bladder urothelial carcinoma, one of the metastatic solid cancers, the case of mutation in the ESR1 gene is shown in red, and the case in which no mutation occurs is shown in blue. Total survival graph (Overall Survival, left) and disease-free survival graph ( Disease/Progression-free, right) is shown in FIG. 36 .

In the case of mutation in the GATA3 gene in Bladder urothelial carcinoma, one of the metastatic solid cancers, the case in which the GATA3 gene is mutated is shown in red, and the case in which the mutation does not occur is shown in blue. Disease/Progression-free, right) is shown in FIG. 37 .

In the case of mutation in the H3F3B gene in Bladder urothelial carcinoma, one of the metastatic solid cancers, the case in which the mutation occurred in red and the case in which the mutation did not occur are shown in blue. Disease/Progression-free, right) is shown in FIG. 38 .

In the case of mutation in the MYD88 gene in Bladder urothelial carcinoma, one of the metastatic solid cancers, the case of mutation in red and the case of no mutation are shown in blue. Total survival graph (Overall Survival, left) and disease-free survival graph ( Disease/Progression-free, right) is shown in FIG. 39 .

In lung squamous cell carcinoma, one of the metastatic solid cancers, mutations in the CREBBP, ESR1, GATA3, H3F3B, and MYD88 genes are shown in red, and non-mutations are shown in blue. Survival, left) and disease-free survival graph (Disease/Progression-free, right) are shown in FIG. 40 .

In lung squamous cell carcinoma, one of the metastatic solid cancers, the case where the CREBBP gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. Overall survival graph (Overall Survival, left) and disease-free survival graph (Disease/Progression-free, right) is shown in FIG. 41 .

In lung squamous cell carcinoma, one of the metastatic solid cancers, the case of mutation in the ESR1 gene is shown in red and the case in which no mutation occurs is shown in blue. Overall survival graph (Overall Survival, left) and disease-free survival graph (Disease/Progression-free, right) is shown in FIG. 42 .

In lung squamous cell carcinoma, one of metastatic solid cancers, the case of mutation in the GATA3 gene is shown in red, and the case of no mutation is shown in blue. Overall survival graph (Overall Survival, left) and disease-free survival graph (Disease/Progression-free, right) is shown in FIG. 43 .

In lung squamous cell carcinoma, one of the metastatic solid cancers, the case of mutation in the H3F3B gene is shown in red, and the case of no mutation is shown in blue. Overall survival graph (Overall Survival, left) and disease-free survival graph (Disease/Progression-free, right) is shown in FIG. 44 .

In lung squamous cell carcinoma, one of the metastatic solid cancers, the case where the MYD88 gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. Overall survival graph (Overall Survival, left) and disease-free survival graph (Disease/Progression-free, right) is shown in FIG. 45 .

In cutaneous melanoma, one of metastatic solid cancers, the case of mutations in the CREBBP, ESR1, GATA3 and H3F3B genes is shown in red, and the case in which no mutation occurs is shown in blue, showing the total survival rate graph (Overall Survival, left) and A disease-free survival rate graph (Disease/Progression-free, right) is shown in FIG. 46 .

In cutaneous melanoma, one of metastatic solid cancers, the case where the CREBBP gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. Progression-free, right) is shown in FIG. 47 .

In cutaneous melanoma, one of metastatic solid cancers, the case where the ESR1 gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. Progression-free, right) is shown in FIG. 48 .

In cutaneous melanoma, one of metastatic solid cancers, the case where the GATA3 gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. Progression-free, right) is shown in FIG. 49 .

In cutaneous melanoma, one of metastatic solid cancers, the case of mutation in the H3F3B gene is shown in red and the case in which no mutation occurs is shown in blue. Total survival graph (Overall Survival, left) and disease-free survival graph (Disease/ Progression-free, right) is shown in FIG. 50 .

In Cancer of unknown primary, which is one of the metastatic solid cancers, the case of mutations in the CREBBP, ESR1, GATA3 and H3F3B genes is shown in red, and the case in which no mutation occurs is shown in blue. Overall survival rate graph (Overall Survival, The left) and disease-free survival rate graph (Disease/Progression-free, right) are shown in FIG. 51 .

In Cancer of unknown primary, one of the metastatic solid cancers, the case where the CREBBP gene is mutated is shown in red and the case where the mutation does not occur is shown in blue. Total survival rate graph (Overall Survival, left) and disease-free survival rate graph (Disease/Progression-free, right) is shown in FIG. 52 .

In Cancer of unknown primary, one of metastatic solid cancers, the case where the ESR1 gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. Total survival graph (Overall Survival, left) and disease-free survival graph (Disease/Progression-free, right) is shown in FIG. 53 .

In Cancer of unknown primary, one of metastatic solid cancers, the case where the GATA3 gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. Total survival graph (Overall Survival, left) and disease-free survival graph (Disease/Progression-free, right) is shown in FIG. 54 .

In Cancer of unknown primary, which is one of the metastatic solid cancers, the case in which the H3F3B gene is mutated is shown in red and the case in which no mutation occurs is shown in blue. Total survival graph (Overall Survival, left) and disease-free survival graph (Disease/Progression-free, right) is shown in FIG. 55 .

In Pancreatic adenocarcinoma, one of the metastatic solid cancers, the case of mutations in the CREBBP, ESR1 and MYD88 genes is shown in red and the case in which no mutation occurs is shown in blue. Total survival graph (Overall Survival, left) and disease-free survival rate A graph (Disease/Progression-free, right) is shown in FIG. 56 .

In Pancreatic adenocarcinoma, one of the metastatic solid cancers, the case where the CREBBP gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. Progression-free, right) is shown in FIG. 57 .

In Pancreatic adenocarcinoma, one of metastatic solid cancers, the case in which the ESR1 gene is mutated is shown in red, and the case in which no mutation occurs is shown in blue. Progression-free, right) is shown in FIG. 58 .

In Pancreatic adenocarcinoma, one of the metastatic solid cancers, the case where the MYD88 gene is mutated is shown in red and the case where the mutation does not occur is shown in blue. Total survival graph (Overall Survival, left) and disease-free survival graph (Disease/ Progression-free, right) is shown in FIG. 59 .

In Glioblastoma multiforme, one of the metastatic solid cancers, the case of mutations in the CREBBP, ESR1 and GATA3 genes is shown in red and the case in which no mutation occurs is shown in blue. Total survival graph (Overall Survival, left) and disease-free survival graph (Disease/Progression-free, right) is shown in FIG. 60 .

In Glioblastoma multiforme, one of the metastatic solid cancers, the case where the CREBBP gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. -free, right) is shown in FIG. 61 .

In Glioblastoma multiforme, one of the metastatic solid cancers, the case in which the ESR1 gene is mutated is shown in red, and the case in which no mutation occurs is shown in blue. -free, right) is shown in FIG. 62 .

In glioblastoma multiforme, one of the metastatic solid cancers, the case in which the GATA3 gene is mutated is shown in red, and the case in which no mutation occurs is shown in blue. -free, right) is shown in FIG. 63 .

In colorectal adenocarcinoma, one of metastatic solid cancers, the case of mutations in the CREBBP and GATA3 genes is shown in red and the case in which no mutation occurs is shown in blue. Overall survival graph (Overall Survival, left) and disease-free survival graph (Disease) /Progression-free, right) is shown in FIG. 64 .

In colorectal adenocarcinoma, one of metastatic solid cancers, the case where the CREBBP gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. -free, right) is shown in FIG. 65 .

In colorectal adenocarcinoma, one of metastatic solid cancers, the case where the GATA3 gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. -free, right) is shown in FIG. 66 .

In High grade serous ovarian cancer, one of the metastatic solid cancers, the case of mutations in the CREBBP, ESR1 and GATA3 genes is shown in red, and the case of no mutation is shown in blue. Overall survival rate graph (Overall Survival, Left) and a graph of disease-free survival rate (Disease/Progression-free, right) are shown in FIG. 67 .

In high grade serous ovarian cancer, one of metastatic solid cancers, the case where the CREBBP gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. A survival rate graph (Disease/Progression-free, right) is shown in FIG. 68 .

In high grade serous ovarian cancer, one of the metastatic solid cancers, the case of mutation in the ESR1 gene is shown in red, and the case of no mutation is shown in blue. A graph of survival rate (Disease/Progression-free, right) is shown in FIG. 69 .

In High grade serous ovarian cancer, one of the metastatic solid cancers, the case of mutation in the GATA3 gene is shown in red and the case of no mutation is shown in blue, showing a graph of overall survival rate (Overall Survival, left) and disease-free A survival rate graph (Disease/Progression-free, right) is shown in FIG. 70 .

In Stomach adenocarcinoma, one of metastatic solid cancers, the case of mutations in the CREBBP, ESR1 and MYD88 genes is shown in red and the case in which no mutation occurs is shown in blue. Overall survival graph (Overall Survival, left) and disease-free survival graph ( Disease/Progression-free, right) is shown in FIG. 71 .

In gastric adenocarcinoma, one of metastatic solid cancers, the case where the CREBBP gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. free, right) is shown in FIG. 72 .

In gastric adenocarcinoma, one of metastatic solid cancers, the case in which the ESR1 gene is mutated is shown in red and the case in which no mutation occurs is shown in blue. free, right) is shown in FIG. 73 .

In gastric adenocarcinoma, one of metastatic solid cancers, the case in which the MYD88 gene is mutated is shown in red and the case in which no mutation occurs is shown in blue. free, right) is shown in FIG. 74 .

In Renal clear cell carcinoma, which is one of the metastatic solid cancers, the case where the CREBBP and GATA3 genes are mutated is shown in red, and the case where the mutation does not occur is shown in blue. A graph (Disease/Progression-free, right) is shown in FIG. 75 .

In Renal clear cell carcinoma, one of metastatic solid cancers, the case where the CREBBP gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. Disease/Progression-free, right) is shown in FIG. 76 .

In Renal clear cell carcinoma, one of the metastatic solid cancers, the case where the GATA3 gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. Disease/Progression-free, right) is shown in FIG. 77 .

In esophageal adenocarcinoma, one of metastatic solid cancers, the case of mutations in the ESR1 and GATA3 genes is shown in red, and the case in which no mutation occurs is shown in blue. Total survival graph (Overall Survival, left) and disease-free survival graph (Disease/ Progression-free, right) is shown in FIG. 78 .

In esophageal adenocarcinoma, one of metastatic solid cancers, the case in which the ESR1 gene is mutated is shown in red and the case in which no mutation occurs is shown in blue. free, right) is shown in FIG. 79 .

In esophageal adenocarcinoma, one of the metastatic solid cancers, the case where the GATA3 gene is mutated is shown in red and the case where the mutation does not occur is shown in blue. free, right) is shown in FIG. 80 .

In esophageal adenocarcinoma, one of metastatic solid cancers, the case where the CREBBP gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. free, right) is shown in FIG. 81 .

In testicular cancer, one of the metastatic solid cancers, the case of mutations in the CREBBP, ESR1, GATA3 and H3F3B genes is shown in red and the case in which no mutation occurs is shown in blue. Total survival graph (Overall Survival, left) and disease-free survival rate A graph (Disease/Progression-free, right) is shown in FIG. 82 .

In testicular cancer, one of metastatic solid cancers, the case where the CREBBP gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. free, right) is shown in FIG. 83 .

In testicular cancer, one of the metastatic solid cancers, the case where the ESR1 gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. free, right) is shown in FIG. 84 .

In testicular cancer, one of metastatic solid cancers, the case where the GATA3 gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. free, right) is shown in FIG. 85 .

In testicular cancer, one of metastatic solid cancers, the case where the H3F3B gene is mutated is shown in red and the case where the mutation does not occur is shown in blue. free, right) is shown in FIG. 86 .

In intrahepatic cholangiocarcinoma, one of the metastatic solid cancers, the case where the CREBBP gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. -free, right) is shown in FIG. 87 .

In intrahepatic cholangiocarcinoma, one of the metastatic solid cancers, the case where the CREBBP gene is mutated is shown in red, and the case where the mutation does not occur is shown in blue. -free, right) is shown in FIG. 88 .

Through the above results, the survival rate and recurrence of the patient according to the occurrence of mutation in the gene encoding any one selected from the group consisting of CREBBP, ESR1, GATA3, H3F3B and MYD88 was confirmed. It was confirmed that it can predict the prognosis, in particular, survival or recurrence.

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> Metastic interval-specific markers for diagnosing prognosis and determining treatment strategies in metastatic solid cancer patients <130> PD20-211 <160> 5 <170> KoPatentIn 3.0 <210 > 1 <211> 10790 <212> DNA <213> CREBBP(CREB Binding Protein) <400> 1 aattgaggaa tcaacagccg ccatcttgtc gcggacccga ccggggcttc gagcgcgatc 60 tactcggccc cgccggtccc gggccccaca accgcccgcg caccccgctc cgcccggccg 120 gcccgctccg cccggccctc ggcgcccgcc ccggcggccc cgctcgcctc tcggctcggc 180 ctcccggagc ccggcggcgg cggcggcggc agcggcggcg gcggcggcgg aacggggggt 240 gggggggccg cggcggcggc ggcgaccccg ctcggcgcat tgtttttcct cacggcggcg 300 gcggcggcgg gccgcgggcc gggagcggag cccggagccc cctcgtcgtc gggccgcgag 360 cgaattcatt aagtggggcg cgggggggga gcgaggcggc ggcggcggcg gcaccatgtt 420 ctcggggact gcctgagccg cccggccggg cgccgtcgct gccagccggg cccggggggg 480 cggccgggcc gccggggcgc ccccaccgcg gagtgtcgcg ctcgggaggc gggcagggga 540 tgagggggcc gcggccggcg gcggcggcgg cg gccggggg cgggcggtga gcgctgcggg 600 gcgctgttgc tgtggctgag atttggccgc cgcctccccc acccggcctg cgccctccct 660 ctccctcggc gcccgcccgc ccgctcgcgg cccgcgctcg ctcctctccc tcgcagccgg 720 cagggccccc gacccccgtc cgggccctcg ccggcccggc cgcccgtgcc cggggctgtt 780 ttcgcgagca ggtgaaaatg gctgagaact tgctggacgg accgcccaac cccaaaagag 840 ccaaactcag ctcgcccggt ttctcggcga atgacagcac agattttgga tcattgtttg 900 acttggaaaa tgatcttcct gatgagctga tacccaatgg aggagaatta ggccttttaa 960 acagtgggaa ccttgttcca gatgctgctt ccaaacataa acaactgtcg gagcttctac 1020 gaggaggcag cggctctagt atcaacccag gaataggaaa tgtgagcgcc agcagccccg 1080 tgcagcaggg cctgggtggc caggctcaag ggcagccgaa cagtgctaac atggccagcc 1140 tcagtgccat gggcaagagc cctctgagcc agggagattc ttcagccccc agcctgccta 1200 aacaggcagc cagcacctct gggcccaccc ccgctgcctc ccaagcactg aatccgcaag 1260 cacaaaagca agtggggctg gcgactagca gccctgccac gtcacagact ggacctggta 1320 tctgcatgaa tgctaacttt aaccagaccc acccaggcct cctcaatagt aactctggcc 1380 atagcttaat taatcaggct tcacaagggc aggcgcaagt 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cggactcccc tacatgaacc 2280 agccccagac gcagctgcag cctcaggttc ctggccagca accagcacag cctcaaaccc 2340 accagcagat gaggactctc aaccccctgg gaaataatcc aatgaacatt ccagcaggag 2400 gaataacaac agatcagcag cccccaaact tgatttcaga atcagctctt ccgacttccc 2460 tgggggccac aaacccactg atgaacgatg gctccaactc tggtaacatt ggaaccctca 2520 gcactatacc aacagcagct cctccttcta gcaccggtgt aaggaaaggc tggcacgaac 2580 atgtcactca ggacctgcgg agccatctag tgcataaact cgtccaagcc atcttcccaa 2640 cacctgatcc cgcagctcta aaggatcgcc gcatggaaaa cctggtagcc tatgctaaga 2700 aagtggaagg ggacatgtac gagtctgcca acagcaggga tgaatattat cacttattag 2760 cagagaaaat ctacaagata caaaaagaac tagaagaaaa acggaggtcg cgtttacata 2820 aacaaggcat cttggggaac cagccagcct taccagcccc gggggctcag ccccctgtga 2880 ttccacaggc acaacctgtg agacctccaa atggacccct gtccctgcca gtgaatcgca 2940 tgcaagtttc tcaagggatg aattcattta accccatgtc cttggggaac gtccagttgc 3000 cacaagcacc catgggacct cgtgcagcct ccccaatgaa ccactctgtc cagatgaaca 3060 gcatgggctc agtgccaggg atggccattt ctccttcccg aatgcctcag cctcc gaaca 3120 tgatgggtgc acacaccaac aacatgatgg cccaggcgcc cgctcagagc cagtttctgc 3180 cacagaacca gttcccgtca tccagcgggg cgatgagtgt gggcatgggg cagccgccag 3240 cccaaacagg cgtgtcacag ggacaggtgc ctggtgctgc tcttcctaac cctctcaaca 3300 tgctggggcc tcaggccagc cagctacctt gccctccagt gacacagtca ccactgcacc 3360 caacaccgcc tcctgcttcc acggctgctg gcatgccatc tctccagcac acgacaccac 3420 ctgggatgac tcctccccag ccagcagctc ccactcagcc atcaactcct gtgtcgtctt 3480 ccgggcagac tcccaccccg actcctggct cagtgcccag tgctacccaa acccagagca 3540 cccctacagt ccaggcagca gcccaggccc aggtgacccc gcagcctcaa accccagttc 3600 agcccccgtc tgtggctacc cctcagtcat cgcagcaaca gccgacgcct gtgcacgccc 3660 agcctcctgg cacaccgctt tcccaggcag cagccagcat tgataacaga gtccctaccc 3720 cctcctcggt ggccagcgca gaaaccaatt cccagcagcc aggacctgac gtacctgtgc 3780 tggaaatgaa gacggagacc caagcagagg acactgagcc cgatcctggt gaatccaaag 3840 gggagcccag gtctgagatg atggaggagg atttgcaagg agcttcccaa gttaaagaag 3900 aaacagacat agcagagcag aaatcagaac caatggaagt ggatgaaaag aaacctgaag 3960 tgaaagtaga agttaaagag gaagaagaga gtagcagtaa cggcacagcc tctcagtcaa 4020 catctccttc gcagccgcgc aaaaaaatct ttaaaccaga ggagttacgc caggccctca 4080 tgccaaccct agaagcactg tatcgacagg acccagagtc attacctttc cggcagcctg 4140 tagatcccca gctcctcgga attccagact attttgacat cgtaaagaat cccatggacc 4200 tctccaccat caagcggaag ctggacacag ggcaatacca agagccctgg cagtacgtgg 4260 acgacgtctg gctcatgttc aacaatgcct ggctctataa tcgcaagaca tcccgagtct 4320 ataagttttg cagtaagctt gcagaggtct ttgagcagga aattgaccct gtcatgcagt 4380 cccttggata ttgctgtgga cgcaagtatg agttttcccc acagactttg tgctgctatg 4440 ggaagcagct gtgtaccatt cctcgcgatg ctgcctacta cagctatcag aataggtatc 4500 atttctgtga gaagtgtttc acagagatcc agggcgagaa tgtgaccctg ggtgacgacc 4560 cttcacagcc ccagacgaca atttcaaagg atcagtttga aaagaagaaa aatgatacct 4620 tagaccccga acctttcgtt gattgcaagg agtgtggccg gaagatgcat cagatttgcg 4680 ttctgcacta tgacatcatt tggccttcag gttttgtgtg cgacaactgc ttgaagaaaa 4740 ctggcagacc tcgaaaagaa aacaaattca gtgctaagag gctgcagacc acaagactgg 4800 g aaaccactt ggaagaccga gtgaacaaat ttttgcggcg ccagaatcac cctgaagccg 4860 gggaggtttt tgtccgagtg gtggccagct cagacaagac ggtggaggtc aagcccggga 4920 tgaagtcacg gtttgtggat tctggggaaa tgtctgaatc tttcccatat cgaaccaaag 4980 ctctgtttgc ttttgaggaa attgacggcg tggatgtctg cttttttgga atgcacgtcc 5040 aagaatacgg ctctgattgc ccccctccaa acacgaggcg tgtgtacatt tcttatctgg 5100 atagtattca tttcttccgg ccacgttgcc tccgcacagc cgtttaccat gagatcctta 5160 ttggatattt agagtatgtg aagaaattag ggtatgtgac agggcacatc tgggcctgtc 5220 ctccaagtga aggagatgat tacatcttcc attgccaccc acctgatcaa aaaataccca 5280 agccaaaacg actgcaggag tggtacaaaa agatgctgga caaggcgttt gcagagcgga 5340 tcatccatga ctacaaggat attttcaaac aagcaactga agacaggctc accagtgcca 5400 aggaactgcc ctattttgaa ggtgatttct ggcccaatgt gttagaagag agcattaagg 5460 aactagaaca agaagaagag gagaggaaaa aggaagagag cactgcagcc agtgaaacca 5520 ctgagggcag tcagggcgac agcaagaatg ccaagaagaa gaacaacaag aaaaccaaca 5580 agaacaaaag cagcatcagc cgcgccaaca agaagaagcc cagcatgccc aacgtgtcca 5640 atgacct gtc ccagaagctg tatgccacca tggagaagca caaggaggtc ttcttcgtga 5700 tccacctgca cgctgggcct gtcatcaaca ccctgccccc catcgtcgac cccgaccccc 5760 tgctcagctg tgacctcatg gatgggcgcg acgccttcct caccctcgcc agagacaagc 5820 actgggagtt ctcctccttg cgccgctcca agtggtccac gctctgcatg ctggtggagc 5880 tgcacaccca gggccaggac cgctttgtct acacctgcaa cgagtgcaag caccacgtgg 5940 agacgcgctg gcactgcact gtgtgcgagg actacgacct ctgcatcaac tgctataaca 6000 cgaagagcca tgcccataag atggtgaagt gggggctggg cctggatgac gagggcagca 6060 gccagggcga gccacagtca aagagccccc aggagtcacg ccggctgagc atccagcgct 6120 gcatccagtc gctggtgcac gcgtgccagt gccgcaacgc caactgctcg ctgccatcct 6180 gccagaagat gaagcgggtg gtgcagcaca ccaagggctg caaacgcaag accaacgggg 6240 gctgcccggt gtgcaagcag ctcatcgccc tctgctgcta ccacgccaag cactgccaag 6300 aaaacaaatg ccccgtgccc ttctgcctca acatcaaaca caagctccgc cagcagcaga 6360 tccagcaccg cctgcagcag gcccagctca tgcgccggcg gatggccacc atgaacaccc 6420 gcaacgtgcc tcagcagagt ctgccttctc ctacctcagc accgcccggg acccccacac 6480 agcagcccag ca caccccag acgccgcagc cccctgccca gccccaaccc tcacccgtga 6540 gcatgtcacc agctggcttc cccagcgtgg cccggactca gccccccacc acggtgtcca 6600 cagggaagcc taccagccag gtgccggccc ccccaccccc ggcccagccc cctcctgcag 6660 cggtggaagc ggctcggcag atcgagcgtg aggcccagca gcagcagcac ctgtaccggg 6720 tgaacatcaa caacagcatg cccccaggac gcacgggcat ggggaccccg gggagccaga 6780 tggcccccgt gagcctgaat gtgccccgac ccaaccaggt gagcgggccc gtcatgccca 6840 gcatgcctcc cgggcagtgg cagcaggcgc cccttcccca gcagcagccc atgccaggct 6900 tgcccaggcc tgtgatatcc atgcaggccc aggcggccgt ggctgggccc cggatgccca 6960 gcgtgcagcc acccaggagc atctcaccca gcgctctgca agacctgctg cggaccctga 7020 agtcgcccag ctcccctcag cagcaacagc aggtgctgaa cattctcaaa tcaaacccgc 7080 agctaatggc agctttcatc aaacagcgca cagccaagta cgtggccaat cagcccggca 7140 tgcagcccca gcctggcctc cagtcccagc ccggcatgca accccagcct ggcatgcacc 7200 agcagcccag cctgcagaac ctgaatgcca tgcaggctgg cgtgccgcgg cccggtgtgc 7260 ctccacagca gcaggcgatg ggaggcctga acccccaggg ccaggccttg aacatcatga 7320 acccaggaca caacccca ac atggcgagta tgaatccaca gtaccgagaa atgttacgga 7380 ggcagctgct gcagcagcag cagcaacagc agcagcaaca acagcagcaa cagcagcagc 7440 agcaagggag tgccggcatg gctgggggca tggcggggca cggccagttc cagcagcctc 7500 aaggacccgg aggctaccca ccggccatgc agcagcagca gcgcatgcag cagcatctcc 7560 ccctccaggg cagctccatg ggccagatgg cggctcagat gggacagctt ggccagatgg 7620 ggcagccggg gctgggggca gacagcaccc ccaacatcca gcaagccctg cagcagcgga 7680 ttctgcagca acagcagatg aagcagcaga ttgggtcccc aggccagccg aaccccatga 7740 gcccccagca acacatgctc tcaggacagc cacaggcctc gcatctccct ggccagcaga 7800 tcgccacgtc ccttagtaac caggtgcggt ctccagcccc tgtccagtct ccacggcccc 7860 agtcccagcc tccacattcc agcccgtcac cacggataca gccccagcct tcgccacacc 7920 acgtctcacc ccagactggt tccccccacc ccggactcgc agtcaccatg gccagctcca 7980 tagatcaggg acacttgggg aaccccgaac agagtgcaat gctcccccag ctgaacaccc 8040 ccagcaggag tgcgctgtcc agcgaactgt ccctggtcgg ggacaccacg ggggacacgc 8100 tagagaagtt tgtggagggc ttgtagcatt gtgagagcat caccttttcc ctttcatgtt 8160 cttggacctt ttgtactgaa aat ccaggca tctaggttct ttttattcct agatggaact 8220 gcgacttccg agccatggaa gggtggattg atgtttaaag aaacaataca aagaatatat 8280 ttttttgtta aaaaccagtt gatttaaata tctggtctct ctctttggtt tttttttggc 8340 gggggggtgg ggggggttct tttttttccg ttttgttttt gtttgggggg aggggggttt 8400 tgtttggatt ctttttgtcg tcattgctgg tgactcatgc ctttttttaa cgggaaaaac 8460 aagttcatta tattcatatt ttttatttgt attttcaaga ctttaaacat ttatgtttaa 8520 aagtaagaag aaaaataata ttcagaactg attcctgaaa taatgcaagc ttataatgta 8580 tcccgataac tttgtgatgt ttcgggaaga tttttttcta tagtgaactc tgtgggcgtc 8640 tcccagtatt accctggatg ataggaattg actccggcgt gcacacacgt acacacccac 8700 acacatctat ctatacataa tggctgaagc caaacttgtc ttgcagatgt agaaattgtt 8760 gctttgtttc tctgataaaa ctggttttag acaaaaaata gggatgatca ctcttagacc 8820 atgctaatgt tactagagaa gaagccttct tttctttctt ctatgtgaaa cttgaaatga 8880 ggaaaagcaa ttctagtgta aatcatgcaa gcgctctaat tcctataaat acgaaactcg 8940 agaagattca atcactgtat agaatggtaa aataccaact catttcttat atcatattgt 9000 taaataaact gtgtgcaaca gacaaaaag g gtggtccttc ttgaattcat gtacatggta 9060 ttaacactta gtgttcgggg ttttttgtta tgaaaatgct gttttcaaca ttgtatttgg 9120 actatgcatg tgttttttcc ccattgtata taaagtaccg cttaaaattg atataaatta 9180 ctgaggtttt taacatgtat tctgttcttt aagatccctg taagaatgtt taaggttttt 9240 atttatttat atatattttt tgagtctgtt ctttgtaaga catggttctg gttgttcgct 9300 catagcggag aggctggggc tgcggttgtg gttgtggcgg cgtgggtggt ggctgggaac 9360 tgtggcccag gcttagcggc cgcccggagg cttttcttcc cggagactga ggtgggcgac 9420 tgaggtgggc ggctcagcgt tggccccaca cattcgaggc tcacaggtga ttgtcgctca 9480 cacagttagg gtcgtcagtt ggtctgaaac tgcatttggc ccactcctcc atcctccctg 9540 tccgtcgtag ctgccacccc cagaggcggc gcttcttccc gtgttcaggc ggctcccccc 9600 ccccgtacac gactcccaga atctgaggca gagagtgctc caggctcgcg aggtgctttc 9660 tgacttcccc ccaaatcctg ccgctgccgc gcagcatgtc ccgtgtggcg tttgaggaaa 9720 tgctgaggga cagacacctt ggagcaccag ctccggtccc tgttacagtg agaaaggtcc 9780 cccacttcgg gggatacttg cacttagcca catggtcctg cctcccttgg agtccagttc 9840 caggctccct tactgagtgg gtgagacaag ttca caaaaa ccgtaaaact gagaggagga 9900 ccatgggcag gggagctgaa gttcatcccc taagtctacc acccccagca cccagagaac 9960 ccactttatc cctagtcccc caacaaaggc tggtctaggt gggggtgatg gtaattttag 10020 aaatcacgcc ccaaatagct tccgtttggg cccttacatt cacagatagg ttttaaatag 10080 ctgaatactt ggtttgggaa tctgaattcg aggaaccttt ctaagaagtt ggaaaggtcc 10140 gatctagttt tagcacagag ctttgaacct tgagttataa aatgcagaat aattcaagta 10200 aaaataagac caccatctgg cacccctgac cagcccccat tcaccccatc ccaggagggg 10260 aagcacaggc cgggcctccg gtggagattg ctgccactgc tcggcctgct gggttcttaa 10320 cctccagtgt cctcttcatc ttttccaccc gtagggaaac cttgagccat gtgttcaaac 10380 aagaagtggg gctagagccc gagagcagca gctctaagcc cacactcaga aagtggcgcc 10440 ctcctggttg tgcagccttt taatgtgggc agtggagggg cctctgtttc aggttatcct 10500 ggaattcaaa acgttatgta ccaacctcat cctctttgga gtctgcatcc tgtgcaaccg 10560 tcttgggcaa tccagatgtc gaaggatgtg accgagagca tggtctgtgg atgctaaccc 10620 taagtttgtc gtaaggaaat ttctgtaaga aacctggaaa gccccaacgc tgtgtctcat 10680 gctgtatact taagaggaga agaaaaagt c ctatatttgt gatcaaaaag aggaaacttg 10740 aaatgtgatg gtgtttataa taaaagatgg taaaactact tggattcaaa 10790 <210> 2 <211> 6327 <212> DNA <213> ESR1(Estrogen Receptor 1) <400> 2 agctggcgga gggcgttcgt cctgggactg cacttgctcc cgtcgggtcg cccggcttca 60 ccggacccgc aggctcccgg ggcagggccg gggccagagc tcgcgtgtcg gcgggacatg 120 cgctgcgtcg cctctaacct cgggctgtgc tctttttcca ggtggcccgc cggtttctga 180 gccttctgcc ctgcggggac acggtctgca ccctgcccgc ggccacggac catgaccatg 240 accctccaca ccaaagcatc tgggatggcc ctactgcatc agatccaagg gaacgagctg 300 gagcccctga accgtccgca gctcaagatc cccctggagc ggcccctggg cgaggtgtac 360 ctggacagca gcaagcccgc cgtgtacaac taccccgagg gcgccgccta cgagttcaac 420 gccgcggccg ccgccaacgc gcaggtctac ggtcagaccg gcctccccta cggccccggg 480 tctgaggctg cggcgttcgg ctccaacggc ctggggggtt tccccccact caacagcgtg 540 tctccgagcc cgctgatgct actgcacccg ccgccgcagc tgtcgccttt cctgcagccc 600 cacggccagc aggtgcccta ctacctggag aacgagccca gcggctacac ggtgcgcgag 660 gccggcccgc cggcaaat tcagg cagg gagaa 720 agattggcca gtaccaatga caagggaagt atggctatgg aatctgccaa ggagactcgc 780 tactgtgcag tgtgcaatga ctatgcttca ggctaccatt atggagtctg gtcctgtgag 840 ggctgcaagg ccttcttcaa gagaagtatt caaggacata acgactatat gtgtccagcc 900 accaaccagt gcaccattga taaaaacagg aggaagagct gccaggcctg ccggctccgt 960 aaatgctacg aagtgggaat gatgaaaggt gggatacgaa aagaccgaag aggagggaga 1020 atgttgaaac acaagcgcca gagagatgat ggggagggca ggggtgaagt ggggtctgct 1080 ggagacatga gagctgccaa cctttggcca agcccgctca tgatcaaacg ctctaagaag 1140 aacagcctgg ccttgtccct gacggccgac cagatggtca gtgccttgtt ggatgctgag 1200 cccccgatac tctattccga gtatgatcct accagaccct tcagtgaagc ttcgatgatg 1260 ggcttactga ccaacctggc agacagggag ctggttcaca tgatcaactg ggcgaagagg 1320 gtgccaggct ttgtggattt gaccctccat gatcaggtcc accttctaga atgtgcctgg 1380 ctagagatcc tgatgattgg tctcgtctgg cgctccatgg agcacccagg gaagctactg 1440 tttgctccta acttgctctt ggacaggaac cagggaaaat gtgtagaggg catggtggag 1500 atcttcgaca tgctgctggc tacatcatct cggttccgca tgatgaatct gcagggagag 1560gagtttgtgt gcctcaaatc tattattttg cttaattctg gagtgtacac atttctgtcc 1620 agcaccctga agtctctgga agagaaggac catatccacc gagtcctgga caagatcaca 1680 gacactttga tccacctgat ggccaaggca ggcctgaccc tgcagcagca gcaccagcgg 1740 ctggcccagc tcctcctcat cctctcccac atcaggcaca tgagtaacaa aggcatggag 1800 catctgtaca gcatgaagtg caagaacgtg gtgcccctct atgacctgct gctggagatg 1860 ctggacgccc accgcctaca tgcgcccact agccgtggag gggcatccgt ggaggagacg 1920 gaccaaagcc acttggccac tgcgggctct acttcatcgc attccttgca aaagtattac 1980 atcacggggg aggcagaggg tttccctgcc acggtctgag agctccctgg ctcccacacg 2040 gttcagataa tccctgctgc attttaccct catcatgcac cactttagcc aaattctgtc 2100 tcctgcatac actccggcat gcatccaaca ccaatggctt tctagatgag tggccattca 2160 tttgcttgct cagttcttag tggcacatct tctgtcttct gttgggaaca gccaaaggga 2220 ttccaaggct aaatctttgt aacagctctc tttccccctt gctatgttac taagcgtgag 2280 gattcccgta gctcttcaca gctgaactca gtctatgggt tggggctcag ataactctgt 2340 gcatttaagc tacttgtaga gacccaggcc tggagagtag acattttgcc tctgataagc 2400 actttt taaa tggctctaag aataagccac agcaaagaat ttaaagtggc tcctttaatt 2460 ggtgacttgg agaaagctag gtcaagggtt tattatagca ccctcttgta ttcctatggc 2520 aatgcatcct tttatgaaag tggtacacct taaagctttt atatgactgt agcagagtat 2580 ctggtgattg tcaattcatt ccccctatag gaatacaagg ggcacacagg gaaggcagat 2640 cccctagttg gcaagactat tttaacttga tacactgcag attcagatgt gctgaaagct 2700 ctgcctctgg ctttccggtc atgggttcca gttaattcat gcctcccatg gacctatgga 2760 gagcagcaag ttgatcttag ttaagtctcc ctatatgagg gataagttcc tgatttttgt 2820 ttttattttt gtgttacaaa agaaagccct ccctccctga acttgcagta aggtcagctt 2880 caggacctgt tccagtgggc actgtacttg gatcttcccg gcgtgtgtgt gccttacaca 2940 ggggtgaact gttcactgtg gtgatgcatg atgagggtaa atggtagttg aaaggagcag 3000 gggccctggt gttgcattta gccctggggc atggagctga acagtacttg tgcaggattg 3060 ttgtggctac tagagaacaa gagggaaagt agggcagaaa ctggatacag ttctgaggca 3120 cagccagact tgctcagggt ggccctgcca caggctgcag ctacctagga acattccttg 3180 cagaccccgc attgcccttt gggggtgccc tgggatccct ggggtagtcc agctcttctt 3240 catttcccag cgtggccctg gttggaagaa gcagctgtca cagctgctgt agacagctgt 3300 gttcctacaa ttggcccagc accctggggc acgggagaag ggtggggacc gttgctgtca 3360 ctactcaggc tgactggggc ctggtcagat tacgtatgcc cttggtggtt tagagataat 3420 ccaaaatcag ggtttggttt ggggaagaaa atcctccccc ttcctccccc gccccgttcc 3480 ctaccg cctc cactcctgcc agctcatttc cttcaatttc ctttgaccta taggctaaaa 3540 aagaaaggct cattccagcc acagggcagc cttccctggg cctttgcttc tctagcacaa 3600 ttatgggtta cttccttttt cttaacaaaa aagaatgttt gatttcctct gggtgacctt 3660 attgtctgta attgaaaccc tattgagagg tgatgtctgt gttagccaat gacccaggtg 3720 agctgctcgg gcttctcttg gtatgtcttg tttggaaaag tggatttcat tcatttctga 3780 ttgtccagtt aagtgatcac caaaggactg agaatctggg agggcaaaaa aaaaaaaaaa 3840 gtttttatgt gcacttaaat ttggggacaa ttttatgtat ctgtgttaag gatatgttta 3900 agaacataat tcttttgttg ctgtttgttt aagaagcacc ttagtttgtt taagaagcac 3960 cttatatagt ataatatata tttttttgaa attacattgc ttgtttatca gacaattgaa 4020 tgtagtaatt ctgttctgga tttaatttga ctgggttaac atgcaaaaac caaggaaaaa 4080 tatttagttt tttttttttt ttttgtatac ttttcaagct accttgtcat gtatacagtc 4140 atttatgcct aaagcctggt gattattcat ttaaatgaag atcacatttc atatcaactt 4200 ttgtatccac agtagacaaa atagcactaa tccagatgcc tattgttgga tactgaatga 4260 cagacaatct tatgtagcaa agattatgcc tgaaaaggaa aattattcag ggcagctaat 4320 tttgctttta c caaaatatc agtagtaata tttttggaca gtagctaatg ggtcagtggg 4380 ttctttttaa tgtttatact tagattttct tttaaaaaaa ttaaaataaa acaaaaaaaa 4440 atttctagga ctagacgatg taataccagc taaagccaaa caattataca gtggaaggtt 4500 ttacattatt catccaatgt gtttctattc atgttaagat actactacat ttgaagtggg 4560 cagagaacat cagatgattg aaatgttcgc ccaggggtct ccagcaactt tggaaatctc 4620 tttgtatttt tacttgaagt gccactaatg gacagcagat attttctggc tgatgttggt 4680 attgggtgta ggaacatgat ttaaaaaaaa actcttgcct ctgctttccc ccactctgag 4740 gcaagttaaa atgtaaaaga tgtgatttat ctggggggct caggtatggt ggggaagtgg 4800 attcaggaat ctggggaatg gcaaatatat taagaagagt attgaaagta tttggaggaa 4860 aatggttaat tctgggtgtg caccagggtt cagtagagtc cacttctgcc ctggagacca 4920 caaatcaact agctccattt acagccattt ctaaaatggc agcttcagtt ctagagaaga 4980 aagaacaaca tcagcagtaa agtccatgga atagctagtg gtctgtgttt cttttcgcca 5040 ttgcctagct tgccgtaatg attctataat gccatcatgc agcaattatg agaggctagg 5100 tcatccaaag agaagaccct atcaatgtag gttgcaaaat ctaaccccta aggaagtgca 5160 gtctttgatt tgatttc cct agtaaccttg cagatatgtt taaccaagcc atagcccatg 5220 ccttttgagg gctgaacaaa taagggactt actgataatt tacttttgat cacattaagg 5280 tgttctcacc ttgaaatctt atacactgaa atggccattg atttaggcca ctggcttaga 5340 gtactccttc ccctgcatga cactgattac aaatactttc ctattcatac tttccaatta 5400 tgagatggac tgtgggtact gggagtgatc actaacacca tagtaatgtc taatattcac 5460 aggcagatct gcttggggaa gctagttatg tgaaaggcaa atagagtcat acagtagctc 5520 aaaaggcaac cataattctc tttggtgcag gtcttgggag cgtgatctag attacactgc 5580 accattccca agttaatccc ctgaaaactt actctcaact ggagcaaatg aactttggtc 5640 ccaaatatcc atcttttcag tagcgttaat tatgctctgt ttccaactgc atttcctttc 5700 caattgaatt aaagtgtggc ctcgttttta gtcatttaaa attgttttct aagtaattgc 5760 tgcctctatt atggcacttc aattttgcac tgtcttttga gattcaagaa aaatttctat 5820 tctttttttt gcatccaatt gtgcctgaac ttttaaaata tgtaaatgct gccatgttcc 5880 aaacccatcg tcagtgtgtg tgtttagagc tgtgcaccct agaaacaaca tattgtccca 5940 tgagcaggtg cctgagacac agaccccttt gcattcacag agaggtcatt ggttatagag 6000 acttgaatta ataagtgaca tt atgccagt ttctgttctc tcacaggtga taaacaatgc 6060 tttttgtgca ctacatactc ttcagtgtag agctcttgtt ttatgggaaa aggctcaaat 6120 gccaaattgt gtttgatgga ttaatatgcc cttttgccga tgcatactat tactgatgtg 6180 actcggtttt gtcgcagctt tgctttgttt aatgaaacac acttgtaaac ctcttttgca 6240 ctttgaaaaa gaatccagcg ggatgctcga gcacctgtaa acaattttct caacctattt 6300 gatgttcaaa taaagaatta aactaaa 6327 <210> 3 <211> 3083 <212> DNA < 213> GATA3(GATA Binding Protein 3) <400> 3 gaacactgag ctgcctggcg ccgtcttgat actttcagaa agaatgcatt ccctgtaaaa 60 aaaaaaaaaa aatactgaga gagggagaga gagagagaag aagagagaga gacggaggga 120 gagcgagaca gagcgagcaa cgcaatctga ccgagcaggt cgtacgccgc cgcctcctcc 180 tcctctctgc tcttcgctac ccaggtgacc cgaggaggga ctccgcctcc gagcggctga 240 ggaccccggt gcagaggagc ctggctcgca gaattgcaga gtcgtcgccc ctttttacaa 300 cctggtcccg ttttattctg ccgtacccag tttttggatt tttgtcttcc ccttcttctc 360 tttgctaaac gacccctcca agataatttt taaaaaacct tctcctttgc tcacctttgc 420 ttcccagcct ccttcccagcct ccctgacccc caaat gacc gcaggagc cccccgacct cccaggcgga ccgccctccc tccccgcgcg cgggttccgg 540 gcccggcgag agggcgcgag cacagccgag gccatggagg tgacggcgga ccagccgcgc 600 tgggtgagcc accaccaccc cgccgtgctc aacgggcagc acccggacac gcaccacccg 660 ggcctcagcc actcctacat ggacgcggcg cagtacccgc tgccggagga ggtggatgtg 720 ctttttaaca tcgacggtca aggcaaccac gtcccgccct actacggaaa ctcggtcagg 780 gccacggtgc agaggtaccc tccgacccac cacgggagcc aggtgtgccg cccgcctctg 840 cttcatggat ccctaccctg gctggacggc ggcaaagccc tgggcagcca ccacaccgcc 900 tccccctgga atctcagccc cttctccaag acgtccatcc accacggctc cccggggccc 960 ctctccgtct accccccggc ctcgtcctcc tccttgtcgg ggggccacgc cagcccgcac 1020 ctcttcacct tcccgcccac cccgccgaag gacgtctccc cggacccatc gctgtccacc 1080 ccaggctcgg ccggctcggc ccggcaggac gagaaagagt gcctcaagta ccaggtgccc 1140 ctgcccgaca gcatgaagct ggagtcgtcc cactcccgtg gcagcatgac cgccctgggt 1200 ggagcctcct cgtcgaccca ccaccccatc accacctacc cgccctacgt gcccgagtac 1260 agctccggac tcttcccccc cagcagcctg ctgggcggct cccccaccgg cttcggatgc 1320 aagtccaggc ccaag gcccg gtccagcaca gaaggcaggg agtgtgtgaa ctgtggggca 1380 acctcgaccc cactgtggcg gcgagatggc acgggacact acctgtgcaa cgcctgcggg 1440 ctctatcaca aaatgaacgg acagaaccgg cccctcatta agcccaagcg aaggctgtct 1500 gcagccagga gagcagggac gtcctgtgcg aactgtcaga ccaccacaac cacactctgg 1560 aggaggaatg ccaatgggga ccctgtctgc aatgcctgtg ggctctacta caagcttcac 1620 aatattaaca gacccctgac tatgaagaag gaaggcatcc agaccagaaa ccgaaaaatg 1680 tctagcaaat ccaaaaagtg caaaaaagtg catgactcac tggaggactt ccccaagaac 1740 agctcgttta acccggccgc cctctccaga cacatgtcct ccctgagcca catctcgccc 1800 ttcagccact ccagccacat gctgaccacg cccacgccga tgcacccgcc atccagcctg 1860 tcctttggac cacaccaccc ctccagcatg gtcaccgcca tgggttagag ccctgctcga 1920 tgctcacagg gcccccagcg agagtccctg cagtcccttt cgacttgcat ttttgcagga 1980 gcagtatcat gaagcctaaa cgcgatggat atatgttttt gaaggcagaa agcaaaatta 2040 tgtttgccac tttgcaaagg agctcactgt ggtgtctgtg ttccaaccac tgaatctgga 2100 ccccatctgt gaataagcca ttctgactca tatcccctat ttaacagggt ctctagtgct 2160 gtgaaaaaaa aaatgctgaa cattgcatat aacttatatt gtaagaaata ctgtacaatg 2220 actttattgc atctgggtag ctgtaaggca tgaaggatgc caagaagttt aaggaatatg 2280 ggagaaatag tgtggaaatt aagaagaaac taggtctgat attcaaatgg acaaactgcc 2340 agttttgttt cctttcactg gccacagttg tttgatgcat taaaagaaaa taaaaaaaag 2400 aaaaaagaga aaagaaaaaa aaagaaaaaa gttgtaggcg aatcatttgt tcaaagctgt 2460 tggcctctgc aaaggaaata ccagttctgg gcaatcagtg ttaccgttca ccagttgccg 2520 ttgagggttt cagagagcct ttttctaggc ctacatgctt tgtgaacaag tccctgtaat 2580 tgttgtttgt atgtataatt caaagcacca aaataagaaa agatgtagat ttatttcatc 2640 atattataca gaccgaactg ttgtataaat ttatttactg ctagtcttaa gaactgcttt 2700 ctttcgtttg tttgtttcaa tattttcctt ctctctcaat ttttggttga ataaactaga 2760 ttacattcag ttggcctaag gtggttgtgc tcggagggtt tcttgtttct tttccatttt 2820 gtttttggat gatatttatt aaatagcttc taagagtccg gcggcatctg tcttgtccct 2880 attcctgcag cctgtgctga gggtagcagt gtatgagcta ccagcgtgca tgtcagcgac 2940 cctggcccga caggccacgt cctgcaatcg gcccggctgc ctcttcgccc tgtcgtgttc 3000 tgtgttagtg atcactgcct ttaata cagt ctgttggaat aatattataa gcataataat 3060 aaagtgaaaa tattttaaaa cta 3083 <210> 4 <211> 2705 <212> DNA <213> H3F3B(H3.3 Histone B) <400> 4 gagcgcagag cggtttggtc gttcgttggg cggtgctggt ttttcgctcg tcgactgcgg 60 ctcttcctcg ggcagcggaa gcggcgcggc ggtcggagaa gtggcctaaa acttcggcgt 120 tgggtgaaag aaaatggccc gaaccaagca gactgctcgt aagtccaccg gtgggaaagc 180 cccccgcaaa cagctggcca cgaaagccgc caggaaaagc gctccctcta ccggcggggt 240 gaagaagcct catcgctaca ggcccgggac cgtggcgctt cgagagattc gtcgttatca 300 gaagtcgacc gagctgctca tccggaagct gcccttccag aggttggtga gggagatcgc 360 gcaggatttc aaaaccgacc tgaggtttca gagcgcagcc atcggtgcgc tgcaggaggc 420 tagcgaagcg tacctggtgg gtctgttcga agataccaac ctgtgtgcca tccacgctaa 480 gagagtcacc atcatgccca aagacatcca gttggctcgc cggatacggg gagagagagc 540 ttaagtgaag gcagttttta tggcgttttg tagtaaattc tgtaaaatac tttggtttaa 600 tttgtgactt tttttgtaag aaattgttta taatatgttg catttgtact taagtcattc 660 catctttcgtac tcaggatgatagtcagtga tga gaacttcgtac tg c gttgctaata tgcagaaggg atgggtgata cttcttgctt 780 ctcatgatgc atgtttctgt atgttaatga cttgttgggt agctattaag gtactagagt 840 tgataaatgt gtacagggtc cttttgcaat aaaactggtt atgacttgat ccaagtgttt 900 aacaattggg gctgttaagt ctgaccatac atcactgtga tagaatgtgg gctttttcaa 960 gggtgaagat acaagtctta accacagtgt aacttacagt ttcctttaaa aaaaaaaaaa 1020 gtaaacctgg cagctataga atacactatg tgcatttata atagctattt tatatattgt 1080 agtatcaaca tttttaaatt aaatgtttta cattcacaag tggtggggag tcttgtcatt 1140 aaggtgtgtg taatttagag tccagttggt tttcttctga ctgcacttgt tctcatagta 1200 gtaaaatgct atgcgcattt ataccttgca taagtcctca ttctaccaca tgttaaccct 1260 ctagctgata atgcaaacac taactggggg attttattta taagggctct agaaaaaacg 1320 agttattcac accagcatca tcttaactaa cattctgaac tagttagtgc agcttttcat 1380 tgtgttgtgt ggttggtctc ataactaggt tgagtttttc tcctctgctg aggaaacagt 1440 accgaagttc tttttcttgt ggcatttgta ttataaaaac ttggtgtggg ggaggagcac 1500 aaaactccag cccactgaac ctctgccaat taagatggtg ttgggttagg ttacatctgg 1560 ttactgtcct gggaaaatca tttttataga gatggccttc caagtggttt taaaatttac 1620 tgaagttttt aggtcaatta tgtatgttga ctaaatttac aaataaactt gtttatccaa 1680 ctaagtgtcc aaaacctaaa ttgaatgtac taagttttca catgtcccat tatctaggtc 1740 cttgtatact aatgttttga acttagatca tttcaggtgt tgtttggtgg ataaaggaac 1800 cttttattta taaagatact gtagaaagca tgtgaacagc tctctgcttg attaagatgc 1860 cataatagtg ctgtatttgc agtgtgggct aagacaaagt atattaataa gcttttcagc 1920 ccccccactc ccgttccgta gtgtagaagc ccacaggtgt agaactcagt cttaaacttc 1980 agtatgaaac cagtttcctt gtgcgatgat ggccactaaa gcatagtacg tggatgtcag 2040 tgagacagca tgagagccag cagtcatcaa agcgttccac gtttgaagtt agcaactgct 2100 taaagttata ccccattaaa attgctttct caaaagtttg ggttagtttc aaatgtgata 2160 ttttggaggg aaggtaaagt aggtatcttt caggtcgtga taatgagctc ctatgaaagg 2220 atgcaatata atgacccgct tttctagaaa gttcataatc agctctggaa caagcacact 2280 tgattcctca ctgtgcttca gaatgagatt aagatcagat gttggaacgt gctatgctgt 2340 agcgtgtctg gaaacaaagt acacaaacct ggctacggtg atgagttagc ttctgcttac 2400 tacctgtgac aacccaagtg ggtgacacta gtgaa ccttc tccagtctgc aggctggcat 2460 agaaggctct tagattatat tgggcagctt gcaatctgcc gaagcagtga cttgcatttc 2520 cacacttggc ttgagcactc aacccagaag gcgaagatag cttttggttg taggcggctt 2580 cctgtatggg atatccctcg gtaagggtaa aggagcagag gcaaaggaga aaagcagaag 2640 ttgcagctga tgcaggtatc ctatgccctt gatggatgag actaaaataa aatttttgaa 2700 gttaa 2705 <210> 5 <211> 2691 <212> DNA <213> MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) <400> 5 aatgcgaccc gaccgcgctg aggctccagg accgcccgcc atggctgcag gaggtcccgg 60 cgcggggtct gcggccccgg tctcctccac atcctccctt cccctggctg ctctcaacat 120 gcgagtgcgg cgccgcctgt ctctgttctt gaacgtgcgg acacaggtgg cggccgactg 180 gaccgcgctg gcggaggaga tggactttga gtacttggag atccggcaac tggagacaca 240 agcggacccc actggcaggc tgctggacgc ctggcaggga cgccctggcg cctctgtagg 300 ccgactgctc gagctgctta ccaagctggg ccgcgacgac gtgctgctgg agctgggacc 360 cagcattgag gaggattgcc aaaagtatat cttgaagcag cagcaggagg aggctgagaa 420 gcctttacag gtggccgctg tagacagcag tgtccccacgg acagcagggcat 480 accccc tggggcatat gcctgagcgt ttcgatgcct tcatctgcta 540 ttgccccagc gacatccagt ttgtgcagga gatgatccgg caactggaac agacaaacta 600 tcgactgaag ttgtgtgtgt ctgaccgcga tgtcctgcct ggcacctgtg tctggtctat 660 tgctagtgag ctcatcgaaa agaggttggc tagaaggcca cggggtgggt gccgccggat 720 ggtggtggtt gtctctgatg attacctgca gagcaaggaa tgtgacttcc agaccaaatt 780 tgcactcagc ctctctccag gtgcccatca gaagcgactg atccccatca agtacaaggc 840 aatgaagaaa gagttcccca gcatcctgag gttcatcact gtctgcgact acaccaaccc 900 ctgcaccaaa tcttggttct ggactcgcct tgccaaggcc ttgtccctgc cctgaagact 960 gttctgaggc cctgggtgtg tgtgtatctg tctgcctgtc catgtacttc tgccctgcct 1020 cctcctttcg ttgtaggagg aatctgtgct ctacttacct ctcaattcct ggagatgcca 1080 acttcacaga cacgtctgca gcagctggac atcacatttc atgtcctgca tggaaccagt 1140 ggctgtgagt ggcatgtcca cttgctggat tatcagccag gacactatag aacaggacca 1200 gctgagacta agaaggacca gcagagccag ctcagctctg agccattcac acatcttcac 1260 cctcagtttc ctcacttgag gagtgggatg gggagaacag agagtagctg tgtttgaatc 1320 cctgtaggaa atggtgaagc atagctc tgg gtctcctggg ggagaccagg cttggctgcg 1380 ggagagctgg ctgttgctgg actacatgct ggccactgct gtgaccacga cactgctggg 1440 gcagcttctt ccacagtgat gcctactgat gcttcagtgc ctctgcacac cgcccattcc 1500 acttcctcct tccccacagg gcaggtgggg aagcagtttg gcccagccca aggagacccc 1560 accttgagcc ttatttccta atgggtccac ctctcatctg catctttcac acctcccagc 1620 ttctgcccaa ccttcagcag tgacaagtcc ccaagagact cgcctgagca gcttgggctg 1680 cttttcattt ccacctgtca ggatgcctgt ggtcatgctc tcagctccac ctggcatgag 1740 aagggatcct ggcctctggc atattcatca agtatgagtt ctggggatga gtcactgtaa 1800 tgatgtgagc agggagcctt cctccctggg ccacctgcag agagctttcc caccaacttt 1860 gtaccttgat tgccttacaa agttatttgt ttacaaacag cgaccatata aaagcctcct 1920 gccccaaagc ttgtgggcac atgggcacat acagactcac atacagacac acacatatat 1980 gtacagacat gtactctcac acacacaggc accagcatac acacgttttt ctaggtacag 2040 ctcccaggaa cagctaggtg ggaaagtccc atcactgagg gagcctaacc atgtccctga 2100 acaaaaattg ggcactcatc tattcctttt ctcttgtgtc cctactcatt gaaaccaaac 2160 tctggaaagg acccaatgta ccagtattta ta cctctaat gaagcacaga gagaggaaga 2220 gagctgctta aactcacaca acaatgaact gcagacacag ctgttctctc cctctctcct 2280 tcccagagca atttatactt taccctcagg ctgtcctctg gggagaaggt gccatggtct 2340 taggtgtctg tgccccagga cagaccctag gaccctaaat ccaatagaaa atgcatatct 2400 ttgctccact ttcagccagg ctggagcaag gtaccttttc ttaggatctt gggagggaat 2460 ggatgcccct ctctgcatga tcttgttgag gcatttagct gccatgcacc tgtccccctt 2520 taatactggg cattttaaag ccatctcaag aggcatcttc tacatgtttt gtacgcatta 2580 aaataatttc aaagatatct gagaaaagcc gatatttgcc attcttccta tatcctggaa 2640tatatcttgc atcctgagtt tataataata aataatattc taccttggaa a 2691

Claims (21)

Encodes at least one selected from the group consisting of CREBBP (CREB Binding Protein), ESR1 (Estrogen Receptor 1), GATA3 (GATA Binding Protein 3), H3F3B (H3.3 Histone B) and MYD88 (MYD88 Innate Immune Signal Transduction Adapter) A marker composition for predicting treatment effect or prognostic diagnosis according to the metastasis period of a solid cancer patient, comprising a mutation of a gene.
The method of claim 1,
The mutation of the gene encoding CREBBP is characterized in that at least one selected from the group consisting of the following mutations encoded by SEQ ID NO: 1, a marker composition:
Y2189S, Q1756E, S2394F, L829F, S977L, A259T, R1328M, G587R, R672L, T345I, Y1622H, D1480N, P988S, P1096A, R351H, G689R, A2265V, Q662H, R1446C, R1446H, W1472R W Y Y, R1446H, W1472R R1446S, L1499Q, D1435N, R1446P, Y1450N, Y1482C, W1502R, Y1482N, Y1482D, L1499R, W1502C, W1472G, W1502L, I1431S, R1446C, I1431N, Y1503N, V1802M, T396K1778L, R1782V, E5503N, V1802M, T396K1778L, R1782V R1664C, T1260M, T950M, C1408Y, R424Q, R625H, R1081H, R601Q, P248L, M1798I, S1072F, P949L, A1824T, R1682H, R1428C, A206V, Y1167C, A2144V, V1650I, A2591, S136M, R1427W16341, T872, V E1243D, F1439L, R1319Q, R714C, E1012K, R1347W, D1481G, D1273N, A1944P, K1809R, E1247K, P2038L, G706R, P766L, P928S, R1800Q, V1371F, R714H, S945L, S1392Q, S945L, S32557T, R669W, R32557T R1602H, R519K, C1240Y, N645K, P107L, Y1973H, N2141K, S554F, R742L, Q963H, T862M, G21D, A698V, A533T, G2010E, A1510V, P907S, R1851H, Q2292R, Q11249H, K1498Q, N530S, K1498Q, N530S R1866C, P2285H, A1398V, M2192I, T1932M, Q1698L, G1699D, E1020G, N522S, P1889L, H2178Y, P2011S, I1455N, S2065N, K1269N, Q1928H, A259S, R2353W, Y1828C, N797K, P496L, R1378L, S791T, G1404S, Q1941L, L1451211S, Q1941L, L1451211R, S2065N, L1451211R, S2065N, K1269N, Q1928H, A259S V992L, I678M, G252C, H1470L, Q1113H, Q102R, D2433G, E1099K, T1210A, L869F, T537P, V460F, E2404K, A787V, M1021I, P552L, L833V, E637K, P2331S, D1156M, T2066T, R1964C, A190 S767Y, E1459Q, E1452K, N374I, Q1879E, G2162R, E1400Q, F1540S, S893W, E1501K, H1351D, S479I, H1485Y, D1276H, Q2299K, E1626Q, T320I, Q1152E, S2377L, K1271T, R1433H, L1271T, R1433H, K1271T, R, A2419V, Y1125H, S1207F, E1088K, R1317K, V2149M, S139N, P975S, G1305D, R624C, T4668S, P1953S, S247F, S2361F, T1242S, V1429M, L33F, D1543V, S566F, R1341P, P2383L, S237704 L2198Q, S554F, P2352L, P2415L, G219V, P1489T, QP1257HS, P1488L, E548K, D1309N, V1371D, E1400K, E1576D, A1739V, Q610H, L161M, W1545L, C1199F, H2384R, G786P, H2384R, E5281963D A924T, L1181R, F22L, V1818M, P432S, Q21 03K, V1704F, E371Q, D1420A, P2331L, R2195K, P1110L, V824M, D599N, G268R, P2187L, P2155S, S2345F, E996K, G591S, A2046V, Q2324K, M2391I, V1429A, G2132V, P1429A, G2132V P248S, P308S, S1030F, P957A, S646N, R1985L, G1418V, M481V, P543L, P2311L, A2170T, A924V, E1715K, D1263N, P1997L, P1951L, R1173G, P1991L, H17E12Y, S232V2L, H17E12Y2, L232V21374 M1625N, P1208S, H1738N, M1981I, Q1863R, L679F, W1745C, G2236E, G1753V, A1093V, V2056M, A476T, H1413P, V1722E, A924S, R1866L, R1926W, F1632V, K1870P, C398Y, G1870N, C398Y at least one missense mutation selected from the group consisting of S121I, G1411R, N1350I, T1332P, P1488T, D1480H and I1483S;
G572*, Q771*, Q497*, R1360*, R1173*, Q1073*, Q1796*, R1498*, R1103*, R1341*, Q1756*, Q887*, Q1856*, S985*, E349*, R1672*, Q1928* , Y1230*, S1065*, Q2235*, Y1726*, R440*, Y659*, E1243*, Q719*, E1205*, R1392*, R386*, L243*, Q540*, R424*, Q517*, E1000*, Q1148 *, S547*, Q357*, R370*, E1626*, S381*, Q2103*, S331*, Q1852*, Y1828*, K68*, Q963*, Q356*, R2004*, E1559*, Q203*, Q919*, at least one nonsense mutation selected from the group consisting of K1051*, Q1041*, Q1941*, Y1460*, S1030_K1033delins* and W1158*;
I1084Sfs*15, P1946Hfs*30, F1523Sfs*27, H2384Tfs*12, T1574Pfs*61, S801Qfs*29, L524Wfs*6, Q232Rfs*12, P1423Lfs*36, S1065*, P928Rfs*2316, L516F , S893Pfs*27, S1382Yfs*2, L243*, H408Ifs*26, C1444Hfs*6, K1505Rfs*45, E1054Dfs*4, G1815Pfs*149, E72Afs*10, V2012Sfs*28, N2181Kfs*5, E371Kfs*53, E371Kfs*53 7, E1061Rfs*4, K1051Rfs*5, V1057*, L1692Rfs*50, C1178Afs*72, G587Kfs*19, C1311*, M784Ifs*17, T163Afs*13, I1493Yfs*57, E594Dfs*11, C1783Afs*16, and I1783Afs*16 at least one frame shift delete mutation selected from the group consisting of 61;
At least one frame shift selected from the group consisting of L1346Ffs*8, I1084Nfs*3, Q1209Tfs*25, P1947Tfs*19, S1172Qfs*7, P2077Afs*264, H397Afs*30, S1737Rfs*8, G77Afs*9 and S1598Kfs*19. frame shift insert mutation;
M2115_G2120dup, an inframe insert mutation;
at least one inframe delete mutation selected from the group consisting of S1680del K1588del and Q2216del;
X1203_splice, X1305_splice, X406_splice, X1021_splice, X1427_splice, X961_splice, X1465_splice, X1084_splice, X29_splice, X705_splice, X1378_splice, X406_splice, X1305_splice, X1576_splice, X266_splice, X525_splice 및 X406_splice X1465_splice로 이루어진 군으로부터 선택되는 적어도 하나의 적어도 하나의 스플라이스(splice ) mutations; and
CREBBP-CRAMP1L fusion, CREBP-NARFL fusion, TRAP1-CREBBP fusion, CREBBP-intragenic, CREBBP-TRAP1 fusion, CREBBP-TIGD7 fusion, TSG1-CREBBP fusion, CREBBP-SRRM2 fusion, CREBBP-TBL3 fusion and CREBBP-DNASE1 fusion consisting of at least one fusion mutation selected from the group.
The method of claim 1,
The mutation of the gene encoding ESR1 is characterized in that at least one selected from the group consisting of the following mutations in the amino acid sequence encoded by SEQ ID NO: 2, a marker composition:
S554N, D538G, N290K, Y537S, D538G, S433P, G77D, P38L, Y537C, Y537N, D538G, E380Q, L536Q, L536R, Y537S, S463P, L536H, L536P, Y537D, S463P, V2153I, R463P, V V392I, D218N, Q159L, R37L, R243C, R394H, R477Q, R28H, R243H, A361V, E56K, E330K, L370F, H488Y, N519S, T585M, T228A, Q506H, R259Q, M109T, A350E, R269H, S576R, A269H, S576R D564Y, A307P, L410S, Y54C, K206T, L26M, G57C, C237Y, P113L, Q314K, R158C, R157Q, E203V, S338R, D369Y, A65V, D258Y, K32Q, A361E, A361T, R269C, G344D, P333T, R548H, V4 A207T, P25T, D374Y, N532K, S432L, A546D, E542G, V534E, G442R, V418E, F461V, L466Q, G442R, S329Y, Y80H, G160D, M421V, K252N, L540Q, L403R, R277S, E385D, T224I, G selected from the group consisting of L117Q, M437I, G57S, G284E, D564N, N304H, H398P, R193G, K48N, P324S, A593V, A288T, T4A, R211S, R260K, L15V, K4349R, P325S, R363K, E470K, P147Q, V478I and R18349C at least one missense mutation;
at least one nonsense mutation selected from the group consisting of Y60*, C245*, E444*, R256* and K401*;
at least one frame shift delete mutation selected from the group consisting of L536Qfs*2, P99Hfs*10, I326Yfs*17, P99Hfs*10, G96Vfs*13 and *594fs*;
at least one frame shift insert mutation selected from the group consisting of L100Tfs*57, G521Rfs*18 and E275Gfs*5;
at least one inframe insert mutation selected from the group consisting of D538_L539insHD and Q500dup;
at least one inframe delete mutation selected from the group consisting of V422del and Y328_S329del; and
At least one fusion mutation selected from the group consisting of TACR1-ESR1 fusion, ESR1-NCOA3 fusion and ESR1-C6orf97 fusion.
The method of claim 1,
The mutation of the gene encoding GATA3 is characterized in that at least one selected from the group consisting of the following mutations in the amino acid sequence encoded by SEQ ID NO: 3, a marker composition:
N331I, S175W, Y229H, C266S, M293K, R364S, R364G, R364T, R298W, P421L, M356V, G248R, E359K, T420M, S118F, T418M, S407L, A146T, S137L, G100S, P223L, G128W, S4 L347R, R366Q, R305L, P148L, S142L, S402F, P158L, P425I, R9H, H281R, V132I, S369Y, P148T, K387N, G342W, T279M, L347I, S172L, L114I, S213L, A286T, P163Q, G241F, R311S, P148T K358N, K292E, P98T, S82R, G232R, S82I, G143E, C287F, R275W, R9C, S93F, M356I, V337D, S121F, C183R, G278D, Q296K, L190P, S370R, A173T, L130H, S175L, S372F, P134S, S372F, P134S, S397Y G99S, S243Y, A310T, Q362R, N285K, D6H, A207D, P111S, S389I, G55C, S238R, W328C, T215I, H13R, L428Q, S139F, P424S, P111H, T108I, P299L, S230N, A441D, T71M, D335E, T335M at least one missense mutation selected from the group consisting of A176G, P135T and P95H;
at least one nonsense mutation selected from the group consisting of Q73*, R366*, R390*, K377* and S381*;
E359Afs*44, S407Afs*99, S237Afs*28, V378Cfs*26, P135Rfs*60, D335Pfs*16, P408Lfs*98, R329Gfs*17, G246Afs*19, L396Qfs*109, H123Pfs*69, A394436Pfs*110, A394436Pfs* 39, P408Qfs*97, T418Afs*86, P432Tfs*74, G443Vfs*32, P408Qfs*97, M438Wfs*37, T355Qfs*97, F430Sfs*38, G431Tfs*41, T355*, L416Pfs*83, S437Rfs*38, L396RfsHfs At least one frame shift delete selected from the group consisting of *107, S390Rfs*112, A441Pfs*34, P424Rfs*51, K387Rfs*17, C320Wfs*18, R330Mfs*20, N331Gfs*17 and C284Afs*10. ) mutations;
A441Hfs*44, D335Gfs*17, R330Efs*22, H434Pfs*42, S426Yfs*50, P408Afs*99, D335Gfs*17, P408Afs*99, G431Wfs*76, H434Pfs*73, D335Gfs*81, S426AIf 99, S436Lfs*71, G334Wfs*18, C320Lfs*32, S237Qfs*66, S237Qfs*66, S401Vfs*106, S413Qfs*94, P435Tfs*41, M422Dfs*85, V47Gfs*6, *444Lfs*63, A441Rfs*66 , N331Efs*21, S401Ffs*106, S426Afs*82, G314Rfs*38, H405Efs*103, N319Efs*33, T315Kfs*37, R330Nfs*24, H434Tfs*42, R69Qfs*234, C338Lfs*14, R330E4 *90, M356Nfs*15, T440Sfs*68, A332Cfs*20, T332Dfs*30, Y344Sfs*12, N333Kfs*19, G443Pfs*34, P419Afs*88, F430Lfs*77, S402Pfs*3, P435Rfs*42, M422Dfs*85 , S404Hfs*107, M442Hfs*65, N351Kfs*20, V337Gfs*21, H411Pfs*96, D335Vfs*35, T332Rfs*34, I361Rfs*11 and A313Sfs*39. shift insert) mutation;
an inframe insert mutation that is T221delinsPACCELLYVPYVL;
at least one inframe delete mutation selected from the group consisting of K358del, Y345del and M356_K387del;
at least one splice mutation selected from the group consisting of X349_splice and X350_splice; and
At least one fusion mutation selected from the group consisting of GATA3-intragenic and LOC100128811-GATA3 fusion.
The method of claim 1,
The mutation of the gene encoding H3F3B is characterized in that at least one selected from the group consisting of the following mutations in the amino acid sequence encoded by SEQ ID NO: 4, a marker composition:
at least one missense mutation selected from the group consisting of E106K, V47G, D78N, F105L, D107N, E106K, G13R, K5M, R3G, E98K, S32C, Q69K, R18L, A25V, R9S, Q6P, I78T and Q6H;
at least one nonsense mutation selected from the group consisting of E60*, E98* and R50*;
at least one frame shift delete mutation selected from the group consisting of R135Sfs*12, F105Kfs*33 and A2Pfs*35;
Q94Afs*4, a frame shift insert mutation; and
A splice mutation that is X37_splice.
The mutation of the gene encoding MYD88 is characterized in that at least one selected from the group consisting of the following mutations in the amino acid sequence encoded by SEQ ID NO: 5, a marker composition:
K275T, L265P, E139K, S243N, S219C, R301C, R5C, A13V, D184N, M67V, V27A, D288N, P19S, E70K, R301H, S296C, T84A, Y240C, P292T, I130M, T61I, G96D, Q262E, P83S, P11L, P83S at least one missense mutation selected from the group consisting of P9L, R41P, R94H and K271T;
at least one nonsense mutation selected from the group consisting of Q159*, Q189* and E172*;
a frame shift delete mutation that is R101Afs*19;
a splice mutation that is X228_splice; and
At least one fusion mutation selected from the group consisting of MYD88-ACAA1 fusion, MYD88-CTDSPL fusion, OXSR1-MYD88 fusion and MYD88-VILL fusion.
The method of claim 1,
The solid cancer is bladder cancer, colon cancer, stomach cancer, lung cancer, lung adenocarcinoma, breast invasive ductal carcinoma (Breast invasive ductal carcinoma), colon adenocarcinoma (Colon) adenocarcinoma, Prostate adenocarcinoma, Bladder urothelial carcinoma, Lung squamous cell carcinoma, Cutaneous melanoma, Cancer of unknown primary, Pancreatic adenocarcinoma, Glioblastoma multiforme, Colorectal adenocarcinoma, High grade serous ovarian cancer, Stomach adenocarcinoma, Renal clear cell carcinoma , Esophageal adenocarcinoma, testicular cancer, and intrahepatic cholangiocarcinoma, characterized in that selected from the group consisting of, the marker composition.
The method of claim 1,
The solid cancer is characterized in that the metastatic solid cancer, marker composition.
Encodes at least one selected from the group consisting of CREBBP (CREB Binding Protein), ESR1 (Estrogen Receptor 1), GATA3 (GATA Binding Protein 3), H3F3B (H3.3 Histone B) and MYD88 (MYD88 Innate Immune Signal Transduction Adapter) A composition for predicting treatment effect or prognosis diagnosis according to the metastasis period of a solid cancer patient, comprising an agent capable of detecting a mutation in a gene.
10. The method of claim 9,
The mutation of the gene encoding CREBBP is characterized in that at least one selected from the group consisting of the following mutations in the amino acid sequence encoded by SEQ ID NO: 1, composition:
Y2189S, Q1756E, S2394F, L829F, S977L, A259T, R1328M, G587R, R672L, T345I, Y1622H, D1480N, P988S, P1096A, R351H, G689R, A2265V, Q662H, R1446C, R1446H, W1472R W Y Y, R1446H, W1472R R1446S, L1499Q, D1435N, R1446P, Y1450N, Y1482C, W1502R, Y1482N, Y1482D, L1499R, W1502C, W1472G, W1502L, I1431S, R1446C, I1431N, Y1503N, V1802M, T396K1778L, R1782V, E5503N, V1802M, T396K1778L, R1782V R1664C, T1260M, T950M, C1408Y, R424Q, R625H, R1081H, R601Q, P248L, M1798I, S1072F, P949L, A1824T, R1682H, R1428C, A206V, Y1167C, A2144V, V1650I, A2591, S136M, R1427W16341, T872, V E1243D, F1439L, R1319Q, R714C, E1012K, R1347W, D1481G, D1273N, A1944P, K1809R, E1247K, P2038L, G706R, P766L, P928S, R1800Q, V1371F, R714H, S945L, S1392Q, S945L, S32557T, R669W, R32557T R1602H, R519K, C1240Y, N645K, P107L, Y1973H, N2141K, S554F, R742L, Q963H, T862M, G21D, A698V, A533T, G2010E, A1510V, P907S, R1851H, Q2292R, Q11249H, K1498Q, N530S, K1498Q, N530S R1866C, P2285H, A1398V, M2192I, T1932M, Q1698L, G1699D, E1020G, N522S, P1889L, H2178Y, P2011S, I1455N, S2065N, K1269N, Q1928H, A259S, R2353W, Y1828C, N797K, P496L, R1378L, S791T, G1404S, Q1941L, L1451211S, Q1941L, L1451211R, S2065N, L1451211R, S2065N, K1269N, Q1928H, A259S V992L, I678M, G252C, H1470L, Q1113H, Q102R, D2433G, E1099K, T1210A, L869F, T537P, V460F, E2404K, A787V, M1021I, P552L, L833V, E637K, P2331S, D1156M, T2066T, R1964C, A190 S767Y, E1459Q, E1452K, N374I, Q1879E, G2162R, E1400Q, F1540S, S893W, E1501K, H1351D, S479I, H1485Y, D1276H, Q2299K, E1626Q, T320I, Q1152E, S2377L, K1271T, R1433H, L1271T, R1433H, K1271T, R, A2419V, Y1125H, S1207F, E1088K, R1317K, V2149M, S139N, P975S, G1305D, R624C, T4668S, P1953S, S247F, S2361F, T1242S, V1429M, L33F, D1543V, S566F, R1341P, P2383L, S237704 L2198Q, S554F, P2352L, P2415L, G219V, P1489T, QP1257HS, P1488L, E548K, D1309N, V1371D, E1400K, E1576D, A1739V, Q610H, L161M, W1545L, C1199F, H2384R, G786P, H2384R, E5281963D A924T, L1181R, F22L, V1818M, P432S, Q21 03K, V1704F, E371Q, D1420A, P2331L, R2195K, P1110L, V824M, D599N, G268R, P2187L, P2155S, S2345F, E996K, G591S, A2046V, Q2324K, M2391I, V1429A, G2132V, P1429A, G2132V P248S, P308S, S1030F, P957A, S646N, R1985L, G1418V, M481V, P543L, P2311L, A2170T, A924V, E1715K, D1263N, P1997L, P1951L, R1173G, P1991L, H17E12Y, S232V2L, H17E12Y2, L232V21374 M1625N, P1208S, H1738N, M1981I, Q1863R, L679F, W1745C, G2236E, G1753V, A1093V, V2056M, A476T, H1413P, V1722E, A924S, R1866L, R1926W, F1632V, K1870P, C398Y, G1870N, C398Y at least one missense mutation selected from the group consisting of S121I, G1411R, N1350I, T1332P, P1488T, D1480H and I1483S;
G572*, Q771*, Q497*, R1360*, R1173*, Q1073*, Q1796*, R1498*, R1103*, R1341*, Q1756*, Q887*, Q1856*, S985*, E349*, R1672*, Q1928* , Y1230*, S1065*, Q2235*, Y1726*, R440*, Y659*, E1243*, Q719*, E1205*, R1392*, R386*, L243*, Q540*, R424*, Q517*, E1000*, Q1148 *, S547*, Q357*, R370*, E1626*, S381*, Q2103*, S331*, Q1852*, Y1828*, K68*, Q963*, Q356*, R2004*, E1559*, Q203*, Q919*, at least one nonsense mutation selected from the group consisting of K1051*, Q1041*, Q1941*, Y1460*, S1030_K1033delins* and W1158*;
I1084Sfs*15, P1946Hfs*30, F1523Sfs*27, H2384Tfs*12, T1574Pfs*61, S801Qfs*29, L524Wfs*6, Q232Rfs*12, P1423Lfs*36, S1065*, P928Rfs*2316, L516F , S893Pfs*27, S1382Yfs*2, L243*, H408Ifs*26, C1444Hfs*6, K1505Rfs*45, E1054Dfs*4, G1815Pfs*149, E72Afs*10, V2012Sfs*28, N2181Kfs*5, E371Kfs*53, E371Kfs*53 7, E1061Rfs*4, K1051Rfs*5, V1057*, L1692Rfs*50, C1178Afs*72, G587Kfs*19, C1311*, M784Ifs*17, T163Afs*13, I1493Yfs*57, E594Dfs*11, C1783Afs*16, and I1783Afs*16 at least one frame shift delete mutation selected from the group consisting of 61;
At least one frame shift selected from the group consisting of L1346Ffs*8, I1084Nfs*3, Q1209Tfs*25, P1947Tfs*19, S1172Qfs*7, P2077Afs*264, H397Afs*30, S1737Rfs*8, G77Afs*9 and S1598Kfs*19. frame shift insert mutation;
M2115_G2120dup, an inframe insert mutation;
at least one inframe delete mutation selected from the group consisting of S1680del K1588del and Q2216del;
X1203_splice, X1305_splice, X406_splice, X1021_splice, X1427_splice, X961_splice, X1465_splice, X1084_splice, X29_splice, X705_splice, X1378_splice, X406_splice, X1305_splice, X1576_splice, X266_splice, X525_splice 및 X406_splice X1465_splice로 이루어진 군으로부터 선택되는 적어도 하나의 적어도 하나의 스플라이스(splice ) mutations; and
CREBBP-CRAMP1L fusion, CREBP-NARFL fusion, TRAP1-CREBBP fusion, CREBBP-intragenic, CREBBP-TRAP1 fusion, CREBBP-TIGD7 fusion, TSG1-CREBBP fusion, CREBBP-SRRM2 fusion, CREBBP-TBL3 fusion and CREBBP-DNASE1 fusion consisting of at least one fusion mutation selected from the group.
10. The method of claim 9,
The mutation of the gene encoding ESR1 is characterized in that at least one selected from the group consisting of the following mutations encoded by SEQ ID NO: 2, a marker composition:
S554N, D538G, N290K, Y537S, D538G, S433P, G77D, P38L, Y537C, Y537N, D538G, E380Q, L536Q, L536R, Y537S, S463P, L536H, L536P, Y537D, S463P, V2153I, R463P, V V392I, D218N, Q159L, R37L, R243C, R394H, R477Q, R28H, R243H, A361V, E56K, E330K, L370F, H488Y, N519S, T585M, T228A, Q506H, R259Q, M109T, A350E, R269H, S576R, A269H, S576R D564Y, A307P, L410S, Y54C, K206T, L26M, G57C, C237Y, P113L, Q314K, R158C, R157Q, E203V, S338R, D369Y, A65V, D258Y, K32Q, A361E, A361T, R269C, G344D, P333T, R548H, V4 A207T, P25T, D374Y, N532K, S432L, A546D, E542G, V534E, G442R, V418E, F461V, L466Q, G442R, S329Y, Y80H, G160D, M421V, K252N, L540Q, L403R, R277S, E385D, T224I, G L117Q, M437I, G57S, G284E, D564N, N304H, H398P, R193G, K48N, P324S, A593V, A288T, T4A, R211S, R260K, L15V, K4349R, P325S, R363K, E470K, P147Q, V478I and R18349C at least one missense mutation;
at least one nonsense mutation selected from the group consisting of Y60*, C245*, E444*, R256* and K401*;
at least one frame shift delete mutation selected from the group consisting of L536Qfs*2, P99Hfs*10, I326Yfs*17, P99Hfs*10, G96Vfs*13 and *594fs*;
at least one frame shift insert mutation selected from the group consisting of L100Tfs*57, G521Rfs*18 and E275Gfs*5;
at least one inframe insert mutation selected from the group consisting of D538_L539insHD and Q500dup;
at least one inframe delete mutation selected from the group consisting of V422del and Y328_S329del; and
At least one fusion mutation selected from the group consisting of TACR1-ESR1 fusion, ESR1-NCOA3 fusion and ESR1-C6orf97 fusion.
10. The method of claim 9,
The mutation of the gene encoding GATA3 is characterized in that at least one selected from the group consisting of the following mutations encoded by SEQ ID NO: 3, a marker composition:
N331I, S175W, Y229H, C266S, M293K, R364S, R364G, R364T, R298W, P421L, M356V, G248R, E359K, T420M, S118F, T418M, S407L, A146T, S137L, G100S, P223L, G128W, S4 L347R, R366Q, R305L, P148L, S142L, S402F, P158L, P425I, R9H, H281R, V132I, S369Y, P148T, K387N, G342W, T279M, L347I, S172L, L114I, S213L, A286T, P163Q, G241F, R311S, P148T K358N, K292E, P98T, S82R, G232R, S82I, G143E, C287F, R275W, R9C, S93F, M356I, V337D, S121F, C183R, G278D, Q296K, L190P, S370R, A173T, L130H, S175L, S372F, P134S, S372F, P134S, S397Y G99S, S243Y, A310T, Q362R, N285K, D6H, A207D, P111S, S389I, G55C, S238R, W328C, T215I, H13R, L428Q, S139F, P424S, P111H, T108I, P299L, S230N, A441D, T71M, D335E, T335M at least one missense mutation selected from the group consisting of A176G, P135T and P95H;
at least one nonsense mutation selected from the group consisting of Q73*, R366*, R390*, K377* and S381*;
E359Afs*44, S407Afs*99, S237Afs*28, V378Cfs*26, P135Rfs*60, D335Pfs*16, P408Lfs*98, R329Gfs*17, G246Afs*19, L396Qfs*109, H123Pfs*69, A394436Pfs*110, A394436Pfs* 39, P408Qfs*97, T418Afs*86, P432Tfs*74, G443Vfs*32, P408Qfs*97, M438Wfs*37, T355Qfs*97, F430Sfs*38, G431Tfs*41, T355*, L416Pfs*83, S437Rfs*38, L396RfsHfs At least one frame shift delete selected from the group consisting of *107, S390Rfs*112, A441Pfs*34, P424Rfs*51, K387Rfs*17, C320Wfs*18, R330Mfs*20, N331Gfs*17 and C284Afs*10. ) mutations;
A441Hfs*44, D335Gfs*17, R330Efs*22, H434Pfs*42, S426Yfs*50, P408Afs*99, D335Gfs*17, P408Afs*99, G431Wfs*76, H434Pfs*73, D335Gfs*81, S426AIf 99, S436Lfs*71, G334Wfs*18, C320Lfs*32, S237Qfs*66, S237Qfs*66, S401Vfs*106, S413Qfs*94, P435Tfs*41, M422Dfs*85, V47Gfs*6, *444Lfs*63, A441Rfs*66 , N331Efs*21, S401Ffs*106, S426Afs*82, G314Rfs*38, H405Efs*103, N319Efs*33, T315Kfs*37, R330Nfs*24, H434Tfs*42, R69Qfs*234, C338Lfs*14, R330E4 *90, M356Nfs*15, T440Sfs*68, A332Cfs*20, T332Dfs*30, Y344Sfs*12, N333Kfs*19, G443Pfs*34, P419Afs*88, F430Lfs*77, S402Pfs*3, P435Rfs*42, M422Dfs*85 , S404Hfs*107, M442Hfs*65, N351Kfs*20, V337Gfs*21, H411Pfs*96, D335Vfs*35, T332Rfs*34, I361Rfs*11 and A313Sfs*39. shift insert) mutation;
an inframe insert mutation that is T221delinsPACCELLYVPYVL;
at least one inframe delete mutation selected from the group consisting of K358del, Y345del and M356_K387del;
at least one splice mutation selected from the group consisting of X349_splice and X350_splice; and
At least one fusion mutation selected from the group consisting of GATA3-intragenic and LOC100128811-GATA3 fusion.
10. The method of claim 9,
The mutation of the gene encoding H3F3B is characterized in that at least one selected from the group consisting of the following mutations encoded by SEQ ID NO: 4, a marker composition:
at least one missense mutation selected from the group consisting of E106K, V47G, D78N, F105L, D107N, E106K, G13R, K5M, R3G, E98K, S32C, Q69K, R18L, A25V, R9S, Q6P, I78T and Q6H;
at least one nonsense mutation selected from the group consisting of E60*, E98* and R50*;
at least one frame shift delete mutation selected from the group consisting of R135Sfs*12, F105Kfs*33 and A2Pfs*35;
Q94Afs*4, a frame shift insert mutation; and
A splice mutation that is X37_splice.
The mutation of the gene encoding MYD88 is characterized in that at least one selected from the group consisting of the following mutations in the amino acid sequence encoded by SEQ ID NO: 5, a marker composition:
K275T, L265P, E139K, S243N, S219C, R301C, R5C, A13V, D184N, M67V, V27A, D288N, P19S, E70K, R301H, S296C, T84A, Y240C, P292T, I130M, T61I, G96D, Q262E, P83S, P11L, P83S at least one missense mutation selected from the group consisting of P9L, R41P, R94H and K271T;
at least one nonsense mutation selected from the group consisting of Q159*, Q189* and E172*;
a frame shift delete mutation that is R101Afs*19;
a splice mutation that is X228_splice; and
At least one fusion mutation selected from the group consisting of MYD88-ACAA1 fusion, MYD88-CTDSPL fusion, OXSR1-MYD88 fusion and MYD88-VILL fusion.
10. The method of claim 9,
The solid cancer is bladder cancer, colon cancer, stomach cancer, lung cancer, lung adenocarcinoma, breast invasive ductal carcinoma (Breast invasive ductal carcinoma), colon adenocarcinoma (Colon) adenocarcinoma, Prostate adenocarcinoma, Bladder urothelial carcinoma, Lung squamous cell carcinoma, Cutaneous melanoma, Cancer of unknown primary, Pancreatic adenocarcinoma, Glioblastoma multiforme, Colorectal adenocarcinoma, High grade serous ovarian cancer, Stomach adenocarcinoma, Renal clear cell carcinoma , Esophageal adenocarcinoma, testicular cancer, and intrahepatic cholangiocarcinoma, characterized in that selected from the group consisting of, the composition.
10. The method of claim 9,
The composition, characterized in that the solid cancer is metastatic solid cancer.
10. The method of claim 9,
The agent is characterized in that it comprises a primer set, a probe or an antibody for the mutation of the gene, the composition.
A kit for predicting treatment effect or prognosis diagnosis according to the metastasis period of a solid cancer patient, comprising the composition of claim 9.
preparing sample DNA from a sample of a solid cancer patient;
amplifying the sample DNA using the kit of claim 18; and
A method of providing information necessary for prognostic diagnosis of solid cancer according to the metastasis period of a solid cancer patient, comprising the step of confirming the presence or absence of a metastasis period-specific marker from the amplification result.
20. The method of claim 19,
The method is a method of predicting the total survival rate or disease-free survival rate of a patient with solid cancer.
20. The method of claim 19,
The solid cancer patient has a mutation in the genes encoding CREBBP, ESR1, GATA3, H3F3B and MYD88, and the survival rate of the solid cancer patient is lower than the survival rate of a person whose mutation is not confirmed in the gene, or the solid cancer recurrence rate of the solid cancer patient The method further comprising; determining that the mutation in the gene is higher than the solid cancer recurrence rate of the unconfirmed person.

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