WO2000040752A2 - Cancer associated genes and their products - Google Patents

Abstract

The application discloses cancer-associated genes and their products, especially those identifiable by SEREX. The genes and products are used to identify, track and treat cancer such as prostate cancer.

Description

CANCER ASSOCIATED GENES AND THEIR PRODUCTS

The invention relates to isolated nucleic acid sequences which are expressed in cancers,

especially prostate cancers, to their protein products and to the use of the nucleic acid and

protein products for the identification and treatment of prostate cancers.

The prostate gland is an accessory sex gland in males which is wrapped around the urethra

as this tube leaves the bladder. The gland secretes an alkaline fluid during ejaculation.

Cancer of the prostate gland is very serious and represents the second leading cause of

death from cancer in men.

Two specific proteins are known to be made in very high concentrations in prostate cancer

cells. These are prostatic acid phosphatase (PAP) and prostate specific antigen (PSA).

These proteins have been characterised and have been used to follow response to therapy.

However, it has been difficult to correlate the presence of these two proteins to the

presence of cancer.

Accordingly, there is a need to identify new genes and proteins which are associated with

the presence of prostate cancer.

The inventors have used a technique known as SEREX (Serological Identification of

Antigens by Recombinant Expression Cloning) to identify genes which are over-expressed

in prostate cancer tissue. This technique was published by Sahin et al (PNAS (USA), 1995, Vol. 92, pages 11810-11813). SEREX uses total RNA isolated from tumour

biopsies from which poly(A)⁺ RNA is then isolated. cDNA is then produced using an

oligo (dT) primer. The cDNA fragments produced are then cloned into a suitable

expression vector, such as a bacteriophage and cloned into a suitable host, such as E.coli.

The clones produced are screened with high-titer IgG antibodies in autologous patient

serum, to identify antigens associated with the tumour.

The inventors have used this technique to identify a number of genes and gene products

associated with prostate cancer. Furthermore, preliminary results have found that some

antigens identified by this technique have been also identified by the inventors as being

associated with other cancers, such as stomach cancer and oesophagial cancer.

A first aspect of the invention provides an isolated mammalian nucleic acid molecule

selected from SEQ.IDJ, SEQ.ID.2. SEQ.ID.3, SEQ.ED.4, SEQ.ID.5, SEQ.ID.6, SEQ.ID.7,

SEQ.ID.8, SEQ.ID.9, SEQ.IDJ 0. SEQ.IDJ 1, SEQJD. 12, SEQ.JD.13 and SEQ.IDJ 4.

Preferably the isolated nucleic acid molecule encodes a mammalian antigen which is

expressed in higher than normal concentrations in cancer cells, compared with normal

non-cancerous cells. Preferably the cancer is prostate cancer.

The invention also includes, within its scope, nucleic acid molecules complementary to

such isolated mammalian nucleic acid molecules.

The nucleic acid molecules of the invention may be DNA, cDNA or RNA. In RNA

molecules "T" (Thymine) residues may be replaced by "U" (Uridine) residues. Preferably, the isolated mammalian nucleic acid molecule is an isolated human nucleic

acid molecule.

The invention further provides nucleic acid molecules comprising at least 15 nucleotides

capable of specifically hybridising to a sequence included within the sequence of a nucleic

acid molecule according to the first aspect of the invention. The hybridising nucleic acid

molecule may either be DNA or RNA. Preferably the molecule is at least 90%

homologous to the nucleic acid molecule according to the first aspect of the invention.

This may be determined by techniques known in the art.

The term ^■"specifically hybridising^" is intended to mean that the nucleic acid molecule can

hybridise to nucleic acid molecules according to the invention under conditions of high

stringency. Typical conditions for high stringency include 0J x SET, 0.1% SDS at 68°C

for 20 minutes.

The invention also encompasses variant DNAs and cDNAs which differ from the

sequences identified above, but encode the same amino acid sequences as the isolated

mammalian nucleic acid molecules, by virtue of redundancy in the genetic code.

Chain-terminating, or "nonsense" codons.

** Also used to specify the initiator formyl-Met-tRNAMet. The Val triplet GUG is therefore "ambiguous" in that it codes both valine and methionine.

The genetic code showing mRNA triplets and the amino acids which they code for. The invention also includes within its scope vectors comprising a nucleic acid according to

the invention. Such vectors include bacteriophages, phagemids, cosmids and plasmids.

Preferably the vectors comprise suitable regulatory sequences, such as promoters and

termination sequences which enable the nucleic acid to be expressed upon insertion into a

suitable host. Accordingly, the invention also includes hosts comprising such a vector.

Preferably the host is E.coli.

A second aspect of the invention provides an isolated protein or peptide obtained from a

nucleic acid sequence according to the invention. Preferably, the protein or peptide is

selected from the following sequences: SEQ ID 15. SEQ ID 16, SEQ ID 17, SEQ ID 18,

SEQ ID 19. SEQ ID 20, SEQ ID 21. SEQ ID 22. SEQ ID 23. SEQ ID 24. SEQ ID 25, SEQ

ID 26 and SEQ ID 27.

The invention further provides polypeptide analogues, fragments or derivatives of

antigenic polypeptides which differ from naturally-occurring forms in terms of the identity

of location of one or more amino acid residues (deletion analogues containing less than all

of the residues specified for the protein, substitution analogues wherein one or more

residues specified are replaced by other residues in addition analogues wherein one or

more amino acid residues are added to a terminal or medial portion of the polypeptides)

and which share some or all properties of the naturally-occurring forms. Preferably such

polypeptides comprise between 1 and 20, preferably 1 and 10 amino acid deletions or

substitutions. Preferably the protein or peptide is at least 95%, 96%, 97%, 98% or 99% identical to the

sequences of the invention. This can be determined conventionally using known computer

programs such as the Bestfit program (Wisconsin Sequence Analysis Package, Version 8

for Unix, Genetics Computer Group, University Research Park, 575 Science Drive,

Madison, WI 53711). When using Bestfit or any other sequence alignment program to

determine whether a particular sequence is, for instance, 95%) identical to a reference

sequence according to the present invention, the parameters are set, of course, such that the

percentage of identity is calculated over the full length of the reference amino acid

sequence and that gaps in homology of up to 5% of the total number of amino acid

residues in the reference sequence are allowed.

The nucleic acids and proteins/peptides of the invention are preferably identifiable using

the SEREX method. However, alternative methods, known in the art, may be used to

identify nucleic acids and protein/peptides of the invention. These include differential

display PCR (DD-PCR), representational difference analysis (RDA) and suppression

subtracted hybridisation (SSH).

All of the nucleic acid molecules according to the invention and the peptides which they

encode are detectable by SEREX (discussed below). The technique uses serum antibodies

from prostate cancer patients to identify the molecules. It is therefore the case that the

gene products identified by SEREX are able to evoke an immune response in a patient and

may be considered as antigens suitable for potentiating further immune reactivity if used as

a vaccine. The third aspect of the invention provides the use of nucleic acids or protein/peptides

according to the invention, to detect or monitor prostate cancer.

The use of a nucleic acid molecule hybridisable under high stringency conditions, a

nucleic acid according to the first aspect of the invention to detect or monitor prostate

cancer is also encompassed. Such molecules may be used as probes, e.g. using PCR.

The expression of genes, and detection of their protein products and/or peptides may be

used to monitor disease progression during therapy or as a prognostic indicator of the

initial disease status of the patient. There are a number of techniques which may be used

to detect the presence of a gene, including the use of Northern blot and reverse

transcription polymerase chain reaction (RT-PCR) which may be used on tissue or whole

blood samples to detect the presence of cancer associated genes. For protein and/or

peptide sequences in-situ staining techniques or enzyme linked ELISA assays or

radio-immune assays may be used. RT-PCR based techniques would result in the

amplification of messenger RNA of the gene of interest (Sambrook, Fritsch and Maniatis,

Molecular Cloning, A Laboratory Manual, 2^nd Edition). ELISA based assays necessitate

the use of antibodies raised against the protein or peptide sequence and may be used for

the detection of antigen in tissue or serum samples (Mclntyre C.A., Rees R.C. et. al.,

Europ. J. Cancer 28, 58-631 (1990)). In-situ detection of antigen in tissue sections also

rely on the use of antibodies, for example, immuno peroxidase staining or alkaline

phosphatase staining (Gaepel, J.R., Rees, R.C. et.al.. Brit. J. Cancer 64. 880-883 (1991)) to

demonstrate expression. Similarly radio-immune assays may be developed whereby

antibody conjugated to a radioactive isotope such as I¹²⁵ is used to detect antigen in the blood (Turkes, A., et.al., Prostate-specific antigen - problems in analysis. Europ. J.

Cancer. 27, 650-652 (1991)).

Blood or tissue samples may be assayed for eleviated concentrations of the nucleic acid

molecules, proteins or peptides.

Kits for detecting or monitoring cancer, such as prostate cancer, using polypeptides,

nucleic acids or antibodies according to the invention are also provided. Such kits may

additionally contain instructions and reagents to carry out the detection or monitoring.

The fourth aspect of the invention provides for the use of nucleic acid molecules according

to the first aspect of the invention or protein/peptide molecules according to the second

aspect of the invention in the prophylaxis or treatment of cancer, or pharmaceutically

effective fragments thereof. By pharmaceutically effective fragment, we mean a fragment

of the molecule which still retains the ability to be a prophylactant or to treat cancer. The

cancer may be prostate cancer.

The molecules are preferably administered in a pharmaceutically amount. Preferably the

dose is between 1 μg/kg. to 10 mg/kg.

The nucleic acid molecules may be used to form DNA-based vaccines. From the

published literature it is apparent that the development of protein, peptide and DNA based

vaccines can promote anti-tumour immune responses. In pre-clinical studies, such

vaccines effectively induce a delayed type hypersensitivity response (DTH), cytotoxic T-lymphocyte activity (CTL) effective in causing the destruction (death by lysis or

apoptosis) of the cancer cell and the induction of protective or therapeutic immunity. In

clinical trials peptide-based vaccines have been shown to promote these immune responses

in patients and in some instances cause the regression of secondary malignant disease.

Antigens expressed in prostate cancer (or other types of cancers) but not in normal tissue

(or only weakly expressed in normal tissue compared to cancer tissue) will allow us to

assess their efficacy in the treatment of cancer by immunotherapy. Protein or peptide

derived from the tumour antigen may be administered with or without immunological

adjuvant to promote T-cell responses and induce prophylactic and therapeutic immunity.

DNA-bascd vaccines preferably consist of part or all of the genetic sequence of the tumour

antigen inserted into an appropriate expression vector which when injected (for example

via the intramuscular, subcutaneous or intradermal route) cause the production of protein

and subsequently activate the immune system. An alternative approach to therapy is to use

antigen presenting cells (for example, dendritic cells. DCs) either mixed with or pulsed

with protein or peptides from the tumour antigen, or transfect DCs with the expression

plasmid (preferably inserted into a viral vector which would infect cells and deliver the

gene into the cell) allowing the expression of protein and the presentation of appropriate

peptide sequences to T-lymphocytes.

Accordingly, the invention provides a nucleic acid molecule according to the invention in

combination with a pharmaceutically-acceptable carrier. A further aspect of the invention provides a method of prophylaxis or treatment of prostate

cancer comprising the administration to a patient of a nucleic acid molecule according to

the invention.

The protein/peptide molecules according to the invention may be used to produce vaccines

to vaccinate males against prostate cancer.

Accordingly, the invention provides a protein or peptide according to the invention in

combination with a pharmaceutically acceptable carrier.

The invention further provides use of a protein or peptide according to the invention in a

prophylaxis or treatment of a cancer such as prostate cancer.

Methods of prophylaxis or treating prostate cancer, by administering a protein or peptide

according to the invention to a patient, are also provided.

Vaccines comprising nucleic acid and/or proteins and peptides according to the invention

are also provided.

The proteins and peptides of the invention may be used to raise antibodies. In order to

produce antibodies to tumour-associated antigens procedures may be used to produce

polyclonal antiserum (by injecting protein or peptide material into a suitable host) or

monoclonal antibodies (raised using hybridoma technology). In addition PHAGE display

antibodies may be produced, this offers an alternative procedure to conventional hybridoma methodology. Having raised antibodies which may be of value in detecting

tumour antigen in tissues or cells isolated from tissue or blood, their usefulness as

therapeutic reagents could be assessed. Antibodies identified for their specific reactivity

with tumour antigen may be conjugated either to drugs or to radioisotopes. Upon injection

it is anticipated that these antibodies localise at the site of tumour and promote the death of

tumour cells through the release of drugs or the conversion of pro-drug to an active

metabolite. Alternatively a lethal effect may be delivered by the use of antibodies

conjugated to radioisotopes. In the detection of secondary/residual disease, antibody

tagged with radioisotope could be used, allowing tumour to be localised and monitored

during the course of therapy.

The term "antibody^"' includes intact molecules as well as fragments such as Fa, F(ab')₂ and

Fv.

The invention accordingly provides a method of treating prostate cancer by the use of one

or more antibodies raised against a protein or peptide of the invention.

The cancer-associated proteins identified may form targets for therapy.

The invention will now be described by reference to the following examples:

Technique used to identify genes encoding tumour antigens (SEREX technique) The technique for the expression of cDNA libraries from human prostate cancer tissue is

described, and was performed according to published methodology (Sahin et.al. Proc Natl.

Acad. Sci. 92, 11810-11813, 1995).

SEREX has been used to analyze gene expression in tumour tissues from human

melanoma, renal cell cancer, astrocytoma, oesophageal squamous cell carcinoma, colon

cancer, lung cancer and Hodgkin's disease. Sequence analysis revealed that several

different antigens, including HOM-MEL-40, HOM-HD-397, HOM-RCC-1J4, NY-

ESO-1, NY-LU-12, NY-CO- 13 and MAGE genes, were expressed in these malignancies,

demonstrating that several human tumour types express multiple antigens capable of

eliciting an immune response in the autologous host. This represents an alternative and

more efficient approach to identify tumour markers, and offers distinct advantages over

previously used techniques:

1 ) the use of fresh tumour specimens to produce the cDNA libraries obviates

the need to culture tumour cells in vitro and therefore circumvents artefacts, such

as loss or neo-antigen expression and genetic and phenotypic diversity generated

by extended culture:

2) the analysis is restricted to antigen-encoding genes expressed by the tumour

in vivo;

3) using cDNA expression cloning, the serological analysis (in contrast to

autologous typing) is not restricted to cell surface antigens, but covers a more

extensive repertoire of cancer-associated proteins (cytosolic, nuclear, membrane,

etc.); 4) in contrast to techniques using monoclonal antibodies, SEREX uses

poly-specific sera to scrutinise single antigens that are highly enriched in lytic

bacterial plaques allowing the efficient molecular identification of antigens

following sequencing of the cDNA. Subsequently the tissue-expression spectrum

of the antigen can be determined by the analysis of the mRNA expression patterns

using northern blotting and reverse transcription-PCR (RT-PCR), on fresh normal

and malignant (autologous and allogeneic) tissues. Likewise, the prevalence of

antibody in cohorts of cancer patients and normal controls can be determined.

Construction of cDNA expression libraries, screening and sequencing

The detailed methodology for SEREX expression cloning established by the inventors is as

follows: Total RNA is isolated from fresh prostate cancer tissues using the guanidinium

thiocyanate-phenol-chloroform extraction method; RNA integrity is determined by

electrophoresis in formalin/MOPS gels. Poly(A)+ RNA is prepared by applying the

prepared RNA sample to a column of oligo (dT) cellulose and cDNA expression libraries

is constructed from 5-8 μg of poly(A)+ RNA; first-strand synthesis is performed using an

oligo(dT) primer with an internal Xho I site and 5-methyl-CTP. cDNA is ligated to EcoRI

adaptors and digested with Xho I and cDNA fragments are cloned directionally into the

bacterophage expression vector, packaged into phage particles, and used to transfect

Escherichia coli. Immuno-screening for the detection of clones reactive with antibodies

present in diluted autologous serum is then performed. Transfection for primary screening

and plaque transfer onto nitrocellulose membranes is followed by pre-incubation of the

membranes with an alkaline phosphatase-conjugated antibody specific for human IgG.

Reactive clones representing expressed IgG heavy chains visualized by staining are eliminated from the study. These pre-stained membranes are then incubated with the

autologous patient serum, and binding to recombinant proteins expressed in lytic plaques

detected by incubation with an alkaline phosphatse-conjugated goat anti-human IgG, and

differentiated from the IgG-heavy chain transcripts. The reactive clones are sub-cloned,

purified, and in vitro excised to pBK-CMV plasmid forms. Plasmid DNA is prepared

using the Wizard (Trade Mark) Miniprep DNA purification system (Promega Corp.,

Southampton, UK). The inserted DNA is evaluated by restriction mapping, and clones

representing different cDNA inserts sequenced using the automated sequencer.

Claims

1. The use of an isolated nucleic acid molecule comprising a sequence selected from

SEQ.IDJ . SEQ.ID.2, SEQ.ID3. SEQ.ID4, SEQ.ID.5, SEQ.ID.6, SEQ.IDJ, SEQ.ID.8,

SEQ.ID.9. SEQ.ID. IO, SEQ.ID. l l, SEQ.ID.12, SEQ.ID.13 and SEQ.ID.14, or variants

capable of hybridising to such a molecule under high stringency conditions, to detect or

monitor cancer.

2. The use of a nucleic acid probe which is capable of hybridising under high

stringency conditions to an isolated nucleic acid molecule comprising a sequence selected

from SEQ.IDJ, SEQ.ID.2, SEQ.ID3, SEQ.ID4, SEQ.ID.5, SEQ.ID.6, SEQ.IDJ,

SEQ.ID.8. SEQ.ID.9, SEQ.ID.IO, SEQ.ID.l l, SEQ.ID.12, SEQ.ID.13 and SEQ.ID.14, or

variants capable of hybridising to such a molecule under high stringency conditions, to

detect or monitor cancer.

3. A method of detecting or monitoring cancer comprising the step of detecting or

monitoring elevated levels of a nucleic acid molecule comprising a sequence selected from

SEQ.I.D1. SEQ.ID.2, SEQ.ID3, SEQ.ID4, SEQ.ID.5, SEQ.ID.6, SEQ.IDJ, SEQ.ID.8,

SEQ.ID.9. SEQ.ID.IO, SEQ.ID.l l, SEQ.ID.12, SEQ.ID.13 and SEQ.ID.14 or variants

capable of hybridising to such a molecule under high stringency conditions, in a sample

from a patient.

4. A method of detecting or monitoring cancer comprising the use of a nucleic acid

molecule or probe according to claim 1 or claim 2 in combination with a reverse

transcription polymerase chain reaction (RT-PCR).

5. A method of detecting or monitoring cancer comprising detecting or monitoring

elevated levels of a protein or peptide comprising an amino acid sequence selected from

SEQ.IDJ5, SEQ.IDJ6, SEQ.IDJ7, SEQ.IDJ8, SEQ.IDJ9, SEQ.ID.20, SEQ.ID.21,

SEQ.ID.22, SEQ.ID.23, SEQ.ID.24, SEQ.ID.25, SEQ.ID.26 and SEQ.ID.27 or a fragment,

homologue or analogue thereof, which encodes a prostate-associated antigen which is

expressed in higher than normal concentrations in prostate cancer cells.

6. A method according to claim 5 comprising the use of an antibody selective for a

protein or peptide as defined in claim 5 to detect the protein or peptide.

7. A method according to claim 7 comprising the use of an Enzyme-linked

Immunosorbant Assay (ELISA).

8. Use or method according to any one of claims 1 to 7, wherein the cancer is prostate

cancer.

9. A kit for use with a method according to any one of claims 3-8 comprising a

nucleic acid, protein or peptide, or an antibody as defined in any one of claims 3-8.

10. A method of prophylaxis or treatment of cancer comprising administering to a

patient a pharmaceutically effective amount of nucleic acid molecule comprising a nucleic

acid sequence selected from SEQ.IDJ, SEQ.ID.2, SEQ.ID3, SEQ.ID4, SEQ.ID.5,

SEQ.ID.6- SEQ.IDJ, SEQ.ID.8. SEQ.ID.9, SEQ.ID.IO, SEQ.ID.l l, SEQ.ID.12,

SEQ.ID.13 and SEQ.ID.14, or variants capable of hybridising molecules under high

stringency conditions, or a pharmaceutically effective fragment thereof.

1 1. A method of prophylaxis or treatment of cancer comprising administering to a

patient a pharmaceutically effective amount of a nucleic acid molecule hybridisable under

high stringency conditions to a nucleic acid molecule comprising a nucleic acid sequence

selected from SEQ.IDJ, SEQ.ID.2, SEQ.ID3, SEQ.ID4, SEQ.ID.5, SEQ.ID.6, SEQ.IDJ,

SEQ.ID.8. SEQ.ID.9, SEQ.ID.IO, SEQ.ID.l l, SEQ.IDJ2, SEQ.IDJ3 and SEQ.IDJ4, or

variants capable of hybridising to such a molecule under high stringency conditions, or a

pharmaceutically effective fragment thereof.

12. A method of prophylaxis or treatment of cancer comprising administering to a

patient a pharmaceutically effective amount of a protein or peptide comprising an amino

acid sequence selected from SEQ.IDJ5, SEQ.IDJ6, SEQ.IDJ7, SEQ.IDJ8, SEQ.IDJ9,

SEQ.ID.20. SEQ.ID.21, SEQ.ID.22, SEQ.ID.23, SEQ.ID.24, SEQ.ID.25, SEQ.ID.26 and

SEQ.ID.27. or a fragment, homologue or analogue thereof, which encodes a

prostate-associated antigen which is expressed in higher than normal concentrations in

prostate cancer cells, or a pharmaceutically effective fragment thereof.

13. A method of prophylaxis or treatment of cancer comprising the step of

administering to a patient a pharmaceutically effective amount of an antibody capable of

specifically binding a protein or peptide comprising an amino acid sequence selected from

SEQJDJ5, SEQ.ID.16, SEQ.IDJ7, SEQ.IDJ 8, SEQ.IDJ9, SEQ.ID.20, SEQ.ID.21,

SEQ.ID.22, SEQ.ID.23, SEQ.ID.24, SEQ.ID.25, SEQ.ID.26 and SEQ.ID.27, or a

fragment, homologue or analogue thereof, which encodes a prostate-associated antigen

which is expressed in higher than normal concentrations in prostate cancer cells.

14. A method according to any one of claims 10 to 11, wherein the cancer is prostate

cancer.

15. A vaccine comprising a nucleic acid molecule having a nucleic acid sequence

selected from SEQ.IDJ, SEQ.ID.2, SEQ.ID3, SEQ.ID4, SEQ.ID.5, SEQ.ID.6, SEQ.IDJ,

SEQ.ID.8, SEQ.ID.9, SEQ.ID.IO, SEQ.ID.l l, SEQ.ID.12, SEQ.ID.13 and SEQ.ID.14, or a

fragment, homologue or analogue thereof, which encodes a prostate-associated antigen

which is expressed in higher than normal concentrations in prostate cancer cells, or a

pharmaceutically effective fragment thereof and a pharmaceutically acceptable carrier.

16. A vaccine comprising a protein or peptide comprising an amino acid sequence

selected from SEQ.IDJ5, SEQ.ID.16, SEQ.IDJ7, SEQJDJ8, SEQ.IDJ 9, SEQ.ID.20,

SEQ.ID.21, SEQ.ID.22, SEQ.ID.23, SEQ.ID.24, SEQ.ID.25, SEQ.ID.26 and SEQ.ID.27,

or a fragment, homologue or analogue thereof, which encodes a prostate-associated antigen which is expressed in higher than normal concentrations in prostate cancer cells, or

a pharmaceutically effective fragment thereof, and a pharmaceutically acceptable carrier.

17. An isolated mammalian nucleic acid molecule comprising a nucleic acid sequence

selected from SEQ.IDJ. SEQ.IDJ, SEQ.ID.IO, SEQ.ID.13 and SEQ.ID.14 or a variant of

a fragment thereof which encodes a prostate-associated antigen which is expressed in

higher than normal concentrations in prostate cancer cells.

18. A vector comprising an isolated mammalian nucleic acid molecule according to

claim 17.

19. A nucleic acid molecule comprising at least 15 nucleotides, the nucleic acid

molecule being capable of hybridising to a molecule according to claim 17 under high

stringency conditions.

20. An isolated protein or peptide comprising an amino acid sequence selected from

SEQ.ID.No.18, SEQ.ID.No.21, SEQ.ID.No.26 and SEQ.ID.No.27, or a fragment,

homologue, analogue, or derivative thereof, which encodes a prostate-associated antigen

which is expressed in higher than normal concentrations in prostate cancer cells. 1

SEQUENCE LISTING

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<213> Home sapiens

<220> <223> ACTIN DEPOLYMERIΞING FACTOR

<400> 5 aaattttgag ctcgcgcgcc tgcangtcga cactagtgga tccaaagaat tcggcacgag 60 gtctctcggt cccgcagccg tgaggaggac ggtctgcata ctcgctgccc gccggctccc 120 tcccccgcgt ccctgcgtgt tgttccagtt tggaacaaga gtccactatt aaagaacgtg 180 gactccaacg tcaaagggcg aaaaaccgtc tatcagggcg atggcccact acgtgaacca 240 tcaccctaat caagtttttt ggggtcgagg tgccgtaaag cactaaatcg gaaccctaaa 300 gggagccccc gatttagagc ttgacgggga aagccggcga acgtggcgaa gaaaggaagg 360 gaagaaaσcg aaaggagcgg gcgctagggc gctggcaagt gtagcggtca cgctgcgcgt 420 aaccaccaca cccgccgcgc ttaatgcgcc gtncagggcg cgtcaggtgg acttttcggg 480 gaaatgtgcg cggaacccta tttgttattt tctaancatt caattgtatc cgctatgaac 540 atacctgtat gctcatatat gaaagagatc tngcgaaaca ct 582

<210> 6

<211> 607

<212> DNA

<213> Homo sapiens

<220>

<223> HUMAN MITOCHONDRIAL GENE

<400> 6 ttttgaggcc gcgcgcctgn ttntcgacac tactggatcc aaagaattcg gcacgagagt 60 aaaacccagc ccatntcccc taacaggggc cctctcagcc ctcctaatga cctccggcct 120 agccatgtga tttcacttcc actccataac gctcctcata ctaggcctac taaccaacat 180 ctaaccatat accaatgatg gcgcgatgta acactgagaa agcacatacc aaggccacca 240 cacaccacct gtccaaaaag gccttcgata cgggataatc ctatttatta cctcagaagt 300 ttttttcttc gcaggatttt tctgagcctt ttaccactcc agcctagccc ctacccccca 360 attaggaggg cactggcccc caacaggcat cacccccgct aaatccccta gaagtccact 420 cctaaacaca tccgtattac tcgcatcagg agtataatnc ctgagctaca tagtctaang 480 aaacaccgna acaatattca agcctggtat acaattactg ggcnctttta cctctnagct 540 aaagtcttag tttcttacct tccncgattc gtacattttn gcnagntncg ctacgattng 600 ctattct 607

<210> 7

<211> 574

<212> DNA

<213> Homo sapiens

<400> 7 aaattttgag cccgcgcgcc tgctngtcga cactagtgga tccnaagaat tcggcacgag 60 aagggctctt ccggcaggga tgcaggctca cagcgccctg gggctggaca ccaccggccg 120 gagcatggcg gacagcacac acggcccggg gcgggaacct tggaaacttt acacagatgg 180 ggagctcagc cattccacgt gtgctttcgc tcagcacaat gcttactaca aacccacgtg 240 tacttccttc cagctggttg ctttttattg ttgctgtctt aaaaaaaaag caacccacgt 300 gtacttcctt ccagcttggt tgctttttat tgttgctgtc ttaaaaaaaa aaaaaaaaaa 360 aaaaanaaaa aanaanaaaa aananaaaan ntnnaaanaa aaaaannccc tnngaagttc 420 ttttaacagc ggnggggncc ccattnnttt tcccccnggg ggccnccagg tagtcgaccc 480 antccncttt ngggggtttn aaaaattngt gnccgtttta acacgtnctg ntggaaacct 540 ggggtaccaa atacctgtng aaaacccttt tcnc 5

<210> 8

<211> 583

<212> DNA

<213> Homo sapiens

<220>

<223> HUMAN RI30S0MAL PROTEIN S8

<400> 3 aaatt^ttgag cgccgcgcgc ctgcn^tgtcg acactactgg atccaaagaa ttcggcacga 60 ggagcga-gg gcatctctcg ggacaactgg cacaagcgcc gcaaaaccgg gggcaagaσa 120 ^aagcc"a:: acaagaagcg gaagtatgag ttggggcgcc cagctgccaa caccaagatt 180 ggcccccgcc gcatccacac agtccgtgtg cggggaggta acaagaaatc cgtgccc_tga 240 ggttgg=cg^t ggggaat ^to tcc^tggggct cagagtgttg tactcgtaaa acaagga_tca 300 cqazqzz z c^tacaa^tgca tc^taataacc gagctggttc gtaccaagac cctgg_tgaag 360 aattgca^tog gctcatcga cagcacaccg taccgacagt ggtacgagtc ccactatgcg 420 ctgccc^t gg cgaagaagg gagccaagct gctctgagga agaagagatt taacaaaacg 480 atctaaaaaa aaannnnnnr. nnannnaaaa aaaacttgga gtctttaacg gcgggccatn 540 atttcnccgg gggrcnggna gnnccattnc tttnngcnnt aat 583

<210> 9

<211> 441

<212> DNA

<213> Home sapiens

<220>

<223> HUMAN RIBOSOMAL PROTEIN L27A

<400> 9 tggagcccgc gcgcctgnag gtcgacacta gtggatccaa agaattcggc acgaggcc_tc 60 cagac^tgagg aagacccgga aacttagggg cccgtgagcc acggccacgg ccgca_taggc 120 aagcaccgga agcacoccgg cggccgcggt aatgctggtg gtctgcatca ccaccgga_tc 180 aacttcgaca aataccacr.c angctacttt gggaaagttg gtangaagca ttaccac_tta 240 aagaggaaco agagc^tto g cccaactgtc aaccttgaca aattgtggac tttgg_tcaσ_t 300 gaacagacac ggg^tgaa^tgc tgctaaaaac aagactgggg ctgctcccat cattga_tgrg 360 g^tgcga-ⁱcgg gc^tc^tacaaa gttctgggaa agggaaagct nccaaagcag cctgtca_tcg 420 tgaaggcoaa tcttcagca c ' ....

<210> 1C

<211> 563

<212> DNA

<213> Homo sapiens

<400> 10 aaattttgag cccgcgcgcc tgctngtcgg acactagtgg atccaaagaa ttcggcacga 60 gacacggcga aaccctgtct ctactaaaac tacaaaaaat tagccaggtg tggtggtggg 120 cacctgtagt cccagctact cgggaggctg aggcaggaga atggtgtgaa cctgggaggt 180 ggagcttgca gtgagcagag atcgtgccac tgcactccag cctgggtgac agagtgagat 240 tctgtctcca aaaaaaaaaa aaaaaaaaaa aaaaanctcn agagtccttt tagagcggcc 300 gnggccccat cgnttttcca cccgggnggg gtcccagggt aaggngtccc caattcgccn 360 tatagngagt ccgtattaca attcactggc cgccgtttta caacgtcgng actggnaaaa 420 ccctgnnntt accaactaaa tcnccttgag aaatcccctt tngcagctgc gaanancaan 480 agcccgaccg tcgccttcaa cagttgccan cctatgnnan nganacaatt taaggttang 540 ggnaactcng tcaatgttgg gtn 563

<210> 11

<211> 579

<212> DNA

<213> Homo sapiens

<220>

<223> HUMAN INSERT cDNA CLONE 2B97G06

<400> 11 tttggagcnc gccgcgcctg ctngtcnnca ctacgtggat ccaaagaatt cggcacgagg 60 ggtggagtcg cggagtagtc ctcatggccg ccccgccgga gcccggtgag cccgaggaga 120 ggaagtccct taagctccta ggatttttag atgttgaaaa tactccctgc gcccggcatt 180 caatattgta tggttcatta ggatctgttg tggcttggct ttggacattt tttgttcact 240 agtagaatta gaagatcatg tgatgttgga gtaggagggt ttatcttggt gactttggga 300 tgctggtttc attgtaggta taattatgca aagcaaagaa tccaggaaag aattgccaga 360 gaagaaatta aaaagaagat atnatatgaa ggtacccacc tcgatcctga aagaaaacac 420 acggcagcag cagcaattga acaatcttga gcatagaagt caatgtaacg aagttagatc 480 accactaaaa catttatgtg cataagctct natcaagtaa taaagttaag ttgtaaaaaa 540 aaaaaaaact cggagncttt aagcggcggg ccatgattn 579

<210> 12

<211> 521

<212> DNA

<213> Homo sapiens

<220>

<223> HUMAN CpG DNA, CLONE 78h2

<400> 12 tnnacttctt gngccgcgcg cctgntngtc gacactngtg gatccaaaga attcggcacg 60 agaaggggaa gaagatcaaa acccaccatg ccccaggctc agcagggagc tgctggatga 120 gaaagggcct gaagtcttgc aggactcact ggatagatgt tattcgactc cttcaggtta 180 tcttgaactg cctgacttag gccagcccta cagcagtgcc tgtttactca ttggaggaac 240 agtaccttgg cttggctctt gacgtggaca gaattaaaaa ggaccaagaa gaggaagaag 300 accaaggccc accatgcccc aggctcagca gggagctgct ggaggtagta gagcctgaag 360 tcttgcagga ctactggata gatgttattc aactccttca gttgtcttga acagcctgac 420 tcctgccagc cctatggaag tccttttatg cattggagga aaacatgttg cttttctctt 480 6 gcgtggaaaa aaaaanannn nncnntnnnc nnnnnntnnc n 521

<210> 13

<211> 407

<212> DNA

<213> Homo sapiens

<400> 13 ggagctccgc gcgcctgcan gtcgacacta cgtggatcca aagaattcga tacgagaagg 60 gctcttccgg cagggatgca ggctcacagc gccctggggc tggacaccac cggccggagc 120 atggcaggac agcacacacg gcccggggcg ggaaccttgg aaactttaca cagatgggga 180 gctcagccat tccacgtg g ctttcgctca gcacaatgct tactacaaac ccacgtgtac 240 ttccttccag cttggttgct ttttattgtt gctgtcttaa aaaaaaagca acccacgtgt 300 acttccttcc agctggztgc tttttattgt tgctgtctta aaaaaaaaaa aaaaaaaaaa 360 aaaaaaaaan annaataaaa aaaanannnn aaanannann nnnnnnn 407

<210> 14

<211> 443

<212> DNA

<213> Homo sapiens

<400> 14 aattttggag cacgcgogcc tgnaggtcga cactagtgga tccaaagaat tcggcacgag 60 attttatgaa aagttagz t cctccctcat ttagacccca atggatacca ttccagagat 120 ctcataaaaa cagacacaga cttctccctc tttatatggt tatcttacga cttacctagt 180 ccttgagtct ggtcat aac tccttggtga ggagagaccc ataagcttag gaagtgctct 240 gcgagaaaga gactgctaag aagtagaggc attagcttgg ccagtgctct agagttgggt 300 aaaatgtaaa tgttatggcg gcgggaagga tggggtagag ggtatgcatg tatgggnaat 360 gggaccatta tttagcagca aaaaggaaag tttgaagaca ttaacaggan ctggttaatt 420 gtagccctta tctgaaanag gaa 443

<210> 15

<211> 98

<212> PRT

<213> Homo sapiens

<400> 15

Asp Xaa Cys Leu lie ?he Gly Xaa Leu Xaa Ser Ser Xaa Ala Ala Phe 1 5 10 15

His Lys Phe Glu Xaa Asn Cys Leu Xaa lie Phe His Thr His Asn Xaa 20 25 30

Cys Ser Pro Asp Leu Phe Leu Leu Arg Leu Met Val Leu Leu Xaa Cys 35 40 45

Phe Ser lie Vai Leu ie Val His Pro Phe Leu Pro Ser Val Phe Ser 50 55 60 Val Leu Pro Leu Phe Phe Gly Leu Tyr Ser Lys Leu Phe Gin Val Pro

⁶⁵ 70 75 80

Gin Lys Gin Leu Phe Arg Thr Phe Leu Ser Val Pro Val He Pro Leu

85 90 95

Pro Gly

<210> 16

<211> 137

<212> PRT

<213> Homo sapiens

<400> 16

Gly Arg Pro Tyr Pro Ala Val Val Pro Leu He Pro Ser Pro Ser Ala ¹ 5 10 ₁₅

Leu Gly Gin Arg Ser Pro Leu Gly Leu Pro Ser Leu Ala Trp Leu Ser 20 25 30

Ser Leu Ala Gin Glu Leu Arg He Pro Gly Ala Gly Glu Leu Pro Thr 35 40 45

Ser Cys Pro Arg Ser Cys Thr Ser Pro Leu Glu Ser Gly Tyr Pro Lys 50 55 60

Thr Lys Pro Gly Lys Arg Leu Thr Tyr Leu Cys Gin His Leu Arg Glu ⁶⁵ 70 75 ₈₀

Pro Trp Ala Ala Ala Cys Arg Tyr Ala Asp Gin Thr His Gin Gly Glu 85 90 95

Pro Tyr Leu Cys Leu Lys Pro Pro Val Glu Gly Glu Met Val Leu Glu 100 105 HO

Ala Val Leu Pro Leu Pro Pro Ser Leu Leu Asn Ser Cys Phe Xaa Arg 115 120 125

Val Gin Pro Leu Ser Val Leu Glu Arg 130 135

<210> 17 <211> 90 <212> PRT 8

<213> Homo sapiens

<400> 17

Arg Glu Arg Trp Asp Gin Val Tyr Lys He Leu Lys Gly Lys Ser Leu ^{1 5} 10 15

Arg Pro Gly Phe Pro Arg Cys Ala Thr Val Arg Ala He Gin His His 20 25 30

Gly Glu Ala Gly Gin Ser Gly Gly Leu Tyr Glu Pro Asn Ser Asn Gly 35 40 4₅

Glu He Lys Gly Ser Asn Pro Val Phe Arg Ala Asn Asn Thr Gly Leu 50 55 60

Ser Glu Ser Thr Lys Ala Tyr Leu Gly Arg Ser Lys Arg Ala Thr Arg ^{65 7}0 75 80

Xaa Gly Lys Glu Arg Leu Gin Gly Phe Gly 85 90

<210> 18

<211> 129

<212> PRT

<213> Homo sapiens

<400> 18

Arg Gly Ala Val Lys Pro Glu Pro Thr Asn Ser Ser Val Glu Val Ser 1 5 10 15

Pro Asp He Tyr Gin Gin Val Arg Asp Glu Leu Lys Arg Ala Ser Val 20 25 30

Ser Gin Ala Val Phe Ala Arg Val Ala Phe Asn Arg Thr Gin Gly Leu 35 40 45

Leu Ser Glu He Leu Arg Lys Glu Glu Asp Pro Arg Thr Ala Ser Gin 50 55 60

Ser Leu Leu Val Asn Leu Arg Ala Met Gin Asn Phe Leu Asn Leu Pro 65 70 75 80

Glu Val Glu Arg Asp Arg He Tyr Gin Asp Glu Arg Glu Arg Ser Met 85 90 95

Asn Xaa Asn Val Ser Met Val Ser Ser Ala Ser Ser Ser Pro Ser Ser 100 105 110 Ser Arg Thr Pro Gin Ala Lys Thr Ser Thr Pro Thr Gin Thr Xaa Leu 115 120 125

Phe

<210> 19

<211> 62

<212> PRT

<213> Homo sapiens

<400> 19

Val Ser Arg Ser Arg Ser Arg Glu Glu Asp Gly Leu His Thr Arg Cys

Pro Pro Ala Pro Ser Pro Ala Ser Leu Arg Val Val Pro Val Trp Asn 20 25 30

Lys Ser Pro Leu Leu Lys Asn Val Asp Ser Asn Val Lys Gly Arg Lys 35 40 45

Thr Val Tyr Gin Gly Asp Gly Pro Leu Arg Glu Pro Ser Pro 50 55 60

<210> 20

<211> 48

<212> PRT

<213> Homo sapiens

<400> 20

His Glu Ser Lys Thr Gin Pro Met Thr Pro Asn Arg Gly Pro Leu Ser 1 5 10 15

Pro Pro Asn Asp Leu Arg Pro Ser His Val He Ser Leu Pro Leu His 20 25 30

Asn Ala Pro His Thr Arg Pro Thr Asn Gin His Leu Thr He Tyr Gin 35 40 45

<210> 21 <211> 171 <212> PRT <213> Homo sapiens

<400> 21

Arg Ala Leu Pro Ala Gly Met Gin Ala His Ser Ala Leu Gly Leu Asp

⁵ 10 15

Thr Thr Gly Arg Ser Met Ala Asp Ser Thr His Gly Pro Gly Arg Glu ²⁰ 25 30

Pro Trp Lys Leu Tyr Thr Asp Gly Glu Leu Ser His Ser Thr Cys Ala ³⁵ 40 ₄₅

Phe Ala Gin His Asn Ala Tyr Tyr Lys Pro Thr Cys Thr Ser Phe Gin ^{50 55} 60

Leu Val Ala Phe Tyr Cys Cys Cys Leu Lys Lys Lys Ala Thr His Val " ⁷° 75 ₈₀

Tyr Phe Leu Pro Ala Trp Leu Leu Phe He Val Ala Val Leu Lys Lys

85 90 95

Lys Lys Lys Lys Lys Xaa Lys Xaa Xaa Lys Lys Xaa Lys Xaa Xaa Lys 100 105 110

Xaa Lys Xaa Xaa Xaa Xaa Ser Ser Phe Asn Ser Xaa Gly Xaa Pro He 115 "° 125

Xaa Phe Pro Xaa Gly Gly Xaa Gin Val Val Asp Pro Xaa Xaa Phe Xaa

130 135 140

Gly Phe Xaa Lys Xaa Val Xaa Val Leu Thr Arg Xaa Xaa Gly Asn Leu 145 150

155 160

Gly Tyr Gin He Pro Xaa Glu Asn Pro Phe Xaa

165 170

<210> 22

<211> 86

<212> PRT

<213> Homo sapiens

<400> 22

Leu Xaa Xaa Lys Xaa Met Xaa Xaa Xaa Asp Pro Arg Xaa Asn Xaa Gly ^{1 5} 10 15 Pro Pro Leu Lys Thr Pro Ser Phe Phe Xaa Xaa Xaa Xaa Xaa Phe Phe

20 25 30

Leu Asp Arg Phe Val Lys Ser Leu Leu Pro Gin Ser Ser Leu Ala Pro

35 40 45

Phe Phe Gly Pro Gly Gin Arg He Val Gly Leu Val Pro Leu Ser Val

^{50 55} 60

Arg Cys Ala Val Asp Glu His Asp Ala He Leu His Gin Gly Leu Gly

65 ^■ 7"0• ¹

80

Thr Asn Gin Leu Gly Tyr 85

<210> 23

<211> 122

<212> PRT

<213> Homo sapiens

<400> 23

Ala Ser Arg Leu Arg Lys Thr Arg Lys Leu Arg Gly His Val Ser His ^{1 5} 10 15

Gly His Gly Arg He Gly Lys His Arg Lys His Pro Gly Gly Arg Gly

20 25 30

Asn Ala Gly Gly Leu His His His Arg He Asn Phe Asp Lys Tyr His

35 40 45

Xaa Xaa Tyr Phe Gly Lys Val Gly Xaa Lys His Tyr His Leu Lys Arg

Asn _{Gln Ser Phe Cys Pro Thr VaJ}_ _{Asn Leu Asp Lys Leu Ti}^ _Leu

80

Val Ser Glu Gin Thr Arg Val Asn Ala Ala Lys Asn Lys Thr Gly Ala ⁸⁵ 90 95

Ala Pro He He Asp Val Val Arg Ser Gly Ser Thr Lys Phe Trp Glu

¹⁰⁰ . 105 ₁₁₀

Arg Glu Ser Xaa Gin Ser Ser Leu Ser Ser 5 120

<210> 24 O 00/40752 ' ^c-

<211> 60

<212> PRT

<213> Homo sapiens

<400> 24

Gly Trp Ser Arg Gly Val Val Leu Met Ala Ala Pro Pro Glu Pro Gly 1 5 10 15

Glu Pro Glu Glu Arg Lys Ser Leu Lys Leu Leu Gly Phe Leu Asp Val 20 25 30

Glu Asn Thr Pro Cys Ala Arg His Ser He Leu Tyr Gly Ser Leu Gly 35 40 45

Ser Val Val Ala Trp Leu Trp Thr Phe Phe Val His 50 55 60

<210> 25

<211> 66

<212> PRT

<213> Homo sapiens

<400> 25

Glu Gly Glu Glu Asp Gin Asn Pro Pro Cys Pro Arg Leu Ser Arg Glu 1 5 10 15

Leu Leu Asp Glu Lys Gly Pro Glu Val Leu Gin Asp Ser Leu Asp Arg 20 25 30

Cys Tyr Ser Thr Pro Ser Gly Tyr Leu Glu Leu Pro Asp Leu Gly Gin 35 40 45

Pro Tyr Ser Ser Ala Cys Leu Leu He Gly Gly Thr Val Pro Trp Leu 50 55 60

Gly Ser

65

<210> 26

<211> 68

<212> PRT

<213> Homo sapiens

<400> 26

Lys Gly Ser Ser Gly Arg Asp Ala Gly Ser Arg Gly Ala Gly His His 1 5 10 15 13

Arg His Gly Arg Thr Ala His Thr Ala Arg Gly Gly Asn Gly Asn Thr ²⁰ 25 30

Met Gly Ser Ser Ala Arg Val Ser Ser Thr Met Thr Thr Asn Arg Val 35 40 ₄₅

Ser Ser Val Ala Tyr Cys Cys Cys Lys Lys Lys Ala Thr His Val Tyr ⁵⁰ " ₆₀

Ala Gly Cys Ser 65

<210> 27

<211> 106

<212> PRT

<213> Homo sapiens

<400> 27

Arg Ala Leu Pro Ala Gly Met Gin Ala His Ser Ala Leu Gly Leu Asp ¹ 5 _{10 1S}

Thr Thr Gly Arg Ser Met Ala Gly Gin His Thr Arg Pro Gly Ala Gly 20 25 30

Thr Leu Glu Thr Leu His Arg Trp Gly Ala Gin Pro Phe His Val Cys 5 40 ₄₅

Phe Arg Ser Ala Gin Cys Leu Leu Gin Thr His Val Tyr Phe Leu Pro ⁵⁰ 55 ₆₀

Ala Trp Leu Leu Phe lie Val Ala Val Leu Lys Lys Lys Gin Pro Thr ^{65 70} 75 80

Cys Thr Ser Phe Gin Leu Val Ala Phe Tyr Cys Cys Cys Leu Lys Lys

⁸⁵ 90 95

Lys Lys Lys Lys Lys Lys Lys Lys Xaa Xaa 100 ₁₀₅