CA2162150A1 - Germline mutations in the mts gene and method for detecting predisposition to cancer at the mts gene - Google Patents

Germline mutations in the mts gene and method for detecting predisposition to cancer at the mts gene

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Publication number
CA2162150A1
CA2162150A1 CA002162150A CA2162150A CA2162150A1 CA 2162150 A1 CA2162150 A1 CA 2162150A1 CA 002162150 A CA002162150 A CA 002162150A CA 2162150 A CA2162150 A CA 2162150A CA 2162150 A1 CA2162150 A1 CA 2162150A1
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Prior art keywords
mts gene
wild
detected
gene
mts
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Granted
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CA002162150A
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French (fr)
Other versions
CA2162150C (en
Inventor
Mark H. Skolnick
Lisa A. Cannon-Albright
Alexander Kamb
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University of Utah Research Foundation UURF
Myriad Genetics Inc
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Publication of CA2162150A1 publication Critical patent/CA2162150A1/en
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Publication of CA2162150C publication Critical patent/CA2162150C/en
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/136—Screening for pharmacological compounds
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/172—Haplotypes

Abstract

The present invention relates to somatic mutations in the Multiple Tumor Suppressor (MTS) gene in human cancers and their use in the diagnosis and prognosis of human cancer. The invention further relates to germ line mutations in the MTS gene and their use in the diagnosis of predisposition to melanoma, leukemia, astrocytoma, glioblastoma, lymphoma, glioma, Hodgkin's lymphoma, CLL, and cancers of the pancreas, breast, thyroid, ovary, uterus, testis, kidney, stomach and rectum. The invention also relates to the therapy of human cancers which have a mutation in the MTS gene, including gene therapy, protein replacement therapy and protein mimetics. Finally, the invention relates to the screening of drugs for cancer therapy.

Claims (59)

1. A method for diagnosing a polymorphism associated with predisposition for cancer including melanoma, leukemia, astrocytoma, glioblastoma, lymphoma, glioma, Hodgkin's lymphoma CLL, and cancers of the pancreas, breast, thyroid, ovary, uterus, testis, kidney, stomach and rectum, in a mammal comprising: detecting a germline alteration of the wild-type MTS gene or its expression products in a mammal sample, said alteration indicating a predisposition to said cancer.
2. The method of claim 1 wherein said MTS gene is MTS1.
3. The method of claim 1 wherein said MTS gene is MTS2.
4. The method of claim 1 wherein said MTS gene is MTS1E.beta..
5. The method of claim 1 wherein said expression product is mRNA of MTS1.
6. The method of claim 1 wherein said expression product is mRNA of MTS2.
7. The method of claim 1 wherein said expression product is mRNA of MTS1E1.beta..
8. The method of claim 5 wherein the alteration of the wild-type MTS gene mRNA is detected by hybridization of the mRNA from said tissue sample to an MTS gene probe.
9. The method of claim 6 wherein the alteration of the wild-type MTS gene mRNA is detected by hybridization of the mRNA from said tissue sample to an MTS gene probe.
10. The method of claim 1 wherein an alteration is detected in the regulatory regions of the MTS
gene.
11. The method of claim 1 wherein the alteration of the wild-type MTS gene is detected by observing shifts in electrophoretic mobility of single-stranded DNA on non-denaturing polyacrylamide gels.
12. The method of claim 1 wherein the alteration of the wild-type MTS gene is detected by hybridization of an MTS gene probe to genomic DNA isolated from said tissue.
13. The method of claim 12 wherein the MTS gene probe hybridizes to an exon selected from the group consisting of nucleotides 891 to 1016 of SEQ ID NO:3 and nucleotides 192 to 498 of SEQ ID NO:4.
14. The method of claim 1 wherein the alteration of the wild-type MTS gene is detected by hybridization with an allele-specific probe.
15. The method of claim 1 wherein the alteration of the wild-type MTS gene is detected by amplifying all or part of the MTS gene in said tissue to produce an amplified sequence and sequencing the amplified sequence.
16. The method of claim 1 wherein the alteration of the wild-type MTS gene is detected by amplifying all or part of the MTS gene for a specific MTS allele.
17. The method of claim 1 wherein the alteration of the wild-type MTS gene is detected by molecularly cloning all or part of the MTS gene in said tissue to produce a cloned sequence and sequencing the cloned sequence.
18. The method of claim 1 wherein the alteration of the wild-type MTS gene is detected by identifying a mismatch between molecules (1) MTS gene genomic DNA or MTS mRNA
isolated from said tissue, and (2) a nucleic acid probe complementary to the human wild-type MTS gene DNA, when molecules (1) and (2) are hybridized to each other to form a duplex.
19. The method of claim 1 wherein the alteration of the wild-type MTS gene is detected by amplification of MTS gene sequences in said tissue and hybridization of the amplified sequences to nucleic acid probes which comprise wild-type MTS gene sequences.
20. The method of claim 1 wherein the alteration of the wild-type MTS gene is detected by amplification of MTS gene sequences in said tissue and hybridization of the amplified sequences to nucleic acid probes which comprise non-wild-type MTS gene sequences.
21. The method of claim 1 wherein the alteration of the wild-type MTS gene is detected by screening for a deletion mutation.
22. The method of claim 1 wherein the alteration of the wild-type MTS gene is detected by screening for a point mutation.
23. The method of claim 1 wherein the alteration of the wild-type MTS gene is detected by screening for an insertion.
24. The method of claim 1 wherein the alteration of the wild-type MTS gene is detected by in situ hybridization of the MTS gene with nucleic acid probes which comprise the MTS gene.
25. The method of claim 1 wherein the expression products are protein molecules.
26. The method of claim 25 wherein the alteration of wild-type MTS gene protein is detected by immunoblotting.
27. The method of claim 25 wherein the alteration of wild-type MTS gene protein is detected by immunocytochemistry.
28. The method of claim 25 wherein the alteration of wild-type MTS gene protein is detected by assaying for binding interactions between MTS gene protein isolated from said tissue and a Cdk.
29. The method of claim 28 wherein said Cdk is Cdk4.
30. The method of claim 25 wherein the alteration of wild-type MTS gene protein is detected by assaying for the inhibition of biochemical activity of a Cdk.
31. The method of claim 30 wherein said Cdk is Cdk4.
32. A method for confirming the lack of a predisposition for cancer at the MTS locus in a mammal, comprising: detecting the wild-type MTS gene or its expression products in a mammal sample, the presence of the wild-type gene or expression products indicating no predisposition to cancer at the MTS locus.
33. The method of claim 32 wherein said MTS gene is MTS1.
34. The method of claim 32 wherein said MTS gene is MTS2.
35. The method of claim 32 wherein said expression product is mRNA of MTS1.
36. The method of claim 32 wherein said expression product is mRNA of MTS2.
37. The method of claim 35 wherein the wild-type MTS gene mRNA is detected by hybridization of the mRNA from said tissue sample to an MTS gene probe.
38. The method of claim 36 wherein the wild-type MTS gene mRNA is detected by hybridization of the mRNA from said tissue sample to an MTS gene probe.
39. The method of claim 32 wherein the wild-type MTS gene is detected by hybridization of an MTS gene probe to genomic DNA isolated from said tissue.
40. The method of claim 39 wherein the MTS gene probe hybridizes to an exon selected from the group consisting of nucleotides 891 to 1016 of SEQ ID NO:3 and nucleotides 192 to 498 of SEQ ID NO:4.
41. The method of claim 32 wherein the wild-type MTS gene is detected by amplifying all or part of the MTS gene in said tissue to produce an amplified sequence and sequencing the amplified sequence.
42. The method of claim 32 wherein the wild-type MTS gene is detected by molecularly cloning all or part of the MTS gene in said tissue to produce a cloned sequence and sequencing the cloned sequence.
43. The method of claim 32 wherein the wild-type MTS gene is detected by in situ hybridization of the MTS gene with nucleic acid probes which comprise the MTS gene.
44. The method of claim 32 wherein the expression products are protein molecules.
45. The method of claim 44 wherein the alteration of wild-type MTS gene protein is detected by immunoblotting.
46. The method of claim 44 wherein the alteration of wild-type MTS gene protein is detected by immunocytochemistry.
47. The method of claim 44 wherein the alteration of wild-type MTS gene protein is detected by assaying for binding interactions between MTS gene protein isolated from said tissue and a Cdk.
48. The method of claim 47 wherein said Cdk is Cdk4.
49. The method of claim 44 wherein the alteration of wild-type MTS gene protein is detected by assaying for the inhibition of biochemical activity of a Cdk.
50. The method of claim 49 wherein said Cdk is Cdk4.
51. An isolated DNA consisting of SEQ ID NO:1 having A at nucleotide 353.
52. An isolated DNA consisting of SEQ ID NO:1 having T at nucleotide 277.
53. A nucleic acid probe complementary to human altered MTS gene sequences whichhybridizes to part of the MTS gene, said part of the MTS gene consisting of SEQ ID NO:1 having A at nucleotide 353.
54. A nucleic acid probe complementary to human altered MTS gene sequences whichhybridizes to part of the MTS gene, said part of the MTS gene consisting of SEQ ID NO:1 having T at nucleotide 277.
55. A replicative cloning vector which comprises the isolated DNA of claim 51 or 52 and a replicon operative in a host cell.
56. An expression system which comprises the isolated DNA of claim 51 or 52 operably linked to suitable control sequences.
57. Recombinant host cells transformed with the replicative cloning vector of claim 55.
58. Recombinant host cells transformed with the expression system of claim 56.
59. A method of producing recombinant MTS polypeptide which comprises culturing cells of claim 58 under conditions effective for the production of said MTS polypeptide.
CA2162150A 1994-03-18 1995-03-17 Germline mutations in the mts gene and method for detecting predisposition to cancer at the mts gene Expired - Lifetime CA2162150C (en)

Applications Claiming Priority (11)

Application Number Priority Date Filing Date Title
US21508794A 1994-03-18 1994-03-18
US21458294A 1994-03-18 1994-03-18
US21508694A 1994-03-18 1994-03-18
US08/215,087 1994-03-18
US08/215,086 1994-03-18
US08/214,582 1994-03-18
US22736994A 1994-04-14 1994-04-14
US08/227,369 1994-04-14
US25193894A 1994-06-01 1994-06-01
US08/251,938 1994-06-01
PCT/US1995/003537 WO1995025813A1 (en) 1994-03-18 1995-03-17 Germline mutations in the mts gene and method for detecting predisposition to cancer at the mts gene

Publications (2)

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CA2162150A1 true CA2162150A1 (en) 1995-09-28
CA2162150C CA2162150C (en) 2010-03-30

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CA2162150A Expired - Lifetime CA2162150C (en) 1994-03-18 1995-03-17 Germline mutations in the mts gene and method for detecting predisposition to cancer at the mts gene

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US (9) US5801236A (en)
EP (1) EP0702730A4 (en)
JP (1) JPH08510391A (en)
CN (1) CN1128049A (en)
AU (1) AU685627B2 (en)
CA (1) CA2162150C (en)
FI (1) FI955416A (en)
NO (1) NO954495L (en)
NZ (1) NZ284612A (en)
RU (1) RU2161309C2 (en)
WO (1) WO1995025813A1 (en)

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CA2162150C (en) 2010-03-30
FI955416A (en) 1996-01-09
US6218146B1 (en) 2001-04-17
AU685627B2 (en) 1998-01-22
JPH08510391A (en) 1996-11-05
US5624819A (en) 1997-04-29
CN1128049A (en) 1996-07-31
NZ284612A (en) 1997-09-22
US6180776B1 (en) 2001-01-30
RU2161309C2 (en) 2000-12-27
NO954495L (en) 1996-01-17
EP0702730A1 (en) 1996-03-27
US5739027A (en) 1998-04-14
US6090578A (en) 2000-07-18
AU2378995A (en) 1995-10-09
US5994095A (en) 1999-11-30
EP0702730A4 (en) 1997-05-07
WO1995025813A1 (en) 1995-09-28
FI955416A0 (en) 1995-11-10
NO954495D0 (en) 1995-11-08
US6037462A (en) 2000-03-14
US5801236A (en) 1998-09-01
US6140473A (en) 2000-10-31

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