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1. (WO2008063655) MARQUEURS DE MÉTHYLATION DE L'ADN ET LEURS MÉTHODES D'UTILISATION
Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

WHAT IS CLAIMED IS:

1. A method for identifying metastases in a subject comprising detecting nucleic acid hypermethylation of one or more genes in one or more samples, wherein detecting nucleic acid hypermethylation identifies metastases.

2. The method of claim 1, wherein the sample comprises cells or tissues selected from the group consisting of: tumor, lymph nodes, bone marrow and blood.

3. The method of claim 2, wherein the sample is from a tumor.

4. The method of claim 2, wherein the sample is from a lymph node.

5. The method of claim 4, wherein the lymph node is a N1 lymph node or a mediastinal lymph node.

6. A method for identifying metastases in a subject comprising detecting nucleic acid hypermethylation of one or more genes in tumor tissue or lymph node, wherein the genes are selected from the group consisting of: genes involved in tumor suppression, DNA repair, apoptosis, anti-proliferation, ras signaling, adhesion, differentiation, development, and cell cycle regulation, wherein detecting nucleic acid hypermethylation identifies metastases.

7. The method of claim 1 or claim 6, wherein the metastases are

micrometastases.

8. The method of claim 1 or claim 6, wherein the one or more genes comprise one or more CpG islands.

9. The method of claim 8, wherein the one or more genes is selected from the group consisting of: H-cadherin, p16, APC, RASSF1A, MGMT, DAPK, and ASC.

10. The method of claim 1 or claim 6, wherein hypermethylation of at least one of the genes is detected.

11. The method of claim 1 or claim 6, wherein hypermethylation of at least two of the genes is detected.

12. A method for identifying micrometastases in a subject comprising detecting nucleic acid hypermethylation of at least one or more genes in a sample comprising tumor and lymph nodes, wherein the sample genes are selected from the group consisting of: H-cadherin, p16, APC, RASSF1A, MGMT, DAPK, and ASC, and wherein detecting nucleic acid methylation identifies micrometastases.

13. The method of claim 12, wherein hypermethylation of at least two of the genes is detected.

14. The method of claim 11 or claim 13, wherein at least two of the genes are selected from p-16 and H-cadherin, H-cadherin and APC, APC and p16, or RASSf1A and p16.

15. The method of claims 1, 6 or 12, wherein the detection of metastases is used to detect or diagnose a proliferative disease.

16. The method of claim 15, wherein the detection or diagnosis is performed after surgery or therapy to treat a proliferative disease.

17. The method of claims 1, 6 or 12 wherein the detection is used to predict the recurrence of a proliferative disease.

18. The method of claims 1, 6 or 12 wherein the detection is used to stage a proliferative disease.

19. The method of any one of claims 15 - 18, wherein the detection is further used to determine a course of treatment for a subject.

20. A method for detecting or diagnosing a proliferative disease in a subject comprising detecting nucleic acid hypermethylation of one or more genes in one or more samples, wherein detecting nucleic acid hypermethylation is used to detect or diagnose a proliferative disease.

21. A method for predicting the recurrence of a proliferative disease in a subject comprising: detecting nucleic acid hypermethylation of one or more genes wherein detecting nucleic acid hypermethylation of one or more genes is a predictor of the recurrence of a proliferative disease.

22. The method of claim 21, wherein hypermethylation of one or more genes is detected in tumor or lymph nodes.

23. The method of claim 22, wherein detection of hypermethylation of one or more genes in lymph nodes is predictive of aggressive disease recurrence.

24. A method for staging or re-staging a proliferative disease in a subject comprising: detecting nucleic acid hypermethylation of one or more genes wherein detecting nucleic acid hypermethylation is used for staging or re-staging a

proliferative disease.

25. The method of claim 24, wherein the stage of proliferative disease is predictive of disease recurrence.

26. The method of claim 24, wherein the stage of proliferative disease determines course of treatment.

27. A method for determining the prognosis of a subject suffering from a proliferative disease comprising: detecting nucleic acid hypermethylation of one or more genes wherein the detection of nucleic acid hypermethylation is used for determining the prognosis of a subject suffering from a proliferative disease.

28. The method of claim 27, wherein the prognosis determines course of treatment.

29. The method of any one of claims 1 - 28, wherein the subject is a human.

30. The method of any one of claims 1 - 28, wherein the method is performed prior to therapeutic intervention for the disease.

31. The method of any one of claims 1 - 28, wherein the method is performed after therapeutic intervention for the disease.

32. The method of claim 30 or 31, wherein the therapeutic intervention is selected from treatment with an agent or surgery.

33. The method of any one of claims 1 - 28, wherein hypermethylation is detected in CpG islands of the one or more genes.

34. The method of claim 33, wherein hypermethylation is detected in CpG islands.

35. A method for detecting or diagnosing a proliferative disease in a subject comprising:

extracting nucleic acid from one or more cell or tissue samples;

detecting nucleic acid hypermethylation of one or more genes in the sample; and

identifying the nucleic acid hypermethylation state of one or more genes, wherein nucleic acid hypermethylation of genes indicates a proliferative disease.

36. A method for predicting the recurrence of a proliferative disease in a subject comprising:

extracting nucleic acid from one or more cell or tissue samples;

detecting nucleic acid hypermethylation of one or more genes in the sample; and

identifying the nucleic acid hypermethylation state of one or more genes, wherein nucleic acid hypermethylation of genes is indicative of the recurrence of a proliferative disease.

37. A method for staging or re-staging a proliferative disease in a subject comprising:

extracting nucleic acid from one or more cell or tissue samples;

detecting nucleic acid hypermethylation of one or more genes in the sample; and

identifying the nucleic acid hypermethylation state of one or more genes, wherein nucleic acid hypermethylation of genes is used for staging or re-staging of a proliferative disease.

38. The method of any one of claims 35 - 37, wherein the tissue samples are selected from tumor, lymph node, bone marrow or blood or a combination thereof.

39. The method of any one of claims 35 - 37, wherein the method determines the course of disease treatment.

40. The method of any one of claims 35 - 37, wherein the method is performed prior to therapeutic intervention for the disease.

41. The method of any one of claims 35 - 37, wherein the method is performed after therapeutic intervention for the disease.

42. The method of claim 40 or 41, wherein the therapeutic intervention is selected from treatment with an agent or surgery.

43. A method of treating a subject having or at risk for having a proliferative disease comprising:

identifying nucleic acid hypermethylation of one or more genes, where nucleic acid hypermethylation indicates having or a risk for having a proliferative disease; and

administering to the subject a therapeutically effective amount of a demethylating agent,

thereby treating a subject having or at risk for having a proliferative disease.

44. The method of claim 43, wherein the method is used in combination with one or more chemotherapeutic agents.

45. The method of any one of claims 35 - 43, further comprising comparing the nucleic acid hypermethylation of one or more genes in the sample with a comparable samples obtained from a normal subject.

46. The method of any one of claims 35- 43 wherein detecting nucleic acid hypermethylation of one or more genes indicates the presence of metastases.

47. The method of claim 46, wherein the metastases are micrometastases.

48. The method of any one of claims 1 - 43, wherein the proliferative disease is a neoplasia.

49. The method of claim 48, wherein the neoplasia is cancer.

50. The method of claim 49, wherein the cancer is a solid tumor.

51. The method of claim 49, wherein the cancer is selected from the group consisting of: lung cancer, pancreatic cancer, esophageal cancer, head and neck cancer, stomach cancer, liver cancer, prostate cancer, gastrointestinal cancer, ovarian cancer, and uterine cancer.

52. The method of any one of claims 6 - 43, wherein the cells or tissues are selected from the group consisting of: tumor, lymph nodes, bone marrow or blood.

53. The method of claim 50, wherein the cells or tissues are from a tumor or the lymph nodes.

54. The method of claim 53, wherein the lymph node is a N1 lymph node or a mediastinal lymph node.

55. A method of identifying an agent that de-methylates hypermethylated nucleic acid comprising:

identifying one or more cell or tissue samples with hypermethylated nucleic acid;

extracting the hypermethylated nucleic acid;

contacting the nucleic acid with one or more nucleic acid de-methylating candidate agents and a control agent;

identifying the nucleic acid hypermethylation state, wherein nucleic acid de-methylation of genes in the sample by the candidate agent compared to the control indicates a demethylating agent,

thereby identifying an agent that de-methylates hypermethylated nucleic acid.

56. The method of any one of claims 6 - 55, wherein the one or more genes are selected from the group consisting of: genes involved in tumor suppression, DNA repair, anti-proliferation, apoptosis, ras signaling, adhesion, differentiation, development, and cell cycle regulation.

57. The method of any one of claims 6 - 55, wherein the one or more genes are selected from a panel consisting of: (1) genes involved in tumor suppression and cell adhesion, (2) genes involved in cell cycle regulation and adhesion, (3) genes involved in tumor suppression and cell cycle regulation, and (4) genes involved in ras signaling and cell cycle control.

58. The method any one of claims 6 - 55, wherein the one or more genes comprise one or more CpG islands.

59. The method of any one of claims 56 - 58, wherein the genes are selected from the group consisting of: p-16, H-cadherin, APC, RASSF1A, MGMT, DAPK, and ASC.

60. The method of any one of claims 56 - 59, wherein the hypermethylation of at least one of the genes is detected.

61. The method of any one of claims 56 - 59, wherein the hypermethylation of at least two of the genes is detected.

62. The method of claim 61, wherein the two genes are selected from p-16 and H-cadherin, H-cadherin and APC, APC and p16, or RASSf1A and p16.

63. The method of any one of the above claims, wherein the detection of nucleic acid methylation is by a quantitative method.

64. The method of any one of the above claims, wherein the detection of nucleic acid methylation is carried out by polymerase chain reaction (PCR) analysis.

65. The method of claim 64, wherein the PCR is methylation specific PCR (MSP).

66. The method of any one of claims 63 - 65, wherein the method of detecting nucleic acid methylation is performed as a high-throughput method.

67. The method of any one of claims 35 - 55, wherein the method is used in combination with the detection of other epigenetic markers.

68. The method of claim 67, wherein the other epigenetic markers are plasma or tumor epigenetic markers.

69. The method of any one of claims 35 - 55, wherein hypermethylation is detected in CpG islands of the one or more genes.

70. The method of any one of the above claims, wherein hypermethylation is detected in CpG islands of the promoter region.

71. A kit for identifying the nucleic acid hypermethylation state of one or more genes comprising gene specific primers for use in polymerase chain reaction (PCR), and instructions for use.

72. A kit for detecting metastases by detecting nucleic acid hypermethylation of one or more genes, the kit comprising gene specific primers for use in polymerase chain reaction (PCR), and instructions for use.

73. The kit of claim 72, wherein the metastases are micrometastases.

74. The kit of claim 71 or 72, wherein the PCR is methylation specific PCR (MSP).

75. The kit of claim 71 or 72, wherein the one or more genes are selected from the group consisting of: genes involved in tumor suppression, DNA repair, anti-proliferation, apotosis, ras signaling, adhesion, differentiation, development, and cell cycle regulation.

76. The kit of claim 71 or 72, wherein one or more genes are selected from a panel consisting of: (1) genes involved in tumor suppression and cell adhesion, (2) genes involved in cell cycle regulation and adhesion, (3) genes involved in tumor suppression and cell cycle regulation, and (4) genes involved in ras signaling and cell cycle control.

77. The kit of claim 71 or 72, wherein the one or more genes comprise one or more CpG islands.

78. The kit of claim 77, wherein the CpG islands are in the promoter region.

79. The kit of claim 71 or 72, wherein the genes are selected from the group consisting of: p-16, H-cadherin, APC, RASSF1A, MGMT, DAPK, and ASC.

80. The kit of claim 71 or 72, wherein the hypermethylation of at least one of the genes is detected.

81. The kit of claim 69 or 70, wherein the hypermethylation of at least two of the genes is detected.

82. The kit of claim 81, wherein the two genes are selected from p-16 and H-cadherin, H-cadherin and APC, APC and p16, or RASSf1A and p16.