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1. WO2011009637 - MARKERS FOR ENDOMETRIAL CANCER

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[ EN ]

CLAIMS

1. An in vitro diagnostic method for the diagnosis of endometrial cancer comprising (1) detecting the level of from 1 to 17 biomarker(s) chosen from P4HB, GMIP, IKBKE, FASTKDl , DDRl , SIRT6, PHKG2, ACAAl , AP1M2, EPS8L2, P2RX4, PPFIBP2, PPP1R16A, CGN, RASSF7, RNFl 83, and TJP3 in a sample from a patient wherein an increased level of said from 1 to 17 biomarkers compared to a control value indicates the existence of endometrial cancer and/or (2) detecting the level of from 1 to 3 biomarkers chosen from EFEMP2, S0CS2, and DCN, wherein a decreased level of EFEMP2, S0CS2, and/or DCN compared to a control value indicates the existence of endometrial cancer.

2. The in vitro diagnostic method of claim 1 comprising detecting the level of

P4HB.

3. The in vitro diagnostic method of claim 1 comprising detecting the level of

EFEMP2.

4. The in vitro method of claim 1 comprising detecting the level of IKBKE.

5. The in vitro diagnostic method of claim 1 comprising detecting the level of

GMIP.

6. The in vitro diagnostic method of claim 2 further comprising detecting the level of one or more of GMIP, IKBKE, or EFEMP2.

7. The in vitro diagnostic method of claim 3 further comprising detecting the level of one or more of P4HB, IKBKE, or GMIP.

8. The in vitro diagnostic method of claim 4 further comprising detecting the level of one or more of GMIP, EFEMP2, or P4HB.

9. The in vitro diagnostic method of any one of claims 2 to 8 further comprising detecting the level of FASTKDl .

10. The in vitro diagnostic method of any one of claims 2 to 9 further comprising detecting the level of DDRl .

11. The in vitro diagnostic method of any one of claims 2 to 10 further comprising detecting the level of SIRT6.

12. The in vitro diagnostic method of any one of claims 2 to 1 1 further comprising detecting the level of PHKG2.

13. The in vitro diagnostic method of any one of claims 2 to 12 further comprising detecting the level of from 1 to 12 biomarkers chosen from ACAAl , AP1M2, EPS8L2, P2RX4, PPFIBP2, PPP1R16A, CGN, RASSF7, RNF183, TJP3, SOCS2, and DCN.

14. The in vitro diagnostic of any one of claims 1 to 13 wherein said patient has a risk factor for endometrial cancer or is being screened for endometrial cancer.

15. The in vitro diagnostic method of any one of claims 1 to 14 wherein said sample from said patient is (obtained) from a patient with abnormal uterine bleeding or wherein said patient suffers from abnormal uterine bleeding.

16. The in vitro diagnostic method of any one of claims 1 to 15 wherein said sample from said patient is (obtained) from a patient having an endometrium with increased thickness or wherein said patient has an endometrium with increased thickness.

17. The in vitro diagnostic method of any one of claims 1 to 16 wherein said sample from said patient is (obtained) from a pre-menopausal, peri- menopausal, or post-menopausal patient or wherein said patient is a premenopausal, peri-menopausal, or post-menopausal patient.

18. The in vitro diagnostic method of claim 17 wherein said patient is premenopausal.

19. The in vitro diagnostic method of claims 17 wherein said patient is peri- menopausal.

20. The in vitro diagnostic method of claim 17 wherein said patient is post- menpausal.

21. The in vitro diagnostic method of any one of claims 1 to 20 wherein said sample is chosen from a tissue sample, blood and/or serum, and uterine fluid.

22. The in vitro diagnostic method of claim 21 wherein said sample is a uterine fluid sample.

23. The in vitro diagnostic method of claim 22 wherein said uterine fluid sample is obtained by aspiration.

24. The in vitro diagnostic method of any one of claims 1 to 23 wherein the level of the biomarkers is determined with an antibody.

25. The in vitro diagnostic method of any one of claims 1 to 23 wherein the level of the biomarker(s) is determined by RT-PCR.

26. The in vitro diagnostic method of any one of claims 1 to 25, wherein said markers are chosen from P4HB, IKBKE, EFEMP2, SOCS2, FASTKDl , GMIP, DDRl , SIRT6, PHKG2, EPS8L2, and PPP1R16A, P2RX4, RASSF7, and TJP3.

27. The in vitro diagnostic method of any one of claims 1 to 26 wherein said marker(s) is chosen from P2RX4, P4HB, PHKG2, PPFIBP2, and SOCS2.

28. The in vitro diagnostic method of any one of claims 1 to 26, wherein said marker(s) is chosen from P4HB, RASSF7, RNFl 83 and IKBKE.

29. The in vitro diagnostic method of any one of claims 1 to 28 wherein from 2 to 20 markers are detected.

30. The in vitro diagnostic method of any one of claims 1 to 29, wherein a combination of the following markers is detected: P4HB, EFEMP2, SIRT6, GMIP, FASTKDl and DDRl .

31. The in vitro diagnostic method of any one of claims 1 to 29, wherein a combination of the following markers is detected: P4HB, EFEMP2, SIRT6, GMIP, FASTKDl and PHKG2.

32. The in vitro diagnostic method of claims 1 to 29, wherein a combination of the following markers is detected: P4HB, EFEMP2, SIRT6, ACAAl, AP1M2, EPS8L2, IKBKE, P2RX4, PPFIBP2 and PPP1R16A.

33. The in vitro diagnostic method of any one of claims 1 to 32 wherein one or more additional biomarkers are detected.

34. The in vitro diagnostic method of claim 33 wherein said one or more additional biomarkers are chosen from differential diagnosis biomarkers, prognostic biomarkers, biomarkers useful for detecting endometrial cancer, biomarkers for classify endometrial cancer and auxiliary biomarkers for detecting endometrial cancer.

35. The in vitro diagnostic method of claim 33 or 34 wherein one or more additional biomarkers are chosen from differential diagnosis biomarkers.

36. The in vitro diagnostic method of claim 33 or 34 wherein one or more auxiliary biomarkers are chosen from prognostic markers.

37. The in vitro diagnostic method of claim 33 or 34 wherein one or more auxiliary biomarkers are chosen from endometrial cancer classification markers.

38. A nucleic acid chosen from

IKBKE mRNA, cDNA, or a complement thereof;

P4HB mRNA, cDNA, or a complement thereof;

SOCS2 mRNA, cDNA, or a complement thereo;f

GMIP mRNA, cDNA, or a complement thereof;

DDRl mRNA, cDNA, or a complement thereof;

EPS8L2 mRNA, cDNA, or a complement thereof; and

PPP1R16A mRNA, cDNA, or a complement thereof,

for use in diagnosing endometrial cancer.

39. A nucleic acid chosen from

Primers for IKBKE;

Primers for P4HB;

Primers for SOCS2;

Primers for GMIP;

Primers for DDRl;

Primers for EPS8L2; and

Primers for PPP1R16A;

for use in diagnosing endometrial cancer.

40. A nucleic acid chosen from

probe for IKBKE;

probe for P4HB;

probe for SOCS2;

probe for GMIP;

probe for DDRl ;

probe for EPS8L2; and

probe for PPP1R16A,

for use in diagnosing endometrial cancer.

41. A kit comprising two or more probes of claim 40, for use in diagnosing endometrial cancer.

42. A kit comprising primers for two or more primers pairs of claim 39 for use in diagnosing endometrial cancer.

43. An antibody chosen from

an antibody to IKBKE;

an antibody to P4HB;

an antibody to SOCS2;

an antibody to GMIP;

an antibody to DDRl;

an antibody to EPS8L2; and

an antibody to PPP1R16A,

for use in diagnosing endometrial cancer.

44. A kit comprising antibodies to two or more antibodies of claim 43 for use in diagnosing endometrial cancer.

45. A kit for obtaining uterine fluid for use in diagnosing endometrial cancer by assessing the levels of from 1-20 biomarkers as defined in claim 1.

46. The in vitro diagnostic method of any one of claim 1 to 37 comprising determining the level of 2 biomarkers.

47. The in vitro diagnostic method of any one of claims 1 to 37 comprising determining the level of 3 biomarkers.

48. The in vitro diagnostic method of any one of claims 1 to 37 comprising determining the level of 4 biomarkers.

49. The in vitro diagnostic method of any one of claims 1 to 37 comprising determining the level of 5 biomarkers.

50. The in vitro diagnostic method of any one of claims 1 to 37 comprising determining the level of 7 biomarkers.

51. The in vitro diagnostic method of any one of claims 1 to 37 comprising determining the level of 10 biomarkers.

52. The in vitro diagnostic method of any one of claims 1 to 37 comprising determining the level of 15 biomarkers.

53. The in vitro diagnostic method of claim any one of claims 1 to 37 comprising determining the level of 20 biomarkers.

54. An in vitro diagnostic method for diagnosing endometrial cancer comprising obtaining a uterine fluid aspirate sample from a patient having a symptom or risk factor for endometrial cancer and determining the level of from 1 to 100 biomarkers markers that are differentially expressed in endometrial cancer as compared to control values representative of individuals not affected by endometrial cancer, wherein (1) if the levels of 1 to 100 biomarkers are upregulated in the endometrial aspirate sample in the patient and in the control value then the patient has an increased likelihood of having endometrial cancer and wherein (2) if the level of the 1 to 100 biomarkers are downregulated in the aspirate sample and then the patient has an increased likelihood of having endometrial cancer.

55. A nucleic acid chosen from

ACAAl mRNA, cDNA, or a complement thereof;

AP1M2 mRNA, cDNA, or a complement thereof;

CGN mRNA, cDNA, or a complement thereojf

FASTKDl mRNA, cDNA, or a complement thereof;

P2RX4 mRNA, cDNA, or a complement thereof;

RASSF7 mRNA, cDNA, or a complement thereof;

RNFl 83 mRNA, cDNA, or a complement thereof;

PHKG2 mRNA, cDNA, or a complement thereof;

PPFIBP2 mRNA, cDNA, or a complement thereof,

SIRT6 mRNA, cDNA, or a complement thereof, TJP3 mRNA, cDNA, or a complement thereof;

EFEMP2 mRNA, cDNA, or a complement thereof; and DCN mRNA, cDNA, or a complement thereof, for use in diagnosing endometrial cancer,

56. A nucleic acid chosen from

Primers for ACAAl;

Primers for AP 1M2;

Primers for CGN;

Primers for FASTKDl;

Primers for P2RX4;

Primers for RASSSF7;

Primers for RNFl 83;

Primers for SIRT6;

Primers for PPFIBP2;

Primers for PHKG2;

Primers for TJP3;

Primers for EFEMP2;and

Primers for DCN;

for use in diagnosing endometrial cancer.

57. A nucleic acid chosen from

probe for ACAAl;

probe for AP1M2;

probe for CGN;

probe for FASTKDl;

probe for P2RX4;

probe for RASSF7;

probe for RNF183;

probe for SIRT6;

probe for PPFIBP2;

probe for PKHG2;

probe for T JP3;

probe for EFEMP2; and

probe for DCN,

for use in diagnosing endometrial cancer.

58. An antibody chosen from

an antibody to ACAAl ;

an antibody to AP1M2;

an antibody to CGN;

an antibody to FASTKDl;

an antibody to P2RX4;

an antibody to RASSF7;

an antibody to RNFl 83;

an antibody to SIRT6;

an antibody to PPFIBP2;

an antibody to PKHG2;

an antibody to TJP3;

an antibody to EFEMP2; and

an antibody to DCN,

for use in diagnosing endometrial cancer endometrial cancer.

59. An in vitro diagnostic method for diagnosing endometrial cancer comprising providing or obtaining a uterine fluid sample from a human patient having a symptom or risk factor for a gynecological cancer and determining the level of RNA expression of from 2 to 9 biomarkers chosen from P4HB, EFEMP2, GMIP1 IKBKE, DDRl, FASTKDl, SIRT6, PKHG2, and SOCS2 by quantitative PCR wherein an increased level of from 1 to 7 biomarkers chosen from P4HB, GMIP, IKBKE, DDRl, FASTKDl, SIRT6, and PKHG2 and/or a decreased level of EFEMP2 or SOCS2 as compared to control indicates the existence of endometrial cancer.

60. The method of claim 59 wherein the gynecological cancer is endometrial cancer.

61. The method of claim 59 or 60 wherein the markers are 2 to 8 biomarkers chosen from P4HB, EFEMP2, GMIP, IKBKE, DDRl, FASTKDl, SIRT6, and PKHG2.

62. The method of claim 59 or 60 wherein the markers are 2 to 8 biomarkers chosen from P4HB, GMIP, IKBKE, DDRl, FASTKDl, SIRT6, PKHG2, and SOCS2.

63. The method of any one of claims 1 to 37, 46 to 54 and 59 to 62, wherein said detecting the level comprises contacting said one or more biomarkers with primers and reagents capable of amplifying specifically said one or more biomarkers and detecting the level of said amplified one or more biomarkers with a probe or probes that hybridize to said amplified biomarker.

64. The method of claim 63, wherein said probe hybrids specifically to said amplified biomarker.

65. The method of any one of claims 1 to 37, 46 to 54 and 59 to 64, wherein P4HB and EFEMP2 are detected.

66. The method of any one of claims 1 to 37, 46 to 54 and 59 to 64, wherein P4HB and IKBKE are detected.

67. The method any one of claims 1 to 37, 46 to 54 and 59 to 64, wherein P4HB and GMIP are detected.

68. The method of any one of claims 1 to 37, 46 to 54 and 59 to 64, wherein EFEMP2 and IKBKE are detected.

69. The method of any one of claims 1 to 37, 46 to 54 and 59 to 64, wherein EFEMP2 and P4HB are detected.

70. The method of any one of claims 1 to 37, 46 to 54 and 59 to 64, wherein P4HB, GMIP, and IKBKE are detected.

71. The method any one of claims 1 to 37, 46 to 54 and 59 to 64, wherein P4HB, GMIP, and IKBKE are detected.

72. The method of any one of claims 1 to 37, 46 to 54 and 59 to 64, wherein a combination of markers is detected wherein said combination comprises IKBKE and P4HB; IKBKE and SOCS2; P4HB and SOCS2; GMIP and IKBKE; GMIP and P4HB; GMIP and SOCS2; GMIP, SOCS2, and IKBKE; GMIP, SOCS2, and P4HB; GMIP, IKBKE, and P4HB; IKBKE.P4HB, and SOCS2; GMIP, IKBKE, P4HB, and SOCS2; GMIP, SOCS2, IKBKE, and EPS8L2; GMIP, SOCS2, P4HB, and EPS8L2; GMIP, IKBKE, P4HB, and EPS8L2; IKBKE, P4HB, SOCS2, and EPS8L2; GMIP, IKBKE1 P4HB, SOCS2, and DDRl; GMIP, IKBKE, P4HB, SOCS2, EPS8L2, and

PPP1R16A; GMIP, IKBKE, P4HB, SOCS2, PHKG2, and RASSF7; GMIP, IKBKE, P4HB, SOCS2, EPS8L2, and DDRl; GMIP, IKBKE, P4HB, SOCS2, EPS8L2, PPP1R16A, and DDRl; DDRl, EPS8L2, GMIP, IKBKE, P2RX4, P4HB, PHKG2, PPP1R16A, RASSF7, SIRT6, TJP3, and SOCS2; or DDRl, EPS8L2, GMIP, IKBKE, P2RX4, P4HB, PHKG2, PPP1R16A, RASSF7, SIRT6, TJP3, RNF183 and SOCS2.

73. The method of any one of claims 1 to 37, 46 to 54 and 59 to 64, wherein a combination of markers is detected wherein said combination comprises GMIP, IKBKE, P4HB, SOCS2 and FASTKDl; GMIP, IKBKE, P4HB, SOCS2 and DDRl; GMIP, IKBKE, P4HB, SOCS2 and PHKG2; GMIP, IKBKE, P4HB, SOCS2 and SIRT6; GMIP, IKBKE, P4HB, SOCS2 and ACAAl; GMIP, IKBKE, P4HB, SOCS2 and EFEMP2; GMIP, IKBKE, P4HB, SOCS2 and EPS8L2; GMIP, IKBKE, P4HB, SOCS2 and P2RX4; GMIP, IKBKE, P4HB, SOCS2 and PPFIBP2; GMIP, IKBKE, P4HB, SOCS2 and PPP1R16A; GMIP, IKBKE, P4HB, SOCS2, ACAAl and FASTKDl; GMIP, IKBKE, P4HB, SOCS2, PHKG2 and FASTKDl; GMIP, IKBKE, P4HB, SOCS2, SIRT6 and FASTKDl; ACAAl, AP1M2, EPS8L2, IKBKE, P2RX4, P4HB, PPFIBP2, PPP1R16A, SIRT6, and EFEMP2; GMIP, IKBKE, P4HB, and EFEMP2; DDRl, FASTKDl, PHKG2, SIRT6, SOCS2, GMIP, IKBKE, P4HB, and EFEMP2; DDRl, FASTKDl, PHKG2, SIRT6, GMIP,

IKBKE, P4HB, and EFEMP2; or P4HB, EFEMP2, IKBKE, GMIP, and FASTKDl.

74. The method of any one of claims 1 to 37, 46 to 54 and 59 to 64, wherein a combination of markers is detected wherein said combination comprises GMIP, IKBKE, P4HB, EFEMP2 and FASTKDl; GMIP, IKBKE, P4HB, EFEMP2and DDRl; GMIP, IKBKE, P4HB, EFEMP2 and PHKG2; GMIP, IKBKE, P4HB, EFEMP2 and SIRT6; GMIP, IKBKE, P4HB, EFEMP2 and ACAAl ; GMIP, IKBKE, P4HB, SOCS2 and EFEMP2; GMIP, IKBKE, P4HB, EFEMP2 and EPS8L2; GMIP, IKBKE, P4HB, EFEMP2 and P2RX4; GMIP, IKBKE, P4HB, EFEMP2 and PPFIBP2; GMIP, IKBKE, P4HB, EFEMP2and PPP1R16A; GMIP, IKBKE, P4HB, EFEMP2, ACAAl and FASTKDl; GMIP, IKBKE, P4HB, EFEMP2, PHKG2 and FASTKDl; or GMIP, IKBKE, P4HB, EFEMP2, SIRT6 and FASTKDl.

75. The in vitro diagnostic method of any one of claims 1 to 37, 46 to 54 and 59 to 74 comprising providing a uterine fluid sample obtained from a patient with a pipelle device or syringe wherein the patient has a risk factor or symptom of endometrial cancer; contacting said sample with an agent capable of preserving, preventing, or lessening the degradation of RNA in said uterine fluid sample; determining in said sample the expression level of mRNA corresponding to said from 1 to 20 markers and one or more endogenous genes using quantitative PCR; normalizing the expression level of said from 1 to 20 biomarkers with the one or more endogenous genes; comparing the normalized level of the from 1 to 20 biomarkers to a control value wherein differential expression of froml to 20 of the biomarkers indicates endometrial cancer or an increased likelihood of endometrial cancer.

76. The method of claim 75 wherein said one or more endogenous genes are chosen from POLR2A, B2M, PFNl, HMBS, G6PD, and PABPNl.