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1. WO2020022895 - SIGNATURES GÉNIQUES POUR PRÉDIRE LA MÉTASTASE D'UN MÉLANOME ET D'UN PRONOSTIC DE PATIENT

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Claims

1. A method for classifying an individual afflicted with primary cutaneous

melanoma, comprising determining in a sample from said individual a gene expression signature, wherein the gene expression signature comprises three or more of the following genes: ITGB3, PLAT, SPP1, GDF15 and IL8.

2. A method for determining a treatment and/or diagnostic work-up schedule for an individual afflicted with cutaneous melanoma, comprising determining in a sample from said individual the level of expression of three or more of the following genes: ITGB3, PLAT, SPP1, GDF15 and IL8 and determining a treatment and/or diagnostic work-up schedule based on the expression levels.

3. A method for predicting the prognosis of an individual afflicted with primary cutaneous melanoma, comprising determining in a sample from said individual a gene expression signature, wherein the gene expression signature comprises three or more of the following genes: ITGB3, PLAT, SPP1, GDF15 and IL8.

4. The method of any of the preceding claims, wherein the individual is classified as having a metastasis-positive SLN or is classified as having a metastasis-negative SLN.

5. The method of any of the preceding claims, wherein the individual is selected for SLNB based on said classification and/or expression levels.

6. The method of any of the preceding claims, wherein an individual classified as having a metastasis-positive SLN is treated by performing a SLNB.

7. The method of any of the preceding claims, wherein the prognosis of the

individual is determined based on the gene expression levels.

8. The method of claim 7, wherein an individual is classified as having a poor

prognosis or a good prognosis.

9. The method of any of the preceding claims, wherein the gene expression signature comprises three or more of the following genes: ITGB3, PLAT, GDF15 and IL8.

10. The method of claim 9, wherein the gene expression signature comprises ITGB3, PLAT, GDF15 and IL8.

11. The method of any of the preceding claims, wherein the gene expression signature further comprises MLANA, LOXL4, SERPINE2, and TGFBR1.

12. The method of claim 11, wherein the gene expression signature further comprises ADIPOQ.

13 The method of claim 11 or 12, wherein the gene expression signature further comprises PRKCB, ADAM12, LGALSl.

14. The method of any of the preceding claims, further comprising classifying an individual afflicted with primary cutaneous melanoma, comprising determining in a sample from said individual a gene expression signature, wherein the gene expression signature comprises at least one of the following genes: KRT14, SPPl, FN1, LOXL3.

15. A method for classifying an individual afflicted with primary cutaneous

melanoma, comprising determining in a sample from said individual a gene expression signature, wherein the gene expression signature comprises at least one of the following genes: KRT14, SPPl, FNl, and LOXL3.

16. The method of claim 14 orl5, wherein the individual is classified as having a metastasis-positive N-SLN or having a metastasis-negative N-SLN.

17. The method of claim 14 orl5, wherein an individual classified as having a

metastasis-positive N-SLN is treated by performing a surgical procedure, such as by surgical lymph node dissection.

18. The method of any one of claims 14-17, wherein an individual classified as having a metastasis-positive N-SLN is treated by providing a cancer treatment to the individual.

19. A method for treating an individual afflicted with primary cutaneous melanoma, comprising

- determining in a sample from said individual a gene expression signature, wherein the gene expression signature comprises three or more of the following genes: ITGB3, PLAT, SPPl, GDF15 and IL8,

- classifying said individual as having a metastasis-positive SLN and/or a poor prognosis based on the gene expression signature, and

- treating said individual by performing a SLNB and/or providing a cancer treatment to said individual.

20. The method of claim 18, wherein the gene expression signature comprises three or more of the following genes: ITGB3, PLAT, GDF15 and IL8.

21. The method of claim 20, wherein the gene expression signature comprises ITGB3, PLAT, GDF15 and IL8.

22. The method of claim 21, wherein the gene expression signature further comprises MLANA, LOXL4, SERPINE2, and TGFBR1.

23. The method of claim 22, wherein the gene expression further comprises ADIPOQ.

24. The method of claim 22 or 23, wherein the gene expression signature further

comprises PRKCB, ADAM12, LGALSl.

25. A method for treating an individual afflicted with primary cutaneous melanoma, comprising

- determining in a sample from said individual a gene expression signature, wherein the gene expression signature comprises at least one of the following genes KRT14, SPPl, FNl, and LOXL3,

- classifying said individual as high risk for having a metastasis-positive N-SLN based on the gene expression signature, and

- treating said individual by performing a complete lymph node dissection and/or providing a cancer treatment to said individual.

26. The method of any of the preceding claims wherein the method for classifying

further comprises determining the age of the individual and/or the Breslow depth, optionally also determining the ulceration of the melanoma lesion.

27. The method of any of the preceding claims wherein the sample is a biopsy from a primary cutaneous melanoma lesion.

28. The method of any of the preceding claims wherein the expression is determined by the detection of RNA, preferably mRNA.

29. A method for analyzing a gene signature in an individual afflicted with primary cutaneous melanoma, said method comprising

- extracting RNA from a primary cutaneous melanoma lesion from said

individual;

- reverse transcribing an RNA transcript of at least three of the following genes ITGB3, PLAT, SPPl, GDF15 and IL8, to produce cDNAs of the RNA transcripts; and

- amplifying the cDNAs to produce amplicons from the cDNAs for determination of expression levels of the RNA transcripts.

30. The method of claim 29, wherein the gene expression signature comprises three or more of the following genes: ITGB3, PLAT, GDF15 and IL8.

31. The method of claim 30, wherein the gene expression signature comprises ITGB3, PLAT, GDF15 and IL8.

32. The method of claim 31, wherein the gene expression signature further comprises MLANA, LOXL4, SERPINE2, and TGFBRl.

33. The method of claim 32, wherein the gene expression signature further comprises ADIPOQ.

34. The method of claim 32 or 33, wherein the gene expression signature further comprises PRKCB, ADAM12, LGALSl.

35. The method of claims 29-34, further comprising reverse transcribing an RNA

transcript at least one of the following genes KRT14, SPP1, FN1, and LOXL3, to produce cDNAs of the RNA transcripts.

36. A method for analyzing a gene signature in an individual afflicted with primary cutaneous melanoma, said method comprising

- extracting RNA from a primary cutaneous melanoma lesion from said

individual;

- reverse transcribing an RNA transcript of at least one of the following genes KRT14, SPP1, FN1, and LOXL3, to produce cDNAs of the RNA transcripts; and

- amplifying the cDNAs to produce amplicons from the cDNAs for determination of expression levels of the RNA transcripts.

37. The method of any one of claims 29-36, wherein said method is performed using quantitative PCR.

38. The method of claim 37, wherein the amplicon expression levels have been

normalized against a level of an amplicon from a cDNA of at least one reference RNA transcript in the sample, preferably wherein the reference RNA transcript is selected from ACTB, RPLP0 and/or RPL8.

39. The method of claim 38, wherein the amplicon expression levels are threshold cycle (Ct) values.

40. The method of any of the preceding claims wherein the individual has Tla or Tib thin melanomas, preferably wherein the individual has Tla thin melanoma.

41. A kit for use in classifying an individual afflicted with primary cutaneous

melanoma, said kit comprising primer pairs for amplifying:

a) three or more of the following genes: ITGB3, PLAT, SPP1, GDF15 and IL8; and/or

b) at least one of the following genes: KE.T14, SPP1, FN1, and LOXL3, and optionally

c) at least one reference gene.

42. The kit according to claim 41, wherein the reference gene is ACTB, RPLP0 and/or RPL8.

43. The kit according to any one of claims 41-42, further comprising one or more of the following: DNA polymerase, deoxynucleoside triphosphates, buffer, and Mg2+·.

44. The kit of claims 41-43, wherein said kit comprises primer pairs for amplifying ITGB3, PLAT, GDF15 and IL8.

45. The kit of claim 44, wherein said kit comprises primer pairs for amplifying

ITGB3, PLAT, GDF15 and IL8.

46. The kit of claim 45, wherein said kit comprises primer pairs for amplifying

MLANA, LOXL4, ADIPOQ, SERPINE2, and TGFBRl.

47. The kit of claim 46, wherein the kit further comprises primer pairs for amplifying ADIPOQ.

48. The kit of claim 46 or 47, wherein said kit further comprises primer pairs for amplifying PRKCB, ADAM12, LGALSl.