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1. (WO2015175705) MUTATIONS GÉNIQUES ET ALTÉRATIONS DU NOMBRE DE COPIES DE EGFR, KRAS ET MET
Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

CLAIMS

WHAT IS CLAIMED IS:

1. A method comprising:

(a) detecting, in a sample comprising polynucleotides from a subject, at least one EGFR nucleotide sequence variant that encodes an amino acid or codon sequence variant selected from consisting of G465V, T130A, D1083N, 1491R, K467I, T211T,K1061T and V876M; and

(b) administering to the subject a cancer treatment other than anti-EGFR therapy

2. The method of claim 1, wherein the at least one EGFR nucleotide sequence variant is selected from the group consisting of G>T G465V, A>G T130A, G>A D1083N, T>G I491R, A>T K467I, C>G T211T,A>C K1061T, and G>A V876M.

3. The method of claim 1, wherein the subject has colorectal cancer.

4. The method of claim 1, wherein the subject has colorectal cancer and has been treated with anti-EGFR therapy.

5. The method of claim 1, wherein the detecting comprises detecting a plurality of EGFR nucleotide sequence variants.

6. The method of claim 1, wherein the detecting further comprises detecting amplification of an EGFR gene.

7. The method of claim 1, wherein the administering comprises administering to the subject a cancer treatment other than (i) anti-EGFR antibodies or (ii) cetuximab.

8. The method of claim 1, wherein the sample comprises cell free DNA.

9. The method of claim 1, wherein the sample is a blood sample or a tumor sample.

10. The method of claim 1, wherein the subject has a cancer that is un-responsive to cetuximab.

11. The method of claim 1, wherein the subject has a cancer selected from the group consisting of colorectal cancer and head and neck cancer.

12. The method of claim 10, wherein the cancer treatment comprises

administering an antibody directed to an epitope of EGFR other than the epitope against which cetuximab is directed.

13. The method of claim 1, wherein the cancer treatment other than anti-EGFR therapy comprises a treatment other than administration of an EGFR-directed antibody.

14. The method of claim 1, wherein the subject is refractory to 5-FU-based therapy.

15. The method of claim 1, wherein the detecting comprises DNA sequencing.

16. The method of claim 1, wherein the detecting comprises high-throughput DNA sequencing.

17. The method of claim 1, wherein the detecting comprises sequence capture of polynucleotides containing the at least one EGFR nucleotide sequence variant.

18. The method of claim 1, wherein the detecting is performed with a sensitivity of at leas t any of 1 % , 0.1 % or 0.01 % .

19. The method of claim 1, wherein the detecting is performed with a specificity of 99%, 99.9% or 99.99%.

20. A method comprising:

(a) monitoring, at one or more times, a subject undergoing anti-EGFR therapy, wherein the monitoring comprises detecting the presence of at least one EGFR nucleotide sequence variant that encodes an amino acid or codon sequence variant selected from the group consisting of G465V, T130A, D1083N, I491R, K467I, T211T, K1061T and V876M; and

(b) when the amino acid or codon sequence variant is detected, administering to the subject a cancer treatment other than the anti-EGFR therapy.

21. The method of claim 20, wherein the subject suffers from colorectal cancer.

22. The method of claim 20, wherein the monitoring comprises monitoring the subject at a plurality of different times.

23. The method of claim 20, wherein the presence of at least one EGFR nucleotide sequence variant is monitored in a sample from the subject, wherein the sample comprises cell free DNA.

24. The method of claim 20, wherein the monitoring further comprises monitoring the patient to detect amplification of an EGFR gene and, when the amplification of the EGFR gene is detected, administering to the subject a cancer treatment other than the anti-EGFR therapy.

25. The method of claim 20, further comprising ceasing the anti-EGFR therapy when the presence of the at least one EGFR nucleotide sequence variant is detected

26. A method comprising:

(a) in a sample comprising nucleic acids from a cancer cell of a subject, selectively enriching for one or more nucleic acids comprising EGFR nucleotide sequences, to produce an enriched sample;

(b) sequencing the one or more nucleic acids comprising EGFR nucleotide sequences from the enriched sample to produce sequence reads;

(c) determining, among the sequence reads, a presence or an absence of at least one EGFR nucleotide sequence variant encoding an amino acid or codon sequence variant selected from the group consisting of G465V, T130A, D1083N, 1491R, K467I, T211T,K1061T and V876M; and

(d) classifying the subject as having a cancer un-responsive to anti-EGFR therapy.

27. The method of claim 26, wherein the determining comprises determining the presence or the absence of a plurality of EGFR nucleotide sequence variants.

28. A method comprising administering to a subject having a cancer characterized by at least one EGFR nucleotide sequence variant that encodes an amino acid or codon sequence variant selected from the group consisting of G465V, T130A, D1083N,I491R, K467I, T21 IT, K1061T and V876M, a cancer treatment other than anti-EGFR therapy.

29. A composition comprising one or more solid supports, each of the one or more solid supports having attached thereto a nucleic acid capture probe, wherein each nucleic acid capture probe comprises a nucleotide sequence that hybridizes, under stringent hybridization conditions, to an EGFR nucleotide sequence within 200 nucleotides of a codon encoding an amino acid selected from any of positions: 465, 130, 1083, 491, 467, 211, 1061 and 876.

30. The composition of claim 29, wherein the one or more solid supports have attached thereto a plurality of nucleic acid capture probes, each of the plurality of nucleic acid capture probes hybridizing to a different one of the EGFR nucleotide sequences.

31. The composition of claim 29, wherein the one or more solid supports comprise magnetically attractable particles.

32. A system comprising a computer readable medium comprising machine-executable code that, upon execution by a computer processor, implements a method comprising:

(a) receiving into memory sequence reads of polynucleotides;

(b) determining, among the sequence reads, an identity of nucleotides within codons encoding an EGFR amino acid selected from any of positions: 465, 130, 1083, 491, 467, 211, 1061 and 876; and

(c) reporting a presence of at least one EGFR nucleotide sequence variant encoding an amino acid or codon sequence variant selected from the group consisting of G465V, T130A, D1083N,1491R, K467I, T211T, K1061T, and V876M, and, optionally, a relative quantity of the nucleotide sequence variant compared with a nucleotide sequence at a same position of a reference human genome.

33. A method comprising:

(a) detecting, in a sample comprising polynucleotides from a subject, at least one KRAS mutation and at least one KRAS gene amplification; and

(b) administering to the subject a cancer treatment other than anti-EGFR therapy.

34. The method of claim 33, wherein the subject has colorectal cancer.

35. The method of claim 33, wherein the subject has colorectal cancer and has been treated with the anti-EGFR therapy.

36. The method of claim 33, wherein the sample comprises cell free DNA.

37. The method of claim 33, wherein the at least one KRAS mutation is selected from the group consisting of G12C, G12R, G13D and Q61H.

38. A method comprising:

(a) monitoring, at one or more times, a subject undergoing anti-EGFR therapy, wherein monitoring comprises detecting the presence of at least one KRAS nucleotide sequence variant and at least one KRAS gene amplification; and

(b) when the at least one KRAS nucleotide sequence variant and the at least one KRAS gene amplification are detected, administering to the subject a cancer treatment other than the anti-EGFR therapy.

39. The method of claim 38, wherein the at least one KRAS nucleotide sequence variant is not detected in a primary tumor of the subject or is not detected in a prior test for a presence of a KRAS nucleotide sequence variant in the subject.

40. The method of claim 39, wherein the at least one KRAS nucleotide sequence variant is selected from the group consisting of G12C, G12R, G13D and Q61H.

41. A method comprising:

(a) in a sample comprising nucleic acids from a cancer cell of a subject, selectively enriching for one or more nucleic acids comprising KRAS nucleotide sequences, to produce an enriched sample;

(b) sequencing the one or more nucleic acids comprising KRAS nucleotide sequences from the enriched sample to produce sequence reads;

(c) determining, among the sequence reads, a presence of at least one KRAS nucleotide sequence variant and a presence of at least one KRAS gene amplification; and

(d) classifying the subject as having a cancer un-responsive to anti-EGFR therapy.

42. The method of claim 41, wherein the at least one KRAS nucleotide sequence variant is not detected in a primary tumor of the subject or is not detected in a prior test for a presence of a KRAS nucleotide sequence variant in the subject.

43. The method of claim 42, wherein the at least one nucleotide sequence variant is selected from the group consisting of G12C, G12R, G13D and Q61H.

44. A method comprising administering to a subject having a cancer characterized by at least one KRAS nucleotide sequence variant and at least one KRAS gene amplification, a cancer treatment other than anti-EGFR therapy.

45. The method of claim 44, wherein the at least one KRAS nucleotide sequence variant is not detected in a primary tumor of the subject or is not detected in a prior test for a presence of a KRAS nucleotide sequence variant in the subject.

46. The method of claim 45, wherein the at least one KRAS nucleotide sequence variant is selected from the group consisting of G12C, G12R, G13D and Q61H.

47. A system comprising a computer readable medium comprising machine-executable code that, upon execution by a computer processor, implements a method comprising:

(a) receiving into memory sequence reads of polynucleotides;

(b) determining, among said sequence reads, (i) an identity of nucleotide variants of a KRAS gene and (ii) amplification of a KRAS gene

(c) reporting, a presence of at least one KRAS nucleotide sequence variant and amount of KRAS gene amplification.

48. A method comprising:

(a) detecting, in a sample comprising polynucleotides from a subject, at least one KRAS mutation not detected in a primary tumor of the subject; and

(b) administering to the subject a cancer treatment other than anti-EGFR therapy.

49. The method of claim 48, wherein the at least one KRAS mutation is selected from the group consisting of G12C, G12R, G13D and Q61H.

50. A method comprising:

(a) monitoring, at one or more times, a subject undergoing anti-EGFR therapy, wherein the monitoring comprises detecting a new appearance of at least one KRAS nucleotide sequence variant; and

(b) when the at least one KRAS nucleotide sequence variant is detected, administering to the subject a cancer treatment other than the anti-EGFR therapy.

51. The method of claim 50, wherein the at least one KRAS nucleotide sequence variant is selected from the group consisting of G12C, G12R, G13D and Q61H.

52. A method comprising administering to a subject having a cancer

characterized by at least one KRAS nucleotide sequence variant not present in a primary tumor, a cancer treatment other than anti-EGFR therapy.

53. The method of claim 52, wherein the at least one KRAS nucleotide sequence variant is selected from the group consisting of G12C, G12R, G13D and Q61H.

54. A method comprising:

(a) detecting, in a sample comprising polynucleotides from a subject, a presence of a gene amplification in MET; and

(b) when the gene amplification is detected, administering to the subject a cancer treatment other than anti-EGFR therapy.

55. The method of claim 54, wherein the detecting further comprises detecting a presence of a gene amplification in either or both of EGFR and KRAS.

56. A method comprising:

(a) detecting, in a sample comprising polynucleotides from a subject, a presence of at least one sequence variant and/or at least one gene amplification in a gene selected from EGFR, KRAS, BRAF, MET, SMO, MYC, NRAS, ERBB2, ALK, Notch, PIK3CA and APC; and

(b) when the at least one sequence variant and/or the at least one gene amplification is detected, administering to the subject a cancer treatment other than anti-EGFR therapy.

57. The method of claim 56, wherein the cancer treatment other than anti-EGFR therapy is administered when the at least one sequence variant and/or the at least one gene amplification is detected in at least any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 of the genes.

58. The method of claim 56, wherein the cancer treatment other than anti-EGFR therapy is a therapy effective on a cancer in which such a sequence variant and/or gene amplification is detected.

59. A method comprising:

(a) detecting, in a sample comprising polynucleotides from a subject, at least one EGFR nucleotide sequence variant that encodes an amino acid or codon sequence variant selected from the group consisting of G465V, T130A, D1083N, 1491R, K467I, T21 IT, K1061T, and V876M;

(b) detecting, in the sample comprising polynucleotides from the subject, a presence of at least one of a KRAS nucleotide sequence variant and a KRAS gene amplification; and

(c) administering to the subject a cancer treatment other than anti-EGFR therapy.

60. The method of claim 59, wherein the subject has colorectal cancer.

61. The method of claim 59, wherein the subject has colorectal cancer and has been treated with anti-EGFR therapy.

62. The method of claim 59, wherein step (a) comprises detecting a plurality of EGFR nucleotide sequence variants.

63. The method of claim 59, wherein step (a) further comprises detecting amplification of an EGFR gene.

64. The method of claim 59, wherein the at least one KRAS nucleotide sequence variant is a mutation in KRAS.

65. The method of claim 64, wherein the mutation in KRAS is selected from the group consisting of G12C, G12R, G13D and Q61H.

66. The method of claim 59, wherein step (b) comprises detecting at least one KRAS nucleotide sequence variant and at least one KRAS gene amplification.

67. The method of claim 59, wherein the sample comprises cell free DNA.

68. A method comprising:

(a) detecting, in a sample comprising polynucleotides from a subject, a gene amplification in at least one of EGFR, BRAF, MYC, and SMO;

(b) when the gene amplification in at least one of EGFR, BRAF, MYC, and SMO is detected, administering to the subject a cancer treatment other than anti-EGFR therapy.