Methods and materials for assessing loss of heterozygosity

• US 9,388,472 B2
• Filed: 06/18/2014
• Issued: 07/12/2016
• Est. Priority Date: 12/21/2011
• Status: Active Grant

• Current Assignee: Myriad Genetics, Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Myriad Genetics
• Inventors: Abkevich, Victor, Gutin, Alexander, Timms, Kirsten, Lanchbury, Jerry
• Primary Examiner(s): Johannsen, Diana B
• Application Number:
  US14/307,708
• Publication Number:
  US 20150018527A1
• Time in Patent Office: 755 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/282 Platinum compounds
• CPC Class Codes: A61K 33/243 Platinum; Compounds thereof
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12Q 1/6886 for cancer immunoassay for cancer G01N33/574
• CPC Class Codes: C12Q 2600/106 Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/154 Methylation markers
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: G16B 20/10 Ploidy or copy number detection
• CPC Class Codes: G16B 20/20 Allele or variant detection, e.g. single nucleotide polymorphism [SNP] detection

Abstract

This document provides methods and materials involved in assessing samples (e.g., cancer cells) for the presence of a loss of heterozygosity (LOH) signature. For example, methods and materials for determining whether or not a cell (e.g., a cancer cell) contains an LOH signature are provided. Materials and methods for identifying cells (e.g., cancer cells) having a deficiency in homology directed repair (HDR) as well as materials and methods for identifying cancer patients likely to respond to a particular cancer treatment regimen also are provided.

Claims

1. A method of treating cancer, comprising:

(1) assaying a cancer cell sample obtained from a test breast or ovarian cancer patient to detect a test number of Indicator LOH Regions in at least ten pairs of human chromosomes, wherein an Indicator LOH Region is equal to or longer than a first length but shorter than the length of the whole chromosome containing the Indicator LOH Region, and wherein the first length is at least 5 megabases;

(2) providing a test value equal to or derived from the test number of Indicator LOH Regions detected in (1);

(3) determining that said test value exceeds a reference value equal to or derived from a reference number of Indicator LOH Regions in said at least ten pairs of human chromosomes in cancer cell samples of a population of reference breast or ovarian cancer patients, wherein said reference number of Indicator LOH Regions is at least five; and

(4) administering to the test breast or ovarian patient a treatment regimen comprising one or both of a platinum chemotherapy agent or a PARP inhibitor drug.

2. The method of claim 1 comprising assaying said cancer cell sample to detect a test number of Indicator LOH Regions in at least 15 pairs of human chromosomes.

3. The method of claim 1 comprising assaying said cancer cell sample to detect a test number of Indicator LOH Regions in at least 21 pairs of human chromosomes.

4. The method of claim 1, wherein the first length is at least 10 megabases.

5. The method of claim 1, wherein the first length is at least 12 megabases.

6. The method of claim 1, wherein the first length is at least 15 megabases.

7. The method of claim 1, wherein the reference number of Indicator LOH Regions is at least ten.

8. The method of claim 1, wherein the reference number of Indicator LOH Regions is at least 12.

9. The method of claim 1, wherein the reference number of Indicator LOH Regions is at least 15.

10. The method of claim 1, wherein the platinum chemotherapy agent is carboplatin.

11. The method of claim 1, wherein the PARP inhibitor drug is olaparib.

12. A method of treating cancer, comprising:

(1) assaying a cancer cell sample obtained from a test breast or ovarian cancer patient to detect a test number of Indicator LOH Regions in at least ten pairs of human chromosomes, wherein

(a) the assaying in (1) comprises genotyping a plurality of single nucleotide polymorphism loci by

(i) enriching the sample for DNA molecules each comprising at least one locus from the plurality of single nucleotide polymorphism loci, wherein the plurality of single nucleotide polymorphism loci comprises at least 1,000 single nucleotide polymorphism loci and wherein there is at least one single nucleotide polymorphism locus located on average every 500 kb within each chromosome of the ten pairs of human chromosomes; and

(ii) assaying the test DNA molecules to determine whether each locus in the plurality of single nucleotide polymorphism loci is homozygous or heterozygous;

(b) an Indicator LOH Region is defined as a genomic region wherein all single nucleotide polymorphism loci genotyped in (a) are homozygous, wherein such genomic region is equal to or longer than a first length but shorter than the length of the whole chromosome containing the genomic region, and wherein the first length is at least 5 megabases;

(2) providing a test value equal to or derived from the test number of Indicator LOH Regions detected in (1);

(3) determining that said test value exceeds a reference value equal to or derived from a reference number of Indicator LOH Regions in said at least ten pairs of human chromosomes in patient cancer cell samples of a population of reference breast or ovarian cancer patients, wherein said reference number of Indicator LOH Regions is at least five; and

(4) administering to the test breast or ovarian cancer patient a treatment regimen comprising one or both of a platinum chemotherapy agent or a PARP inhibitor drug.

13. The method of claim 12 comprising assaying said cancer cell sample to detect a test number of Indicator LOH Regions in at least 15 pairs of human chromosomes.

14. The method of claim 12 comprising assaying said cancer cell sample to detect a test number of Indicator LOH Regions in at least 21 pairs of human chromosomes.

15. The method of claim 12, wherein the plurality of single nucleotide polymorphism loci comprises at least 10,000 single nucleotide polymorphism loci.

16. The method of claim 12, wherein the plurality of single nucleotide polymorphism loci comprises at least 25,000 single nucleotide polymorphism loci.

17. The method of claim 12, wherein the plurality of single nucleotide polymorphism loci comprises at least 50,000 single nucleotide polymorphism loci.

18. The method of claim 12, wherein the first length is at least 10 megabases.

19. The method of claim 12, wherein the first length is at least 12 megabases.

20. The method of claim 12, wherein the first length is at least 15 megabases.

21. The method of claim 12, wherein the reference number of Indicator LOH Regions is at least ten.

22. The method of claim 12, wherein the reference number of Indicator LOH Regions is at least 12.

23. The method of claim 12, wherein the reference number of Indicator LOH Regions is at least 15.

24. The method of claim 12, wherein the platinum chemotherapy agent is carboplatin.

25. The method of claim 12, wherein the PARP inhibitor drug is olaparib.

26. A method of treating cancer, comprising:

(1) assaying a cancer cell sample obtained from a test breast or ovarian cancer patient to detect a test number of Indicator LOH Regions in at least ten pairs of human chromosomes, wherein an Indicator LOH Region is equal to or longer than a first length but shorter than the length of the whole chromosome containing the Indicator LOH Region, and wherein the first length is at least 5 megabases;

(2) providing a test value equal to or derived from the test number of Indicator LOH Regions detected in (1);

(3) determining whether said test value exceeds a reference value equal to or derived from a reference number of Indicator LOH Regions in at least ten pairs of human chromosomes in cancer cell samples of a population of reference breast or ovarian cancer patients, wherein said reference number of Indicator LOH Regions is at least five; and

either

(4)(a) administering to the test breast or ovarian patient a treatment regimen comprising one or both of a platinum chemotherapy agent or a PARP inhibitor drug if said test value exceeds said reference value;

or

(4)(b) administering to the test breast or ovarian patient a treatment regimen not comprising one or both of a platinum chemotherapy agent or a PARP inhibitor drug if said test value does not exceed said reference value.

27. The method of claim 26 comprising assaying said cancer cell sample to detect a test number of Indicator LOH Regions in at least 15 pairs of human chromosomes.

28. The method of claim 26 comprising assaying said cancer cell sample to detect a test number of Indicator LOH Regions in at least 21 pairs of human chromosomes.

29. The method of claim 26, wherein the first length is at least 10 megabases.

30. The method of claim 26, wherein the first length is at least 12 megabases.

31. The method of claim 26, wherein the first length is at least 15 megabases.

32. The method of claim 26, wherein the reference number of Indicator LOH Regions is at least ten.

33. The method of claim 26, wherein the reference number of Indicator LOH Regions is at least 12.

34. The method of claim 26, wherein the reference number of Indicator LOH Regions is at least 15.

35. The method of claim 26, wherein the platinum chemotherapy agent is carboplatin.

36. The method of claim 26, wherein the PARP inhibitor drug is olaparib.