METHODS AND MATERIALS FOR ASSESSING HOMOLOGOUS RECOMBINATION DEFICIENCY IN BREAST CANCER SUBTYPES
Provided herein are methods and materials involved in assessing samples (e.g., cancer cells) for the presence of homologous recombination deficiency (HRD) or an HRD signature. For example, methods and materials for determining whether or not a cell (e.g., a cancer cell) contains an HRD 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.
1 .- 73 . (canceled)
74 . A method for determining homologous recombination (HR) deficiency status of a triple negative breast cancer (TNBC) cell of a patient, comprising:
(1) determining, in a sample comprising the TNBC cell of the patient, a combined number of Loss of Heterozygosity (LOH), Telomeric-Allelic Imbalance (TAI), and Large-scale State Transitions (LST) regions in at least one pair of human chromosomes;
(2) identifying the TNBC cancer cell as likely HR deficient when the combined number of LOH, TAI, and LST regions are greater than 32.
75 . The method of claim 74 , wherein the Indicator LOH Regions are longer than 1.5 megabases in length but shorter than the entire length of the respective chromosome within which the LOH Region is located.
76 . The method of claim 75 , wherein the Indicator LOH Regions are at least 10 or at least 15 megabases in length.
77 . (canceled)
78 . The method of claim 74 , wherein the Indicator TAI Regions are regions with allelic imbalance that (i) extend to one of the subtelomeres, (ii) do not cross the centromere and, and (iii) are longer than 1.5 megabases in length.
79 . The method of claim 78 , wherein the Indicator TAI Regions are at least 10 megabases in length.
80 . The method of claim 74 , wherein the Indicator LST Regions are regions comprising a somatic copy number breakpoint along the length of a chromosome that is between two regions of at least 10 megabases in length after filtering out regions shorter than 3 megabases in length.
81 . The method of claim 74 , wherein the cancer cell is identified as HR deficient when the combined number is 38 or greater.
82 . The method of claim 74 , wherein the cancer cell is identified as HR deficient when the combined number is 42 or greater.
83 . The method of claim 74 , wherein the at least one pair of human chromosomes are autosomes.
84 . The method of claim 74 , wherein the human chromosomes are autosomes and wherein the combined number of Indicator LOH Regions, Indicator TAI Regions, and Indicator LST Regions is determined in at least 10 pairs of the autosomes.
85 . The method of claim 74 , wherein the human chromosomes are autosomes and wherein the number of Indicator LOH Regions, Indicator TAI Regions, and Indicator LST Regions is determined in at least 15 pairs of autosomes.
86 . The method of claim 74 , further comprising assaying at least 150 polymorphic genomic loci in each autosome pair.
87 . The method of claim 74 , further comprising assaying at least 5,000 polymorphic genomic loci in at least 20 human chromosomes, wherein the chromosomes are autosomes.
88 . The method of claim 74 , further comprising calculating a test value derived from the combined number of Indicator LOH Regions, Indicator TAI Regions, and Indicator LST Regions and identifying the cancer cell as HR deficient when the test value exceeds a reference value, wherein the reference value is derived from a reference number of 33 or greater.
89 . The method of claim 88 , wherein the test value is an arithmetic mean of the number of Indicator LOH Regions, Indicator TAI Regions and wherein the reference value is 8 or greater.
90 . The method of claim 88 , wherein the test value is derived by calculating the arithmetic mean of the numbers of Indicator LOH Regions, Indicator TAI Regions and Indicator LST Regions in the sample as follows:
Test Value=(# of Indicator LOH Regions)+(# of Indicator TAI Regions)+(# of Indicator LST Regions)÷3.
91 . The method of claim 74 , further comprising identifying the patient as likely to respond to a cancer treatment regimen comprising a DNA damaging agent, anthracycline, topoisomerase I inhibitor, or PARP inhibitor based identifying the cancer cell as likely HR deficient.
92 . The method of claim 91 , wherein the DNA damaging agent is cisplatin, carboplatin, oxalaplatin, or picoplatin, the anthracycline is epirubincin or doxorubicin, the topoisomerase I inhibitor is campothecin, topotecan, or irinotecan, or the PARP inhibitor is iniparib, olaparib, or velapirib.
93 . (canceled)
94 . The method of claim 74 , wherein the breast cancer cell is BRCA1/2 deficient.
95 . The method of claim 74 , wherein the combined number consists of the number of Indicator LOH Regions, Indicator TAI Regions, and Indicator LST Regions.