Methods and materials for assessing homologous recombination deficiency
Inventors
Abkevich, Victor • Timms, Kirsten • Gutin, Alexander • Reid, Julia
Assignees
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Publication Number
US-10400287-B2
Publication Date
2019-09-03
Expiration Date
Abstract
This document provides 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.
Core Innovation
The invention provides a method of treating cancer in which a specimen comprising a cancer cell obtained from a cancer patient is assayed to determine whether the specimen harbors a deleterious mutation in either the BRCA1 gene or the BRCA2 gene. The assaying includes extracting genomic DNA into a sample, enriching the sample for DNA molecules whose collective sequence comprises the coding regions of the BRCA1 gene and the BRCA2 gene, and sequencing the DNA molecules or DNA molecules derived therefrom.
In addition to detecting BRCA1/BRCA2 deleterious mutations, the method assays a specimen to detect a number of Indicator LOH Regions, a number of Indicator TAI Regions, and a number of LSTs in at least ten pairs of human chromosomes of the cancer cell. The method specifies structural definitions for Indicator LOH Regions, Indicator TAI Regions, and LST breakpoints, and performs SNP locus genotyping by analyzing DNA molecules each comprising at least one locus from a plurality of single nucleotide polymorphism loci.
The method determines a test value equal to or derived from the sum of the number of Indicator LOH Regions, the number of Indicator TAI Regions, and the number of LST breakpoints detected. The test value is compared to a reference value equal to or derived from the sum of those detected in cancer cell specimens of a population of reference cancer patients, wherein the reference value is 5 or greater, and this comparison is used together with the BRCA1/BRCA2 deleterious mutation detection to select a treatment regimen that administers a platinum agent or PARP inhibitor, or to select a regimen excluding a platinum agent or PARP inhibitor.
Claims Coverage
The document includes one independent claim. The independent claim covers BRCA1/BRCA2 deleterious mutation detection by enriched sequencing of BRCA1/BRCA2 coding regions combined with genome-wide HRD feature counting across at least ten pairs of human chromosomes, followed by selecting a treatment regimen that either includes or excludes a platinum agent or PARP inhibitor based on a test value compared to a reference value.
BRCA1/BRCA2 deleterious mutation detection by enriched sequencing of coding regions
Assaying a first specimen comprising a cancer cell obtained from a cancer patient to determine whether the specimen harbors a deleterious mutation in either the BRCA1 gene or the BRCA2 gene, wherein assaying comprises extracting genomic DNA into a sample, enriching the sample for DNA molecules whose collective sequence comprises the coding regions of the BRCA1 gene and the BRCA2 gene, and sequencing the DNA molecules or DNA molecules derived therefrom.
HRD feature detection across at least ten pairs of human chromosomes using Indicator LOH Regions, Indicator TAI Regions, and LST breakpoints
Assaying either the first specimen or a second specimen to detect a number of Indicator LOH Regions, a number of Indicator TAI Regions, and a number of LSTs in at least ten pairs of human chromosomes of the cancer cell.
SNP locus genotyping configuration for HRD feature analysis
Assaying comprises analyzing DNA molecules each comprising at least one locus from a plurality of single nucleotide polymorphism loci to determine the genotype at each locus.
Test value derived from summed HRD feature counts and comparison to a reference value
Determining a test value equal to or derived from the sum of the number of Indicator LOH Regions, the number of Indicator TAI Regions and the number of LST breakpoints detected, and using the test value relative to a reference value equal to or derived from the sum of the number of Indicator LOH Regions, the number of Indicator TAI Regions and the number of LST breakpoints detected in cancer cell specimens of a population of reference cancer patients, wherein the reference value is 5 or greater.
Treatment selection including versus excluding a platinum agent or PARP inhibitor based on BRCA1/BRCA2 status and HRD test value
Administering either a treatment regimen comprising a platinum agent or PARP inhibitor when either a deleterious mutation in either the BRCA1 gene or the BRCA2 gene is detected or the test value is greater than the reference value, or a treatment regimen excluding a platinum agent or PARP inhibitor when neither the deleterious mutation is detected nor the test value is greater than the reference value.
Overall, the independent claim combines BRCA1/BRCA2 deleterious mutation detection by enriched sequencing of BRCA1/BRCA2 coding regions, HRD-related counting of Indicator LOH Regions, Indicator TAI Regions, and LST breakpoints across at least ten chromosome pairs using SNP locus genotyping, computing a test value from summed feature counts and comparing it to a reference value of 5 or greater, and selecting a cancer treatment regimen that either includes or excludes a platinum agent or PARP inhibitor based on these results.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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