Methods and materials for assessing loss of heterozygosity
Inventors
Abkevich, Victor • Gutin, Alexander • Timms, Kirsten • Lanchbury, Jerry
Assignees
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Publication Number
US-10612098-B2
Publication Date
2020-04-07
Expiration Date
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.
Core Innovation
The document describes a system for detecting a homologous recombination deficiency in a cancer cell obtained from a patient by assaying DNA to genotype a plurality of single nucleotide polymorphism loci on at least five pairs of human chromosomes. The assay detects either a homozygous or heterozygous genotype at each locus in the plurality of single nucleotide polymorphism loci.
Based on the detected genotypes, the system reconstructs and evaluates loss of heterozygosity patterns by defining Indicator LOH Regions as LOH segments that are equal to or longer than a first length but shorter than the length of the whole chromosome containing the Indicator LOH Region, with the first length being at least 1.5 megabases. A test value is calculated equal to or derived from the number of Indicator LOH Regions in the at least five pairs of human chromosomes.
The calculated test value is compared to a reference value equal to or derived from a reference number of Indicator LOH Regions in cancer cell samples of a population of reference patients. The system detects a homologous recombination deficiency when the test value exceeds the reference value, and detects no homologous recombination deficiency when the test value does not exceed the reference value.
The document links LOH-based classification to HDR-deficiency and HDR-pathway gene deficiencies and uses an LOH signature to predict cancer treatment response to DNA damaging regimens, including platinum compounds, anthracyclines, topoisomerase I inhibitors, radiation, and PARP inhibitors. Experimental validation in ovarian discovery and validation cohorts is described showing that large LOH region counts correlate with BRCA1/BRCA2 HDR deficiency, and that an HRD score correlates with HR deficiency and is associated with survival and treatment response.
Claims Coverage
The document includes one independent claim that defines a system for detecting homologous recombination deficiency using multi-chromosome SNP genotyping, computation of a test value based on Indicator LOH Region counts, and a comparison to a population-derived reference value. Additional dependent claims refine quantitative thresholds for SNP loci coverage, chromosomal pair coverage, Indicator LOH Region length and reference-number criteria.
Multi-chromosome SNP genotyping for Indicator LOH detection
A sample analyzer assays a sample of DNA extracted from or derived from the cancer cell to genotype a plurality of single nucleotide polymorphism loci on at least five pairs of human chromosomes, including enriching for test DNA molecules comprising loci and assaying each locus to detect a homozygous or heterozygous genotype.
Test value based on Indicator LOH Region counts with defined length bounds
A computer sub-system calculates, based on the genotypes detected, a test value equal to or derived from the number of Indicator LOH Regions in the at least five pairs of human chromosomes, where 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 where the first length is at least 1.5 megabases.
Reference-value comparison from reference patient population to detect HRD
The computer sub-system determines whether the test value exceeds a reference value equal to or derived from a reference number of Indicator LOH Regions in cancer cell samples of a population of reference patients, and detects homologous recombination deficiency if the test value exceeds the reference value and detects no homologous recombination deficiency if the test value does not exceed the reference value.
Overall claim coverage centers on computing an Indicator LOH Region-based test value from multi-chromosome SNP genotypes and calling homologous recombination deficiency by comparing that test value to a reference value derived from reference patient populations.
Stated Advantages
Detects homologous recombination deficiency in a cancer cell by using a LOH signature based on Indicator LOH Regions.
Provides classification of cancer cells as having a homologous recombination deficiency or no homologous recombination deficiency based on comparison to a reference value derived from reference patient samples.
Correlates LOH region counts with BRCA1/BRCA2 HDR deficiency.
Associates an HRD score with HR deficiency across cohorts.
Associates HRD status with survival and treatment response.
Documented Applications
Predicting cancer treatment response to DNA damaging regimens, including platinum compounds, anthracyclines, topoisomerase I inhibitors, radiation, and PARP inhibitors.
Assessing HDR deficiency using an LOH signature in cancer genomes on non-X/Y chromosomes and connecting HDR/HRD status to HDR-pathway gene deficiencies including BRCA1/BRCA2 and RAD51C.
Using ovarian discovery and validation cohorts to show correlation between large LOH region counts and BRCA1/BRCA2 HDR deficiency, and to relate HRD score to survival and treatment response.
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