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-9388472-B2
Publication Date
2016-07-12
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 invention provides methods of treating cancer in a test breast or ovarian cancer patient by assaying a cancer cell sample to detect a test number of Indicator LOH Regions. The Indicator LOH Regions are genomic regions 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 at least 5 megabases, and the detection is performed across at least ten pairs of human chromosomes.
The method provides a test value equal to or derived from the test number of Indicator LOH Regions and determines that the 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, where the reference number is at least five. Based on whether the test value exceeds the reference value, the method administers a treatment regimen comprising one or both of a platinum chemotherapy agent or a PARP inhibitor drug.
In related embodiments, the assaying comprises genotyping a plurality of single nucleotide polymorphism loci. An Indicator LOH Region is defined as a genomic region in which all single nucleotide polymorphism loci genotyped are homozygous, while the region length is equal to or longer than the first length but shorter than the length of the whole chromosome containing the region, with the first length at least 5 megabases.
Claims Coverage
The partial content includes three independent claims covering a LOH-region quantified decision workflow that uses a defined Indicator LOH Region length window across at least ten pairs of human chromosomes, compares a test value to a reference value from a reference patient population, and administers a platinum chemotherapy and/or PARP inhibitor regimen based on the comparison. The inventive features are expressed differently across independent claims, including a general LOH detection/compare/administer method and a SNP-locus genotyping-based method.
Indicator LOH Region counting across chromosome pairs and length window
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.
Test value derivation and comparison to reference value from reference population
Providing a test value equal to or derived from the test number of Indicator LOH Regions detected, and 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.
Treatment regimen selection using platinum chemotherapy and/or PARP inhibitors when test value exceeds reference value
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.
SNP-locus genotyping workflow for Indicator LOH Region determination
Assaying the cancer cell sample comprises genotyping a plurality of single nucleotide polymorphism loci by enriching the sample for DNA molecules each comprising at least one locus from the plurality of single nucleotide polymorphism loci, and assaying the test DNA molecules to determine whether each locus is homozygous or heterozygous, wherein an Indicator LOH Region is defined as a genomic region wherein all single nucleotide polymorphism loci genotyped are homozygous and the 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.
Conditional administration based on exceeding a reference value
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 administering 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 administering 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.
Across the independent claims, the core claimed inventive concept is using a defined length-window Indicator LOH Region and a LOH-derived test value across at least ten pairs of human chromosomes, comparing the test value to a reference value derived from a reference number of Indicator LOH Regions in a reference breast or ovarian cancer patient population, and selecting whether to administer a regimen comprising one or both of a platinum chemotherapy agent and a PARP inhibitor.
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