Integrated machine-learning framework to estimate homologous recombination deficiency

A computer system comprising:

• one or more processors;
• and
• a non-transitory computer-readable medium including computer-executable instructions that, when executed by the one or more processors, cause the processors to perform a method of determining a homologous recombination deficiency (HRD) status of a test subject afflicted with a cancer, the method comprising:
• (A) generating, based on a first plurality of sequence reads of a first DNA sample from a cancerous tissue of the subject and a second plurality of sequence reads of a second DNA sample from a non-cancerous tissue of the subject, a set of genomic data for the test subject comprising:
• (i) a heterozygosity status for a first plurality of DNA damage repair genes in the genome of the cancerous tissue of the subject, wherein the heterozygosity status derives from a count of a number of unique frameshift mutations or a number of unique truncating mutations detected in the first plurality of DNA damage repair genes in the genome of the cancerous tissue of the subject,
• (ii) a measure of the loss of heterozygosity, on a proportionate scale, across the genome of the cancerous tissue of the subject,
• (iii) a first measure of variant alleles detected in a second plurality of DNA damage repair genes in the genome of the cancerous tissue of the subject, wherein the first measure of variant alleles derives from a first count of a number of unique mutations associated with a loss of homologous recombination detected in the second plurality of DNA damage repair genes in the genome of the cancerous tissue of the subject, and
• (iv) a second measure of variant alleles detected in the second plurality of DNA damage repair genes in the genome of the non-cancerous tissue of the subject, wherein the second measure of variant alleles derives from a second count of a number of unique mutations associated with loss of homologous recombination detected in the second plurality of DNA damage repair genes in the genome of the cancerous tissue of the subject;
• (B) determining a measure of tumor purity in the test subject using the first plurality of sequence reads;
• (C) using the tumor purity in the test subject to verify that the tumor purity in the test subject satisfies a tumor purity threshold;
• (D) applying a scaling construct to the set of genomic data thereby obtaining a scaled set of genomic data, wherein the scaling construct is derived from normalization of the set of genomic data from each subject in a training cohort of subjects, wherein the training cohort of subjects includes a first subset of subjects having HRD and a second subject of subjects free of HRD;
• and
• (E) inputting, after the using (C), the scaled set of genomic data into a classifier thereby determining a probability that the test subject has HRD.

A non-transitory computer-readable storage medium having stored thereon program code instructions that, when executed by a processor, cause the processor to perform a method of determining a homologous recombination deficiency (HRD) status of a test subject afflicted with a cancer, the method comprising:

• (A) generating, based on a first plurality of sequence reads of a first DNA sample from a cancerous tissue of the subject and a second plurality of sequence reads of a second DNA sample from a non-cancerous tissue of the subject, a set of genomic data for the test subject comprising:
• (i) a heterozygosity status for a first plurality of DNA damage repair genes in the genome of the cancerous tissue of the subject, wherein the heterozygosity status derives from a count of a number of unique frameshift mutations or a number of unique truncating mutations detected in the first plurality of DNA damage repair genes in the genome of the cancerous tissue of the subject,
• (ii) a measure of the loss of heterozygosity, on a proportionate scale, across the genome of the cancerous tissue of the subject,
• (iii) a first measure of variant alleles detected in a second plurality of DNA damage repair genes in the genome of the cancerous tissue of the subject, wherein the first measure of variant alleles derives from a first count of a number of unique mutations associated with a loss of homologous recombination detected in the second plurality of DNA damage repair genes in the genome of the cancerous tissue of the subject, and
• (iv) a second measure of variant alleles detected in the second plurality of DNA damage repair genes in the genome of the non-cancerous tissue of the subject, wherein the second measure of variant alleles derives from a second count of a number of unique mutations associated with loss of homologous recombination detected in the second plurality of DNA damage repair genes in the genome of the cancerous tissue of the subject:
• (B) determining a measure of tumor purity in the test subject using the first plurality of sequence reads;
• (C) using the tumor purity in the test subject to verify that the tumor purity in the test subject satisfies a tumor purity threshold;
• (D) applying a scaling construct to the set of genomic data thereby obtaining a scaled set of genomic data, wherein the scaling construct is derived from normalization of the set of genomic data from each subject in a training cohort of subjects, wherein the training cohort of subjects includes a first subset of subjects having HRD and a second subject of subjects free of HRD;
• and
• (E) inputting, after the using (C), the scaled set of genomic data into a classifier thereby determining a probability that the test subject has HRD.