Pan-Cancer Analysis of <i>BRCA1</i> and <i>BRCA2</i> Genomic Alterations and Their Association With Genomic Instability as Measured by Genome-Wide Loss of Heterozygosity.

Abstract

BRCA1 or BRCA2 loss of function results in homologous recombination deficiency (HRD), which is targetable by poly (ADP-ribose) polymerase (PARP) inhibitors and other DNA-damaging agents. In cancers associated with germline <i>BRCA1/2</i> alterations (<i>BRCA1/2</i>-associated cancers: breast, ovarian, pancreatic, prostate), <i>BRCA1/2</i> alterations result in HRD and are biomarkers for PARP inhibitor use. In other (non-<i>BRCA1/2</i>-associated) cancer types, the association between <i>BRCA1/2</i> alteration and HRD is less clear. A total of 234,154 tumor samples were sequenced by hybrid capture-based comprehensive genomic profiling. Somatic, germline, and zygosity status was determined computationally. <i>BRCA1/2</i> alterations were classified as predicted germline/somatic and biallelic/monoallelic. Genome-wide loss of heterozygosity (gLOH) was evaluated as a marker of HRD. <i>BRCA1/2</i> alterations were observed at a 4.7% frequency. <i>BRCA1/2</i> mutations were predicted germline in 57.4% of <i>BRCA1/2</i>-associated and 37.2% of non-<i>BRCA1/2</i>-associated cancers. The fraction of <i>BRCA1/2</i>-altered cases that were biallelic was 68.7%, with a higher biallelic fraction in <i>BRCA1/2</i>-associated (89.9%) versus non-<i>BRCA1/2</i>-associated cancers (43.6%). Differences in tissue distribution of biallelic <i>BRCA1</i> versus <i>BRCA2</i> alterations were noted, including a higher rate of biallelic <i>BRCA2</i> alteration in prostate cancer. Biallelic <i>BRCA1/2</i> alteration was observed at a 3.2% frequency (<i>BRCA1/2</i>-associated cancers, 8.9%; non-<i>BRCA1/2</i>-associated cancers, 1.3%) and > 1% frequency in at least 13 cancer types. Across cancer types, biallelic <i>BRCA1/2</i> alteration was associated with increased gLOH versus monoallelic or wild-type <i>BRCA1/2</i>; predicted germline or somatic mutations were both associated with elevated gLOH. Biallelic <i>BRCA1/2</i> alterations were associated with elevated gLOH in diverse cancer types, including those not traditionally associated with <i>BRCA1/2</i> cancer syndromes. Biomarker development for PARP inhibitors should integrate methods to distinguish biallelic from monoallelic <i>BRCA1/2</i> status, and biallelic <i>BRCA1/2</i> alteration should be broadly evaluated across cancer types as a biomarker for underlying HRD and PARP inhibitor sensitivity.