PURPOSE

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 alterations (-associated cancers: breast, ovarian, pancreatic, prostate), alterations result in HRD and are biomarkers for PARP inhibitor use. In other (non--associated) cancer types, the association between alteration and HRD is less clear.

METHODS

A total of 234,154 tumor samples were sequenced by hybrid capture-based comprehensive genomic profiling. Somatic, germline, and zygosity status was determined computationally. alterations were classified as predicted germline/somatic and biallelic/monoallelic. Genome-wide loss of heterozygosity (gLOH) was evaluated as a marker of HRD.

RESULTS

alterations were observed at a 4.7% frequency. mutations were predicted germline in 57.4% of -associated and 37.2% of non--associated cancers. The fraction of -altered cases that were biallelic was 68.7%, with a higher biallelic fraction in -associated (89.9%) versus non--associated cancers (43.6%). Differences in tissue distribution of biallelic versus alterations were noted, including a higher rate of biallelic alteration in prostate cancer. Biallelic alteration was observed at a 3.2% frequency (-associated cancers, 8.9%; non--associated cancers, 1.3%) and > 1% frequency in at least 13 cancer types. Across cancer types, biallelic alteration was associated with increased gLOH versus monoallelic or wild-type ; predicted germline or somatic mutations were both associated with elevated gLOH.

CONCLUSION

Biallelic alterations were associated with elevated gLOH in diverse cancer types, including those not traditionally associated with cancer syndromes. Biomarker development for PARP inhibitors should integrate methods to distinguish biallelic from monoallelic status, and biallelic alteration should be broadly evaluated across cancer types as a biomarker for underlying HRD and PARP inhibitor sensitivity.