Pan-cancer analysis of BRCA1 and BRCA2 genomic alterations and their association with genomic instability as measured by genome-wide loss of heterozygosity

Ethan S. Sokol, Dean Pavlick, Hossein Khiabanian, Garrett M. Frampton, Jeffrey S. Ross, Jeffrey P. Gregg, Primo N. Lara, Steffi Oesterreich, Neeraj Agarwal, Andrea Necchi, Vincent A. Miller, Brian Alexander, Siraj M. Ali, Shridar Ganesan, Jon H. Chung

Research output: Contribution to journalArticle

Abstract

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 BRCA1/2 alterations (BRCA1/2-associated cancers: breast, ovarian, pancreatic, prostate), BRCA1/2 alterations result in HRD and are biomarkers for PARP inhibitor use. In other (non–BRCA1/ 2-associated) cancer types, the association between BRCA1/2 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. BRCA1/2 alterations were classified as predicted germline/somatic and biallelic/monoallelic. Genome-wide loss of heterozygosity (gLOH) was evaluated as a marker of HRD. RESULTS BRCA1/2 alterations were observed at a 4.7% frequency. BRCA1/2 mutations were predicted germline in 57.4% of BRCA1/2-associated and 37.2% of non–BRCA1/2-associated cancers. The fraction of BRCA1/2-altered cases that were biallelic was 68.7%, with a higher biallelic fraction in BRCA1/2-associated (89.9%) versus non–BRCA1/2-associated cancers (43.6%). Differences in tissue distribution of biallelic BRCA1 versus BRCA2 alterations were noted, including a higher rate of biallelic BRCA2 alteration in prostate cancer. Biallelic BRCA1/2 alteration was observed at a 3.2% frequency (BRCA1/2-associated cancers, 8.9%; non–BRCA1/2-associated cancers, 1.3%) and . 1% frequency in at least 13 cancer types. Across cancer types, biallelic BRCA1/2 alteration was associated with increased gLOH versus monoallelic or wild-type BRCA1/2; predicted germline or somatic mutations were both associated with elevated gLOH. CONCLUSION Biallelic BRCA1/2 alterations were associated with elevated gLOH in diverse cancer types, including those not traditionally associated with BRCA1/2 cancer syndromes. Biomarker development for PARP inhibitors should integrate methods to distinguish biallelic from monoallelic BRCA1/2 status, and biallelic BRCA1/2 alteration should be broadly evaluated across cancer types as a biomarker for underlying HRD and PARP inhibitor sensitivity.

Original languageEnglish (US)
Pages (from-to)442-465
Number of pages24
JournalJCO Precision Oncology
Volume3
DOIs
StatePublished - Jan 1 2019

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Sokol, E. S., Pavlick, D., Khiabanian, H., Frampton, G. M., Ross, J. S., Gregg, J. P., Lara, P. N., Oesterreich, S., Agarwal, N., Necchi, A., Miller, V. A., Alexander, B., Ali, S. M., Ganesan, S., & Chung, J. H. (2019). Pan-cancer analysis of BRCA1 and BRCA2 genomic alterations and their association with genomic instability as measured by genome-wide loss of heterozygosity. JCO Precision Oncology, 3, 442-465. https://doi.org/10.1200/PO.19.00345