Reversion mutations in germline BRCA1/2-mutant tumors reveal a BRCA-mediated phenotype in non-canonical histologies

Yonina R. Murciano-Goroff, Alison M. Schram, Ezra Y. Rosen, Helen Won, Yixiao Gong, Anne Marie Noronha, Yelena Y. Janjigian, Zsofia K. Stadler, Jason C. Chang, Soo-Ryum Yang, Diana Mandelker, Kenneth Offit, Michael F. Berger, Mark T. A. Donoghue, Chaitanya Bandlamudi () and Alexander Drilon ()
Additional contact information
Yonina R. Murciano-Goroff: Memorial Sloan Kettering Cancer Center
Alison M. Schram: Memorial Sloan Kettering Cancer Center
Ezra Y. Rosen: Memorial Sloan Kettering Cancer Center
Helen Won: Memorial Sloan Kettering Cancer Center
Yixiao Gong: Memorial Sloan Kettering Cancer Center
Anne Marie Noronha: Memorial Sloan Kettering Cancer Center
Yelena Y. Janjigian: Memorial Sloan Kettering Cancer Center
Zsofia K. Stadler: Memorial Sloan Kettering Cancer Center
Jason C. Chang: Weill Cornell Medical College
Soo-Ryum Yang: Weill Cornell Medical College
Diana Mandelker: Memorial Sloan Kettering Cancer Center
Kenneth Offit: Memorial Sloan Kettering Cancer Center
Michael F. Berger: Weill Cornell Medical College
Mark T. A. Donoghue: Memorial Sloan Kettering Cancer Center
Chaitanya Bandlamudi: Memorial Sloan Kettering Cancer Center
Alexander Drilon: Memorial Sloan Kettering Cancer Center

Nature Communications, 2022, vol. 13, issue 1, 1-10

Abstract: Abstract The association between loss of BRCA1/2 and a homologous recombination deficiency phenotype is lineage dependent. In BRCA-associated cancers such as breast, ovarian, pancreas and prostate, this phenotype confers sensitivity to PARP inhibitors and platinum-therapies. Somatic reversion mutations restoring BRCA1/2 function mediate resistance, and have exclusively been reported in BRCA-associated tumors. In this study, we analyze matched tumor and normal sequencing from 31,927 patients and identify 846 (2.7%) patients with germline BRCA1/2 variants across 43 different cancer types, including 11 with somatic reversion mutations. While nine are in BRCA-associated tumors, we find two reversion mutations in non-BRCA-associated histologies, namely lung and esophagogastric adenocarcinomas. Both were detected following platinum therapy. Whole exome sequencing confirms the homologous recombination deficiency phenotype of these tumors. While reversion mutations arise in all BRCA-associated cancer types, here we show that reversion mutations arising post-platinum in non-BRCA associated histologies, while rare, may indicate BRCA1/2 mediated tumorigenesis.

Date: 2022
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DOI: 10.1038/s41467-022-34109-8

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