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


Authors: Murciano-Goroff, Y. R.; Schram, A. M.; Rosen, E. Y.; Won, H.; Gong, Y.; Noronha, A. M.; Janjigian, Y. Y.; Stadler, Z. K.; Chang, J. C.; Yang, S. R.; Mandelker, D.; Offit, K.; Berger, M. F.; Donoghue, M. T. A.; Bandlamudi, C.; Drilon, A.
Article Title: Reversion mutations in germline BRCA1/2-mutant tumors reveal a BRCA-mediated phenotype in non-canonical histologies
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. © 2022, The Author(s).
Journal Title: Nature Communications
Volume: 13
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2022-11-23
Start Page: 7182
Language: English
DOI: 10.1038/s41467-022-34109-8
PROVIDER: scopus
PMCID: PMC9684575
PUBMED: 36418296
DOI/URL:
Notes: Article -- Export Date: 1 December 2022 -- Source: Scopus
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MSK Authors
  1. Kenneth Offit
    790 Offit
  2. Zsofia Kinga Stadler
    393 Stadler
  3. Yelena Yuriy Janjigian
    399 Janjigian
  4. Michael Forman Berger
    768 Berger
  5. Alexander Edward Drilon
    634 Drilon
  6. Alison Michele Schram
    125 Schram
  7. Helen Hyeong-Eun Won
    109 Won
  8. Jason Chih-Peng Chang
    141 Chang
  9. Diana Lauren Mandelker
    179 Mandelker
  10. Ezra Y Rosen
    49 Rosen
  11. Yixiao Gong
    7 Gong
  12. Soo Ryum Yang
    81 Yang