Tumour lineage shapes BRCA-mediated phenotypes Research Letter


Authors: Jonsson, P.; Bandlamudi, C.; Cheng, M. L.; Srinivasan, P.; Chavan, S. S.; Friedman, N. D.; Rosen, E. Y.; Richards, A. L.; Bouvier, N.; Selcuklu, S. D.; Bielski, C. M.; Abida, W.; Mandelker, D.; Birsoy, O.; Zhang, L.; Zehir, A.; Donoghue, M. T. A.; Baselga, J.; Offit, K.; Scher, H. I.; O’Reilly, E. M.; Stadler, Z. K.; Schultz, N.; Socci, N. D.; Viale, A.; Ladanyi, M.; Robson, M. E.; Hyman, D. M.; Berger, M. F.; Solit, D. B.; Taylor, B. S.
Title: Tumour lineage shapes BRCA-mediated phenotypes
Abstract: Mutations in BRCA1 and BRCA2 predispose individuals to certain cancers1–3, and disease-specific screening and preventative strategies have reduced cancer mortality in affected patients4,5. These classical tumour-suppressor genes have tumorigenic effects associated with somatic biallelic inactivation, although haploinsufficiency may also promote the formation and progression of tumours6,7. Moreover, BRCA1/2-mutant tumours are often deficient in the repair of double-stranded DNA breaks by homologous recombination8–13, and consequently exhibit increased therapeutic sensitivity to platinum-containing therapy and inhibitors of poly-(ADP-ribose)-polymerase (PARP)14,15. However, the phenotypic and therapeutic relevance of mutations in BRCA1 or BRCA2 remains poorly defined in most cancer types. Here we show that in the 2.7% and 1.8% of patients with advanced-stage cancer and germline pathogenic or somatic loss-of-function alterations in BRCA1/2, respectively, selective pressure for biallelic inactivation, zygosity-dependent phenotype penetrance, and sensitivity to PARP inhibition were observed only in tumour types associated with increased heritable cancer risk in BRCA1/2 carriers (BRCA-associated cancer types). Conversely, among patients with non-BRCA-associated cancer types, most carriers of these BRCA1/2 mutation types had evidence for tumour pathogenesis that was independent of mutant BRCA1/2. Overall, mutant BRCA is an indispensable founding event for some tumours, but in a considerable proportion of other cancers, it appears to be biologically neutral—a difference predominantly conditioned by tumour lineage—with implications for disease pathogenesis, screening, design of clinical trials and therapeutic decision-making. © 2019, The Author(s), under exclusive licence to Springer Nature Limited. Analysis of more than 17,000 tumours suggests that the contribution of germline and somatic mutations in the BRCA1 and BRCA2 genes to oncogenesis depends on tumour lineage. © 2019, © 2019, The Author(s), under exclusive licence to Springer Nature Limited.
Keywords: adult; human tissue; unclassified drug; gene mutation; major clinical study; advanced cancer; cancer risk; cancer staging; antineoplastic agent; letter; phenotype; allele; cytotoxic t lymphocyte antigen 4 antibody; enzyme inhibition; gene function; chemosensitivity; brca1 protein; brca2 protein; heterozygote; carcinogenesis; germ line; tumor suppressor gene; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor; gene inactivation; genetic risk; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; mutant; penetrance; protein antibody; molecular pathology; programmed death 1 ligand 1 antibody; programmed death 1 receptor antibody; receptor antibody; zygosity; human; male; female; priority journal; hereditary tumor syndrome; malignant neoplasm
Journal Title: Nature
Volume: 571
Issue: 7766
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2019-07-25
Start Page: 576
End Page: 579
Language: English
DOI: 10.1038/s41586-019-1382-1
PUBMED: 31292550
PROVIDER: scopus
PMCID: PMC7048239
DOI/URL:
Notes: Erratum issued, see DOI: 10.1038/s41586-019-1839-2 -- Letter -- Source: Scopus
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MSK Authors
  1. Kenneth Offit
    764 Offit
  2. Mark E Robson
    644 Robson
  3. David Solit
    729 Solit
  4. Liying Zhang
    128 Zhang
  5. Zsofia Kinga Stadler
    361 Stadler
  6. Marc Ladanyi
    1277 Ladanyi
  7. David Hyman
    352 Hyman
  8. Agnes Viale
    241 Viale
  9. Ahmet Zehir
    336 Zehir
  10. Nancy Bouvier
    68 Bouvier
  11. Eileen O'Reilly
    679 O'Reilly
  12. Nicholas D Socci
    241 Socci
  13. Michael Forman Berger
    701 Berger
  14. Howard Scher
    1110 Scher
  15. Wassim Abida
    141 Abida
  16. Barry Stephen Taylor
    236 Taylor
  17. Nikolaus D Schultz
    429 Schultz
  18. Jose T Baselga
    483 Baselga
  19. Karl Philip Jonsson
    50 Jonsson
  20. Diana Lauren Mandelker
    153 Mandelker
  21. Craig Bielski
    23 Bielski
  22. Ozge Birsoy
    65 Birsoy
  23. Michael Lain Cheng
    15 Cheng
  24. Shweta S Chavan
    32 Chavan
  25. Ezra Y Rosen
    38 Rosen