Tumour lineage shapes BRCA-mediated phenotypes Journal Article


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.
Article 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
DOI/URL:
Notes: Letter -- Source: Scopus
Altmetric Score
MSK Authors
  1. Kenneth Offit
    543 Offit
  2. Mark E Robson
    401 Robson
  3. David Solit
    466 Solit
  4. Liying Zhang
    94 Zhang
  5. Zsofia Kinga Stadler
    165 Stadler
  6. Marc Ladanyi
    923 Ladanyi
  7. David Hyman
    224 Hyman
  8. Agnes Viale
    211 Viale
  9. Ahmet Zehir
    168 Zehir
  10. Nancy Bouvier
    33 Bouvier
  11. Eileen O'Reilly
    357 O'Reilly
  12. Nicholas D Socci
    191 Socci
  13. Michael Forman Berger
    422 Berger
  14. Howard Scher
    883 Scher
  15. Wassim Abida
    47 Abida
  16. Barry Stephen Taylor
    153 Taylor
  17. Nikolaus D Schultz
    217 Schultz
  18. Jose T Baselga
    438 Baselga
  19. Karl Philip Jonsson
    30 Jonsson
  20. Craig Bielski
    10 Bielski
  21. Ozge Birsoy
    11 Birsoy
  22. Michael Lain Cheng
    9 Cheng
  23. Shweta S Chavan
    6 Chavan
  24. Ezra Y Rosen
    3 Rosen