The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index.
Tumour lineage shapes BRCA-mediated phenotypes
Open accessAbstract
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. 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.
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Citations
Cites
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Self-citationOlaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation
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Self-citationRisks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers
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Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer
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Cited by
Molecular profiling for precision cancer therapies
Malone, E. R., Oliva, M., Sabatini, P. J. B., Stockley, T. L., & Siu, L. L. (2020) · Genome Medicine · doi:10.1186/s13073-019-0703-1 · Cited by 913
PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance
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Pan-cancer landscape of homologous recombination deficiency.
Nguyen, L., W. M. Martens, J., Van Hoeck, A., & Cuppen, E. (2020) · Nature communications · doi:10.1038/s41467-020-19406-4 · Cited by 532
“This is consistent with the finding by Jonsson et al.[15] that LOH is enriched in tumors with BRCA1/2 germline pathogenic variants or somatic loss-of-function variants.”
ResultHilton, J., Gelmon, K., Bedard, P. L., Tu, D., Xu, H., Tinker, A. V., Goodwin, R., Laurie, S. A., Jonker, D., Hansen, A. R., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-31199-2 · Cited by 155
Lenis, A. T., Ravichandran, V., Brown, S., Alam, S. M., Katims, A., Truong, H., Reisz, P. A., Vasselman, S., Nweji, B., Autio, K. A., et al. (2024) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-23-3403 · Cited by 80
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Metadata
- 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.
- Venue
- Nature
- Published
- 2019-07
- Volume
- 571
- Issue
- 7766
- Pages
- 576-579
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2958222816
- Cited by
- 401
- References
- 49
- FWCI
- 32.37
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-12-11)
- Open access
- green
- Licence
- www.springer.com/tdm (tdm)
- www.springer.com/tdm (vor)
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- 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., . . . Taylor, B. S. (2019). Tumour lineage shapes BRCA-mediated phenotypes. Nature. https://doi.org/10.1038/s41586-019-1382-1
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