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Compromised BRCA1–PALB2 interaction is associated with breast cancer risk

Oncogene volume 36, pages 4161–4170 (2017)Cite this article

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Abstract

The major breast cancer suppressor proteins BRCA1 and BRCA2 play essential roles in homologous recombination (HR)-mediated DNA repair, which is thought to be critical for tumor suppression. The two BRCA proteins are linked by a third tumor suppressor, PALB2, in the HR pathway. While truncating mutations in these genes are generally pathogenic, interpretation of missense variants remains a challenge. To date, patient-derived missense variants that disrupt PALB2 binding have been identified in BRCA1 and BRCA2; however, there has not been sufficient evidence to prove their pathogenicity in humans, and no variants in PALB2 that disrupt either its BRCA1 or BRCA2 binding have been reported. Here we report on the identification of a novel PALB2 variant, c.104T>C (p.L35P), that segregates in a family with a strong history of breast cancer. Functional analyses showed that L35P abrogates the PALB2–BRCA1 interaction and completely disables its abilities to promote HR and confer resistance to platinum salts and PARP inhibitors. Whole-exome sequencing of a breast cancer from a c.104T>C carrier revealed a second, somatic, truncating mutation affecting PALB2, and the tumor displays hallmark genomic features of tumors with BRCA mutations and HR defects, cementing the pathogenicity of L35P. Parallel analyses of other germline variants in the PALB2 N-terminal BRCA1-binding domain identified multiple variants that affect HR function to varying degrees, suggesting their possible contribution to cancer development. Our findings establish L35P as the first pathogenic missense mutation in PALB2 and directly demonstrate the requirement of the PALB2-BRCA1 interaction for breast cancer suppression.

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Acknowledgements

We thank Olga Aleynikova MD, Andrew Shuen MD, Nelly Sabbaghian MSc, Sonya Zaor MSc and Nancy Hamel MSc for their assistance. BX is supported by the National Cancer Institute (R0A138804 and R01CA188096). WDF is funded by Susan G Komen and the Quebec Breast Cancer Foundation. KAB, SHB, BW and JRF are supported in part by a Cancer Center Support Grant of the National Cancer Institute (grant No P30CA008748). MT is funded by the European Union Seventh Framework Program (2007Y2013)/European Research Council (Grant No. 310018). SLN is supported by Morris and Horowitz Endowed Professorship and the National Cancer Institute (R01CA184585). NZ is a Mitch Garber Postdoctoral Fellow. This research was supported by the Flow Cytometry Core Facility of Rutgers Robert Wood Johnson Medical School, a Shared Resource of The Rutgers Cancer Institute of New Jersey (P30CA072720), and a NIH Shared Instrumentation Grant (1 S10 RR025468).

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Authors and Affiliations

  1. Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA

    T K Foo, S Simhadri, Y Huo & B Xia

  2. Department of Medical Genetics, University of Cambridge, Cambridge, UK

    M Tischkowitz

  3. Department of Medical Genetics and Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada

    T Boshari, N Zayed & W D Foulkes

  4. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    K A Burke, S H Berman, B Weigelt & J S Reis-Filho

  5. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    P Blecua & N Riaz

  6. Department of Population Sciences, Beckman Research Institute at the City of Hope, Duarte, CA, USA

    Y C Ding & S L Neuhausen

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Foo, T., Tischkowitz, M., Simhadri, S. et al. Compromised BRCA1–PALB2 interaction is associated with breast cancer risk. Oncogene 36, 4161–4170 (2017). https://doi.org/10.1038/onc.2017.46

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