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Germline mutations in BRIP1 and PALB2 in Jewish high cancer risk families

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Abstract

Germline mutations in BRCA1 and BRCA2 account for ~30 % of inherited breast cancer. BRIP1 and PALB2 are likely genes for breast cancer susceptibility, based on their roles in maintaining cellular integrity. Indeed, few pathogenic germline mutations in both genes are reported in ethnically diverse breast cancer families. There is a paucity of data on the putative contribution of both genes to inherited breast cancer in Jewish high risk families. High risk Jewish women, none of whom was a carrier of the predominant Jewish mutations in BRCA1/BRCA2, were screened for BRIP1 germline mutations by combined denaturing gradient gel electrophoresis, high resolution melting and sequencing. Direct sequencing of exons and flanking intronic sequences was used for PALB2 mutational analysis. Overall, 149 women, all of high risk, cancer prone families of Ashkenazi origin, were genotyped for BRIP1 mutations: 127 with breast cancer, 22 with ovarian cancer. No truncating mutations were noted and one novel (p.Ala745Thr) and two previously described missense mutations were detected. For PALB2, 93 women were genotyped (87 with breast cancer) of Ashkenazi (n = 32) and non Ashkenazi Jewish origin. Fifteen sequence variants were detected, of these, none was truncating, four were not previously reported, and two (p.Asp871Gly and p.Leu1119Pro) were seemingly pathogenic based on the PolyPhen2 protein prediction algorithm. These missense mutations were not detected in any of 113 healthy Ashkenazi and 109 Moroccan, cancer free controls. In conclusion, germline mutations in BRIP1 and PALB2 contribute marginally to breast cancer susceptibility in ethnically diverse, Jewish high risk families.

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Acknowledgments

We thank all individuals who participated to this study. This study was partially funded by Italian citizens who allocated the 5 × 1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects ‘5 × 1000’). This study was partuially funded by the Israel Cancer Association. This work was done in partial fulfillment of the requirements for a Masters degree for Roni Milgrom and Anya Kushnir at the Department of Human Genetics and Molecular Biology at the Tel-Aviv University, Tel-Aviv, Israel.

Conflict of interest

All authors declare that they have no conflict of interest regarding the data published herein.

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Authors and Affiliations

  1. IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy

    Irene Catucci, Sara Volorio, Filomena Ficarazzi, Paolo Radice & Paolo Peterlongo

  2. Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    Irene Catucci, Paolo Radice & Paolo Peterlongo

  3. The Susanne Levy Gertner Oncogenetics Unit, The Danek Gertner Institute of Genetics, Chaim Sheba Medical Center, Tel-Aviv University, 52621, Tel-Hashomer, Israel

    Roni Milgrom, Anya Kushnir, Yael Laitman & Eitan Friedman

  4. Institute of Human Genetics, the Oncology Institute, Tel-Aviv University, Tel-Aviv, Israel

    Shani Paluch-Shimon

  5. Department of Experimental Oncology, Istituto Europeo di Oncologia, Milan, Italy

    Loris Bernard

  6. The Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

    Eitan Friedman

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  1. Irene Catucci
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  2. Roni Milgrom
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Correspondence to Eitan Friedman.

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Irene Catucci, Roni Milgrom, Eitan Friedman and Paolo Peterlongo have equally contributed to this work.

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Catucci, I., Milgrom, R., Kushnir, A. et al. Germline mutations in BRIP1 and PALB2 in Jewish high cancer risk families. Familial Cancer 11, 483–491 (2012). https://doi.org/10.1007/s10689-012-9540-8

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