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Comprehensive BRCA1 and BRCA2 mutation analyses and review of French Canadian families with at least three cases of breast cancer

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Abstract

Few studies have reported on the comprehensive BRCA1/2 mutation analyses of hereditary breast cancer (HBC) families of French Canadian descent. Here we report the investigation of 82 families with at least 3 cases of breast cancer evaluated for mutations by DNA sequencing and/or multiplex ligation-dependent probe amplification (MLPA) assay. DNA sequencing identified pathogenic mutations in 37 (45.1%) families, of which 70.2% were one of three recurring mutations (BRCA1:R1443X, BRCA2:8765delAG, and BRCA2:E1953X) frequently reported in this founder population; and variants of uncertain clinical significance in 7 (8.5%) families of which two harbored BRCA2:E3002K. MLPA analysis of the 38 DNA sequence-negative families did not reveal any large rearrangements in BRCA1/2. A phenotypic characterization of the cancer families based on pathogenic mutation status revealed that there were significantly fewer very young age at diagnosis breast cancer cases (<36 years) in mutation-negative families (5.9%, 9 of 153) than in BRCA1 (22.8%, 13 of 57; P = 0.0003) or BRCA2 (22.9%, 27 of 118; P < 1× 10E5) mutation-positive families. There were significantly more mutation-positive families (29 of 36, 80.6%) with a very young age of onset of breast cancer case than those that did not (8 of 39, 20.5%) (P < 10E6). The comprehensive mutation analysis of BRCA1/2 suggests that genomic rearrangements are unlikely to account for sequence-negative HBC families and affirms that the presence of a very young age of diagnosis of breast cancer is strongly predictive of mutation carrier status of French Canadian HBC families.

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Abbreviations

BIC:

Breast Information Core

HBC:

Hereditary breast cancer

HBOC:

Hereditary breast and ovarian cancer

HGVS:

Human Genome Variation Society

MLPA:

Multiplex ligation-dependent amplification probe assay

VUS:

Variants of unknown clinical significance

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Acknowledgments

P.N.T is an Associate Professor and Medical Scientist at The Research Institute of the McGill University Health Centre which receives support from the Fonds de la recherche en santé du Québec (FRSQ). Clinical specimens were provided by the Banque de tissus et de données of the Réseau de recherche sur le cancer of the FRSQ affiliated with the Canadian Tumour Repository Network (CRTNet). This study was supported by a grant from The Cancer Research Society to P.N.T.

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Authors and Affiliations

  1. Department of Human Genetics, McGill University, Montreal, QC, Canada

    Luca Cavallone & Patricia N. Tonin

  2. The Research Institute of the McGill University Health Centre, Montreal, QC, Canada

    Suzanna L. Arcand & Patricia N. Tonin

  3. Service de médecine génique, Centre hospitalier de l’Université de Montréal, Montreal, QC, Canada

    Christine M. Maugard

  4. Département de médecine, Université de Montréal, Montreal, QC, Canada

    Christine M. Maugard & Anne-Marie Mes-Masson

  5. Hôpital Notre-Dame, Centre de recherche du centre hospitalier de l’Université de Montréal/Institut du cancer de Montréal, Montreal, QC, Canada

    Christine M. Maugard, Anne-Marie Mes-Masson & Diane Provencher

  6. Département de pathologie, Centre hospitalier de l’Université de Montréal, Montreal, QC, Canada

    Serge Nolet & Louis A. Gaboury

  7. Département de pathologie et biologie cellulaire, Faculté de médecine, Université de Montréal, Montreal, QC, Canada

    Serge Nolet & Louis A. Gaboury

  8. Epidemiology Research Unit, Research Centre, Centre hospitalier de l’Université de Montréal, Montreal, QC, Canada

    Parviz Ghadirian

  9. Département d’obstétrique gynécologie, Division de gynécologie oncologique, Université de Montréal, Montreal, QC, Canada

    Diane Provencher

  10. Department of Medicine, McGill University, Montreal, QC, Canada

    Patricia N. Tonin

  11. Medical Genetics, L10-120, 1650 Cedar Avenue, Montreal, QC, H3B 1A4, Canada

    Patricia N. Tonin

Authors
  1. Luca Cavallone
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  2. Suzanna L. Arcand
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  3. Christine M. Maugard
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  7. Parviz Ghadirian
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  9. Patricia N. Tonin
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Correspondence to Patricia N. Tonin.

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Cavallone, L., Arcand, S.L., Maugard, C.M. et al. Comprehensive BRCA1 and BRCA2 mutation analyses and review of French Canadian families with at least three cases of breast cancer. Familial Cancer 9, 507–517 (2010). https://doi.org/10.1007/s10689-010-9372-3

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