Familial Cancer

, Volume 9, Issue 4, pp 507–517 | Cite as

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

  • Luca Cavallone
  • Suzanna L. Arcand
  • Christine M. Maugard
  • Serge Nolet
  • Louis A. Gaboury
  • Anne-Marie Mes-Masson
  • Parviz Ghadirian
  • Diane Provencher
  • Patricia N. Tonin
Article

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.

Keywords

BRCA1 BRCA2 French Canadian Hereditary breast cancer Multiplex ligation-dependent probe amplification Variant of unknown clinical significance 

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

Supplementary material

10689_2010_9372_MOESM1_ESM.pdf (12 kb)
Supplementary material 1 (PDF 13 kb)

References

  1. 1.
    Tonin PN (2006) The limited spectrum of pathogenic BRCA1 and BRCA2 mutations in the French Canadian breast and breast-ovarian cancer families, a founder population of Quebec, Canada. Bull Cancer 93(9):841–846PubMedGoogle Scholar
  2. 2.
    Tonin PN, Mes-Masson AM, Futreal PA et al (1998) Founder BRCA1 and BRCA2 mutations in French Canadian breast and ovarian cancer families. Am J Hum Genet 63(5):1341–1351CrossRefPubMedGoogle Scholar
  3. 3.
    Oros KK, Ghadirian P, Greenwood CM et al (2004) Significant proportion of breast and/or ovarian cancer families of French Canadian descent harbor 1 of 5 BRCA1 and BRCA2 mutations. Int J Cancer 112(3):411–419CrossRefPubMedGoogle Scholar
  4. 4.
    Oros KK, Ghadirian P, Maugard CM et al (2006) Application of BRCA1 and BRCA2 mutation carrier prediction models in breast and/or ovarian cancer families of French Canadian descent. Clin Genet 70(4):320–329CrossRefPubMedGoogle Scholar
  5. 5.
    Simard J, Tonin P, Durocher F et al (1994) Common origins of BRCA1 mutations in Canadian breast and ovarian cancer families. Nat Genet 8(4):392–398CrossRefPubMedGoogle Scholar
  6. 6.
    Manning AP, Abelovich D, Ghadirian P et al (2001) Haplotype analysis of BRCA2 8765delAG mutation carriers in French Canadian and Yemenite Jewish hereditary breast cancer families. Hum Hered 52(2):116–120CrossRefPubMedGoogle Scholar
  7. 7.
    Oros KK, Leblanc G, Arcand SL et al (2006) Haplotype analysis suggest common founders in carriers of the recurrent BRCA2 mutation, 3398delAAAAG, in French Canadian hereditary breast and/ovarian cancer families. BMC Med Genet 7:23CrossRefPubMedGoogle Scholar
  8. 8.
    Scriver CR (2001) Human genetics: lessons from Quebec populations. Annu Rev Genomics Hum Genet 2:69–101CrossRefPubMedGoogle Scholar
  9. 9.
    Laberge AM, Michaud J, Richter A et al (2005) Population history and its impact on medical genetics in Quebec. Clin Genet 68(4):287–301CrossRefPubMedGoogle Scholar
  10. 10.
    Tonin PN, Maugard CM, Perret C, Mes-Masson AM, Provencher DM (2007) A review of histopathological subtypes of ovarian cancer in BRCA-related French Canadian cancer families. Fam Cancer 6(4):491–497CrossRefPubMedGoogle Scholar
  11. 11.
    Gilks CB, Prat J (2009) Ovarian carcinoma pathology and genetics: recent advances. Hum Pathol 40(9):1213–1223CrossRefPubMedGoogle Scholar
  12. 12.
    Simard J, Dumont M, Moisan AM et al (2007) Evaluation of BRCA1 and BRCA2 mutation prevalence, risk prediction models and a multistep testing approach in French-Canadian families with high risk of breast and ovarian cancer. J Med Genet 44(2):107–121CrossRefPubMedGoogle Scholar
  13. 13.
    Pohlreich P, Zikan M, Stribrna J et al (2005) High proportion of recurrent germline mutations in the BRCA1 gene in breast and ovarian cancer patients from the Prague area. Breast Cancer Res 7(5):R728–R736CrossRefPubMedGoogle Scholar
  14. 14.
    Hamann U, Liu X, Lange S, Ulmer HU, Benner A, Scott RJ (2002) Contribution of BRCA2 germline mutations to hereditary breast/ovarian cancer in Germany. J Med Genet 39(3):E12CrossRefPubMedGoogle Scholar
  15. 15.
    Antoniou AC, Easton DF (2006) Models of genetic susceptibility to breast cancer. Oncogene 25(43):5898–5905CrossRefPubMedGoogle Scholar
  16. 16.
    Antoniou AC, Easton DF (2006) Risk prediction models for familial breast cancer. Future Oncol 2(2):257–274CrossRefPubMedGoogle Scholar
  17. 17.
    Smith P, McGuffog L, Easton DF et al (2006) A genome wide linkage search for breast cancer susceptibility genes. Genes Chromosomes Cancer 45(7):646–655CrossRefPubMedGoogle Scholar
  18. 18.
    Houlston RS, Peto J (2004) The search for low-penetrance cancer susceptibility alleles. Oncogene 23(38):6471–6476CrossRefPubMedGoogle Scholar
  19. 19.
    Guenard F, Labrie Y, Ouellette G, Joly Beauparlant C, Durocher F (2009) Genetic sequence variations of BRCA1-interacting genes AURKA, BAP1, BARD1 and DHX9 in French Canadian Families with high risk of breast cancer. J Hum Genet 54(3):152–161CrossRefPubMedGoogle Scholar
  20. 20.
    Tischkowitz M, Xia B, Sabbaghian N et al (2007) Analysis of PALB2/FANCN-associated breast cancer families. Proc Natl Acad Sci U S A 104(16):6788–6793CrossRefPubMedGoogle Scholar
  21. 21.
    Arcand SL, Maugard CM, Ghadirian P et al (2008) Germline TP53 mutations in BRCA1 and BRCA2 mutation-negative French Canadian breast cancer families. Breast Cancer Res Treat 108(3):399–408CrossRefPubMedGoogle Scholar
  22. 22.
    Foulkes WD, Ghadirian P, Akbari MR et al (2007) Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women. Breast Cancer Res 9(6):R83CrossRefPubMedGoogle Scholar
  23. 23.
    Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G (2002) Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res 30(12):e57CrossRefPubMedGoogle Scholar
  24. 24.
    Antoniou AC, Durocher F, Smith P, Simard J, Easton DF (2006) BRCA1 and BRCA2 mutation predictions using the BOADICEA and BRCAPRO models and penetrance estimation in high-risk French-Canadian families. Breast Cancer Res 8(1):R3CrossRefPubMedGoogle Scholar
  25. 25.
    Moisan AM, Fortin J, Dumont M et al (2006) No Evidence of BRCA1/2 genomic rearrangements in high-risk French-Canadian breast/ovarian cancer families. Genet Test 10(2):104–115CrossRefPubMedGoogle Scholar
  26. 26.
    Puget N, Torchard D, Serova-Sinilnikova OM et al (1997) A 1-kb Alu-mediated germ-line deletion removing BRCA1 exon 17. Cancer Res 57(5):828–831PubMedGoogle Scholar
  27. 27.
    Petrij-Bosch A, Peelen T, van Vliet M et al (1997) BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients. Nat Genet 17(3):341–345CrossRefPubMedGoogle Scholar
  28. 28.
    Vasickova P, Machackova E, Lukesova M et al (2007) High occurrence of BRCA1 intragenic rearrangements in hereditary breast and ovarian cancer syndrome in the Czech Republic. BMC Med Genet 8:32CrossRefPubMedGoogle Scholar
  29. 29.
    Gad S, Aurias A, Puget N et al (2001) Color bar coding the BRCA1 gene on combed DNA: a useful strategy for detecting large gene rearrangements. Genes Chromosomes Cancer 31(1):75–84CrossRefPubMedGoogle Scholar
  30. 30.
    Woodward AM, Davis TA, Silva AG, Kirk JA, Leary JA (2005) Large genomic rearrangements of both BRCA2 and BRCA1 are a feature of the inherited breast/ovarian cancer phenotype in selected families. J Med Genet 42(5):e31CrossRefPubMedGoogle Scholar
  31. 31.
    Armaou S, Konstantopoulou I, Anagnostopoulos T et al (2007) Novel genomic rearrangements in the BRCA1 gene detected in Greek breast/ovarian cancer patients. Eur J Cancer 43(2):443–453CrossRefPubMedGoogle Scholar
  32. 32.
    Lim YK, Lau PT, Ali AB et al (2007) Identification of novel BRCA large genomic rearrangements in Singapore Asian breast and ovarian patients with cancer. Clin Genet 71(4):331–342CrossRefPubMedGoogle Scholar
  33. 33.
    Walsh T, Casadei S, Coats KH et al (2006) Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA 295(12):1379–1388CrossRefPubMedGoogle Scholar
  34. 34.
    Puget N, Stoppa-Lyonnet D, Sinilnikova OM et al (1999) Screening for germ-line rearrangements and regulatory mutations in BRCA1 led to the identification of four new deletions. Cancer Res 59(2):455–461PubMedGoogle Scholar
  35. 35.
    Mazoyer S (2005) Genomic rearrangements in the BRCA1 and BRCA2 genes. Hum Mutat 25(5):415–422CrossRefPubMedGoogle Scholar
  36. 36.
    Montagna M, Dalla Palma M, Menin C et al (2003) Genomic rearrangements account for more than one-third of the BRCA1 mutations in northern Italian breast/ovarian cancer families. Hum Mol Genet 12(9):1055–1061CrossRefPubMedGoogle Scholar
  37. 37.
    Ramus SJ, Harrington PA, Pye C et al (2007) Contribution of BRCA1 and BRCA2 mutations to inherited ovarian cancer. Hum Mutat 28(12):1207–1215CrossRefPubMedGoogle Scholar
  38. 38.
    Gutierrez-Enriquez S, Balmana J, Baiget M, Diez O (2008) Detection of the CHEK2 1100delC mutation by MLPA BRCA1/2 analysis: a worthwhile strategy for its clinical applicability in 1100delC low-frequency populations? Breast Cancer Res Treat 107(3):455–457CrossRefPubMedGoogle Scholar
  39. 39.
    Agata S, Dalla Palma M, Callegaro M et al (2005) Large genomic deletions inactivate the BRCA2 gene in breast cancer families. J Med Genet 42(10):e64CrossRefPubMedGoogle Scholar
  40. 40.
    Evans DG, Lalloo F, Wallace A, Rahman N (2005) Update on the Manchester Scoring System for BRCA1 and BRCA2 testing. J Med Genet 42(7):e39CrossRefPubMedGoogle Scholar
  41. 41.
    Easton DF, Deffenbaugh AM, Pruss D et al (2007) A systematic genetic assessment of 1, 433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. Am J Hum Genet 81(5):873–883CrossRefPubMedGoogle Scholar
  42. 42.
    Gagnon A, Heyer E (2001) Fragmentation of the Quebec population genetic pool (Canada): evidence from the genetic contribution of founders per region in the 17th and 18th centuries. Am J Phys Anthropol 114(1):30–41CrossRefPubMedGoogle Scholar
  43. 43.
    Tonin PN, Perret C, Lambert JA et al (2001) Founder BRCA1 and BRCA2 mutations in early-onset French Canadian breast cancer cases unselected for family history. Int J Cancer 95(3):189–193CrossRefPubMedGoogle Scholar
  44. 44.
    Loman N, Johannsson O, Kristoffersson U, Olsson H, Borg A (2001) Family history of breast and ovarian cancers and BRCA1 and BRCA2 mutations in a population-based series of early-onset breast cancer. J Natl Cancer Inst 93(16):1215–1223CrossRefPubMedGoogle Scholar
  45. 45.
    King MC, Marks JH, Mandell JB (2003) Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302(5645):643–646CrossRefPubMedGoogle Scholar
  46. 46.
    Gershoni-Baruch R, Dagan E, Fried G et al (2000) Significantly lower rates of BRCA1/BRCA2 founder mutations in Ashkenazi women with sporadic compared with familial early onset breast cancer. Eur J Cancer 36(8):983–986CrossRefPubMedGoogle Scholar
  47. 47.
    Hodgson SV, Heap E, Cameron J et al (1999) Risk factors for detecting germline BRCA1 and BRCA2 founder mutations in Ashkenazi Jewish women with breast or ovarian cancer. J Med Genet 36(5):369–373PubMedGoogle Scholar
  48. 48.
    Ghadirian P, Robidoux A, Zhang P et al (2009) The contribution of founder mutations to early-onset breast cancer in French-Canadian women. Clin Genet 76(5):421–426CrossRefPubMedGoogle Scholar
  49. 49.
    Lee E, McKean-Cowdin R, Ma H et al (2008) Evaluation of unclassified variants in the breast cancer susceptibility genes BRCA1 and BRCA2 using five methods: results from a population-based study of young breast cancer patients. Breast Cancer Res 10(1):R19CrossRefPubMedGoogle Scholar
  50. 50.
    Tal A, Arbel-Goren R, Stavans J (2009) Cancer-associated mutations in BRC domains of BRCA2 affect homologous recombination induced by Rad51. J Mol Biol 393(5):1007–1012CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Luca Cavallone
    • 1
  • Suzanna L. Arcand
    • 2
  • Christine M. Maugard
    • 3
    • 4
    • 5
  • Serge Nolet
    • 6
    • 7
  • Louis A. Gaboury
    • 6
    • 7
  • Anne-Marie Mes-Masson
    • 4
    • 5
  • Parviz Ghadirian
    • 8
  • Diane Provencher
    • 5
    • 9
  • Patricia N. Tonin
    • 1
    • 2
    • 10
    • 11
  1. 1.Department of Human GeneticsMcGill UniversityMontrealCanada
  2. 2.The Research Institute of the McGill University Health CentreMontrealCanada
  3. 3.Service de médecine géniqueCentre hospitalier de l’Université de MontréalMontrealCanada
  4. 4.Département de médecineUniversité de MontréalMontrealCanada
  5. 5.Hôpital Notre-DameCentre de recherche du centre hospitalier de l’Université de Montréal/Institut du cancer de MontréalMontrealCanada
  6. 6.Département de pathologieCentre hospitalier de l’Université de MontréalMontrealCanada
  7. 7.Département de pathologie et biologie cellulaire, Faculté de médecineUniversité de MontréalMontrealCanada
  8. 8.Epidemiology Research Unit, Research CentreCentre hospitalier de l’Université de MontréalMontrealCanada
  9. 9.Département d’obstétrique gynécologie, Division de gynécologie oncologiqueUniversité de MontréalMontrealCanada
  10. 10.Department of MedicineMcGill UniversityMontrealCanada
  11. 11.Medical GeneticsMontrealCanada

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