Familial Cancer

, Volume 3, Issue 1, pp 15–20 | Cite as

BRCA1 testing in breast and/or ovarian cancer families from northeastern France identifies two common mutations with a founder effect

  • Danièle Muller
  • Catherine Bonaiti-Pelié
  • Joseph Abecassis
  • Dominique Stoppa-Lyonnet
  • Jean-Pierre Fricker


Objective: The purpose of this study was to determine whether two mutations detected frequently in a population of breast and/or ovarian cancer families originating from the northeastern part of France could be due to a founder effect. Methods: 83 index cases of families ascertained to have a familial breast and/or ovarian cancer history, were screened for mutations in all coding exons of the BRCA1 gene, using combined DGGE and direct sequencing. For haplotype analysis, six polymorphic markers were used for allelotyping of mutation carriers and non carriers from nine families with 3600del11 mutation and four families with G1710X mutation. Results: Of 83 index cases, 27 (32%) had 14 different BRCA1 mutations, one of which (G1710X), had not been reported in other populations. Two mutations were particularly common: 3600del11 in exon 11 accounted for 37% and the nonsense mutation G1710X in exon 18 for 15% of all mutations. We identified a common haplotype for each mutation suggesting a common founder for each recurrent mutation. No specific phenotype could be assigned to any of the common mutations. Conclusions: These data demonstrate geographical clustering and suggest a founder effect for particular BRCA1 mutations, which identification will facilitate carrier detection in French families with breast cancer and breast and/or ovarian cancer.

BRCA1 gene breast cancer founder effect French genetic predisposition mutation ovarian cancer 


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  1. 1.
    Easton DF, Ford D, Bishop DT. Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet 1995; 56: 265–71.PubMedGoogle Scholar
  2. 2.
    Szabo CI, King MC. Population genetics of BRCA1 and BRCA2. Am J Hum Genet 1997; 60: 1013–20.PubMedGoogle Scholar
  3. 3.
    Breast Cancer Information Core (BIC) databases. Retrieved from http://www.nhgri.nih.gov/Intramural_research/Lab_transfer/Bic/) in 1996.Google Scholar
  4. 4.
    Johannesdottir G, Gudmundsson J, Bergthorsson JT et al. High prevalence of the 999 del5 mutation in Icelandic breast and ovarian cancer patients. Cancer Res 1996; 56: 3663–5.PubMedGoogle Scholar
  5. 5.
    Thorlacius S, Olafsdottir G, Tryggvadottir L et al. A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nat Genet 1996; 3: 117–9.CrossRefGoogle Scholar
  6. 6.
    Roa B, Boyd A, Volcik K, Richards C. Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet 1996; 14: 185–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Peelen T, van Vliet M, Petrij-Bosch A et al. A high proportion of novel mutations in BRCA1 with strong founder effects among Dutch and Belgian hereditary breast and ovarian cancer families. Am J Hum Genet 1997; 60: 1041–9.PubMedGoogle Scholar
  8. 8.
    Johannsson O, Ostermeyer EA, Hakansson S et al. Founding BRCA1 mutations in hereditary breast and ovarian cancer in southern Sweden. Am J Hum Genet 1996; 58: 441–50.PubMedGoogle Scholar
  9. 9.
    Mefford HC, Baumbach L, Panguluri RCK et al. Evidence for a BRCA1 founder mutation in families of West African ancestry. Am J Hum Genet 1999; 65: 575–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Gayther SA, Harrington P, Russel P et al. Frequently occuring germ-line mutations of the BRCA1 gene in ovarian cancer families from Russia. Am J Hum Genet. 1997; 60: 1239–42.PubMedGoogle Scholar
  11. 11.
    Csokay B, Tihomirova L, Stengrevics A et al. Strong founder effects in BRCA1 mutation carrier breast cancer patients from Latvia. Mutation in brief no. 258. Online Hum Mutat 1999; 14(1): 92.CrossRefGoogle Scholar
  12. 12.
    Struewing JP, Hartge P, Wacholder S et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med. 1997; 336: 1401–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Thorlacius S, Struewing J, Hartge P et al. Population-based study of risk of breast cancer in carriers of BRCA2 mutation. Lancet 1998; 352: 1337–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Peyrat JP, Vennin P, Hornez L, Bonneterre J. Germ-line BRCA1 mutations in patients from 36 families with breast and/or ovarian cancers in Northern France. Bull Cancer 1997; 84: 4–6 [in French].Google Scholar
  15. 15.
    Stoppa-Lyonnet D, Laurent-Puig P, Essioux L et al. BRCA1 sequence variations in 160 individuals referred to a breast/ovarian family cancer clinic. Institut Curie Breast Cancer Group. Am J Hum Genet 1997; 60: 1021–30.PubMedGoogle Scholar
  16. 16.
    Fricker JP, Muller D, Cutuli B et al. Germ-line mutations at BRCA1 in northeastern France. Bull Cancer 2000; 87: 739–44 [in French].PubMedGoogle Scholar
  17. 17.
    Eisinger F, Alby N, Bremond A et al. [INSERM-FNCLCC collective expertise]. Recommendations for medical management of women with genetic risk of developing breast and/or ovarian cancer. Ann Genet 1999; 42(1): 51–64 [in French].PubMedGoogle Scholar
  18. 18.
    Parmigiani G, Berry D, Aguilar O. Determining carrier probabilities for breast cancer-susceptibility genes BRCA1 and BRCA2. Am J Hum Genet. 1998; 62(1): 145–58.PubMedCrossRefGoogle Scholar
  19. 19.
    Kendall TL, Byerley DJ, Dean R. Isolation of DNA from blood. Anal Biochem 1991; 195: 74–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Friedmann LS, Ostermeyer EA, Szabo C et al. Confirmation of BRCA1 by analysis of germ-line mutations linked to breast and ovarian cancer in ten families. Nat Genet 1994; 8: 399–404.CrossRefGoogle Scholar
  21. 21.
    Neuhausen SL, Swensen J, Miki Y et al. A P1-based physical map of the BRCA1 region from D17S776 to D17S78. Hum Mol Genet 1994; 3: 1919–26.PubMedGoogle Scholar
  22. 22.
    Neuhausen SL, Mazoyer S, Friedman L et al. Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: results of an international study. Am J Hum Genet 1996; 58: 271–80.PubMedGoogle Scholar
  23. 23.
    Brzovic PS, Meza JE, King M-C, Klevit RE. BRCA1 Ring domain cancer-predisposing mutations. Structural consequences and effects on protein–protein interactions. J Biol Chem 2001; 44: 41399–406.CrossRefGoogle Scholar
  24. 24.
    Puget N, Stoppa-Lyonnet D, Sinilnikova O et al. Screening for germ-line rearrangements and regulatory mutations in BRCA1 led to the identification of four new deletions. Cancer Res 1999; 59: 455–61.PubMedGoogle Scholar
  25. 25.
    Gad S, Caux-Moncourtier V, Pages-Berhouet S et al. Significant contribution of large BRCA1 gene rearrangements in 120 French breast and ovarian cancer families. Oncogene 2002; 21: 6841–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Ford D, Easton DF, Stratton M et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet 1998; 62: 676–89.PubMedCrossRefGoogle Scholar
  27. 27.
    Dong J, Chang-Claude J, Wu Y et al. A high proportion of mutations in the BRCA1 gene in German breast/ovarian cancer families with clustering of mutations in the 3′?third of the gene. Hum Genet 1998; 103: 154–61.PubMedCrossRefGoogle Scholar
  28. 28.
    Thompson D, Easton D, the Breast Cancer Linkage Consortium. Variation in BRCA1 cancer risks by mutation position. Cancer Epidemiol Biomark Prev 2002; 11: 329–36.Google Scholar
  29. 29.
    Moslehi R, Chu W, Karlan B et al. BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer. Am J Hum Genet 2000; 66: 1259–72.PubMedCrossRefGoogle Scholar
  30. 30.
    Iau PTC, MacMillan RD, Blamey RW. Germ-line mutations associated with breast cancer susceptibility. Eur J Cancer 2001; 37: 300–21.PubMedCrossRefGoogle Scholar
  31. 31.
    Frank TS, Manley SA, Olopade OI et al. Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk. J Clin Oncol 1998; 16: 2417–25.PubMedGoogle Scholar
  32. 32.
    Neuhausen SL. Ethnic differences in cancer risk resulting from genetic variation. Cancer 1999; 86: 1755–62.CrossRefGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • Danièle Muller
    • 1
  • Catherine Bonaiti-Pelié
    • 2
  • Joseph Abecassis
    • 1
  • Dominique Stoppa-Lyonnet
    • 3
  • Jean-Pierre Fricker
    • 1
  1. 1.Laboratoire de Biologie Tumorale, Centre Paul StraussStrasbourg CedexFrance
  2. 2.INSERM U535 `Génétique Épidémiologique et Structure des Populations Humaines', Hôpital Paul-BrousseVillejuif CedexFrance
  3. 3.Service de Génétique Oncologique, Institut CurieParis Cedex 5France

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