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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
  1. Jacques Simard1,*,
  2. Martine Dumont1,*,
  3. Anne-Marie Moisan1,*,
  4. Valérie Gaborieau2,
  5. Hélène Vézina1,
  6. Francine Durocher1,
  7. Jocelyne Chiquette4,
  8. Marie Plante5,
  9. Denise Avard6,
  10. Paul Bessette7,
  11. Claire Brousseau1,
  12. Michel Dorval8,
  13. Béatrice Godard9,
  14. Louis Houde3,
  15. Yann Joly6,
  16. Marie-Andrée Lajoie1,
  17. Gilles Leblanc1,
  18. Jean Lépine10,
  19. Bernard Lespérance11,
  20. Hélène Malouin3,
  21. Jillian Parboosingh12,
  22. Roxane Pichette11,
  23. Louise Provencher4,
  24. Josée Rhéaume1,
  25. Daniel Sinnett13,
  26. Carolle Samson1,
  27. Jean-Claude Simard1,
  28. Martine Tranchant1,
  29. Patricia Voyer14,
  31. Douglas Easton15,
  32. Sean V Tavtigian2,
  33. Bartha-Maria Knoppers16,
  34. Rachel Laframboise17,
  35. Peter Bridge12,
  36. David Goldgar18
  1. 1Cancer Genomics Laboratory, Oncology and Molecular Endocrinology Research Centre, Centre Hospitalier Universitaire de Québec, Laval University, Quebec City, Quebec, Canada
  2. 2Genetic Epidemiology Unit, International Agency for Research on Cancer, Lyon, France
  3. 3Interdisciplinary Research Group on Demography and Genetic Epidemiology, University of Quebec at Chicoutimi, Chicoutimi, Quebec, Canada
  4. 4Clinique des Maladies du sein Deschênes-Fabia, Hôpital du Saint-Sacrement, Quebec, Canada
  5. 5Gynecology Oncology Division, Hôtel-Dieu de Québec, Centre Hospitalier Universitaire de Québec, Laval University, Quebec City, Quebec, Canada
  6. 6Centre de Recherche en Droit Public, Montreal University, Montreal, Quebec, Canada
  7. 7Department of Obstetrics and Gynecology, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada
  8. 8Unité de Recherche en Santé des Populations, CHA Research Center, Hôpital du Saint-Sacrement, Laval University, Quebec City, Quebec, Canada
  9. 9Programmes de Bioéthiques, Montreal University, Montreal, Quebec, Canada
  10. 10Service Haemato-Oncology, Centre Hospitalier Régional de Rimouski, Rimouski, Quebec, Canada
  11. 11Department of Haemato-Oncology, Hôpital du Sacré-Cœur de Montréal, Montreal, Quebec, Canada
  12. 12Molecular Diagnostic Laboratory, Alberta Children’s Hospital, Calgary, Alberta, Canada
  13. 13Department of Pediatrics, Montreal University, Montreal, Quebec, Canada
  14. 14Clinique des Maladies du sein, Carrefour de Santé de Jonquière, Jonquière, Quebec, Canada
  15. 15Cancer Research UK, Genetic Epidemiology Unit, University of Cambridge, Cambridge, UK
  16. 16Chaire de Recherche en Droit et Médecine, Centre de Recherche en Droit Public, Montreal University, Montreal, Quebec, Canada
  17. 17Medical Genetic Division, Centre Hospitalier Universitaire de Québec, CHUL, Laval University, Quebec City, Quebec, Canada
  18. 18Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah, USA
  1. Correspondence to:
 Dr Jacques Simard
 Canada Research Chair in Oncogenetics, Cancer Genomics Laboratory T3-57, Oncology and Molecular Endocrinology Research Center, CHUL Research Center CHUQ, 2705 Laurier Boulevard, Quebec City, Canada G1V 4G2jacques.simard{at}


Background and objective: In clinical settings with fixed resources allocated to predictive genetic testing for high-risk cancer predisposition genes, optimal strategies for mutation screening programmes are critically important. These depend on the mutation spectrum found in the population under consideration and the frequency of mutations detected as a function of the personal and family history of cancer, which are both affected by the presence of founder mutations and demographic characteristics of the underlying population. The results of multistep genetic testing for mutations in BRCA1 or BRCA2 in a large series of families with breast cancer in the French-Canadian population of Quebec, Canada are reported.

Methods: A total of 256 high-risk families were ascertained from regional familial cancer clinics throughout the province of Quebec. Initially, families were tested for a panel of specific mutations known to occur in this population. Families in which no mutation was identified were then comprehensively tested. Three algorithms to predict the presence of mutations were evaluated, including the prevalence tables provided by Myriad Genetics Laboratories, the Manchester Scoring System and a logistic regression approach based on the data from this study.

Results: 8 of the 15 distinct mutations found in 62 BRCA1/BRCA2-positive families had never been previously reported in this population, whereas 82% carried 1 of the 4 mutations currently observed in ⩾2 families. In the subset of 191 families in which at least 1 affected individual was tested, 29% carried a mutation. Of these 27 BRCA1-positive and 29 BRCA2-positive families, 48 (86%) were found to harbour a mutation detected by the initial test. Among the remaining 143 inconclusive families, all 8 families found to have a mutation after complete sequencing had Manchester Scores ⩾18. The logistic regression and Manchester Scores provided equal predictive power, and both were significantly better than the Myriad Genetics Laboratories prevalence tables (p<0.001). A threshold of Manchester Score ⩾18 provided an overall sensitivity of 86% and a specificity of 82%, with a positive predictive value of 66% in this population.

Conclusion: In this population, a testing strategy with an initial test using a panel of reported recurrent mutations, followed by full sequencing in families with Manchester Scores ⩾18, represents an efficient test in terms of overall cost and sensitivity.

  • MGL, Myriad Genetics Laboratories
  • NCI, National Cancer Institute
  • PCR, polymerase chain reaction
  • ROC, receiver operating characteristic

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  • * These authors contributed equally to this work and should be considered as the first author.

  • Published Online First 11 August 2006

  • Competing interests: The authors declare no competing interests.

  • Funding: This work was supported by the Canadian Institutes of Health Research (CIHR) and their Institute of Cancer and Institute of Gender and Health for the INHERIT BRCAs research programme, Fonds de la Recherche en Santé du Québec (FRSQ)/Réseau de Médecine Génétique Appliquée (RMGA), the Canadian Breast Cancer Research Alliance and the CURE foundation. JS is chairholder of the Canada Research Chair in Oncogenetics.

  • Other members of INHERIT BRCAs involved in this study are as follows: Marc Tremblay, Interdisciplinary Research Group on Demography and Genetic Epidemiology (GRIG), University of Quebec at Chicoutimi, Chicoutimi, Canada; Olga Sinilnikova, International Agency for Research on Cancer (IARC), Lyon, France, and Plate-forme de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon/Centre, Léon Bédard, Lyon, France; Antonis Antoniou, CRC Genetic Epidemiology Unit Strangeways Research Laboratories, University of Cambridge, UK; and Michel Dugas, Département de psychologie, Concordia University & Centre de recherche de l’Hôpital du Sacré-Cœur, Montreal, Canada.

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