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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

Simard Jacques, Dumont Martine, Moisan Anne-Marie, Gaborieau Valérie, Vézina Hélène, Durocher Francine, Chiquette Jocelyne, Plante Marie, Avard Denise, Bessette Paul, Brousseau Claire, Dorval Michel, Godard Béatrice, Houde Louis, Joly Yann, Lajoie Marie-Andrée, Leblanc Gilles, Lepine Jean, Lesperance Bernard, Malouin Hélène, Parboosingh Jillian, Pichette Roxane, Provencher Louise, Rheaume Josée, Sinnett Daniel, Samson Carolle, Simard Jean-Claude, Tranchant Martine, Voyer Patricia, Easton Douglas, Tavtigian Sean V., Knoppers Bartha-Maria, Laframboise Rachel, Bridge Peter et Goldgar David. (2006). 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. Journal of Medical Genetics, 44, (2), p. 107-121.

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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.


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.


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 > or =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 > or =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 > or =18 provided an overall sensitivity of 86% and a specificity of 82%, with a positive predictive value of 66% in this population.


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 > or =18, represents an efficient test in terms of overall cost and sensitivity.

Type de document:Article publié dans une revue avec comité d'évaluation
Pages:p. 107-121
Version évaluée par les pairs:Oui
Identifiant unique:10.1136/jmg.2006.044388
Sujets:Sciences sociales et humaines > Sciences humaines > Histoire
Sciences sociales et humaines > Sciences sociales > Démographie
Sciences de la santé > Sciences médicales > Génétique
Département, module, service et unité de recherche:Départements et modules > Département des sciences humaines
Mots-clés:cancer, prévalence, démographie, génétique
Déposé le:12 oct. 2022 19:27
Dernière modification:12 oct. 2022 19:27
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