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.