title: 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.
abstract: 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 > 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Cancer Genomics Laboratory, Oncology and Molecular Endocrinology Research Centre, Centre Hospitalier Universitaire de Québec, Laval University, Quebec City, Quebec, Canada. jacques.simard@crchul.ulaval.ca
authors.forename: Jacques
authors.initials: J
authors.lastname: Simard
authors.forename: Martine
authors.initials: M
authors.lastname: Dumont
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Moisan
authors.forename: Valérie
authors.initials: V
authors.lastname: Gaborieau
authors.forename: Hélène
authors.initials: H
authors.lastname: Malouin
authors.forename: Francine
authors.initials: F
authors.lastname: Durocher
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Chiquette
authors.forename: Marie
authors.initials: M
authors.lastname: Plante
authors.forename: Denise
authors.initials: D
authors.lastname: Avard
authors.forename: Paul
authors.initials: P
authors.lastname: Bessette
authors.forename: Claire
authors.initials: C
authors.lastname: Brousseau
authors.forename: Michel
authors.initials: M
authors.lastname: Dorval
authors.forename: Béatrice
authors.initials: B
authors.lastname: Godard
authors.forename: Louis
authors.initials: L
authors.lastname: Houde
authors.forename: Yann
authors.initials: Y
authors.lastname: Joly
authors.forename: Marie-Andrée
authors.initials: MA
authors.lastname: Lajoie
authors.forename: Gilles
authors.initials: G
authors.lastname: Leblanc
authors.forename: Jean
authors.initials: J
authors.lastname: Lépine
authors.forename: Bernard
authors.initials: B
authors.lastname: Lespérance
authors.forename: Hélène
authors.initials: H
authors.lastname: Vézina
authors.forename: Jillian
authors.initials: J
authors.lastname: Parboosingh
authors.forename: Roxane
authors.initials: R
authors.lastname: Pichette
authors.forename: Louise
authors.initials: L
authors.lastname: Provencher
authors.forename: Josée
authors.initials: J
authors.lastname: Rhéaume
authors.forename: Daniel
authors.initials: D
authors.lastname: Sinnett
authors.forename: Carolle
authors.initials: C
authors.lastname: Samson
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Simard
authors.forename: Martine
authors.initials: M
authors.lastname: Tranchant
authors.forename: Patricia
authors.initials: P
authors.lastname: Voyer
authors.forename: Douglas
authors.initials: D
authors.lastname: Easton
authors.forename: Sean V
authors.initials: SV
authors.lastname: Tavtigian
authors.forename: Bartha-Maria
authors.initials: BM
authors.lastname: Knoppers
authors.forename: Rachel
authors.initials: R
authors.lastname: Laframboise
authors.forename: Peter
authors.initials: P
authors.lastname: Bridge
authors.forename: David
authors.initials: D
authors.lastname: Goldgar
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D002170:Canada / Q000453:epidemiology; D015331:Cohort Studies; D004273:DNA, Neoplasm / Q000235:genetics; D005190:Family; D005260:Female; D005602:France / Q000208:ethnology; D005784:Gene Amplification; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010051:Ovarian Neoplasms / Q000453:epidemiology / Q000235:genetics*; D016133:Polymerase Chain Reaction; D015995:Prevalence; D012044:Regression Analysis; D018570:Risk Assessment
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D004273:DNA, Neoplasm