BRCA1 and BRCA2 mutation predictions using the BOADICEA and BRCAPRO models and penetrance estimation in high-risk French-Canadian families

Antonis C Antoniou,Paula Smith,Jacques Simard,Douglas F Easton,Francine Durocher

doi:10.1186/bcr1365

Antonis C Antoniou, Paula Smith + Show 3 more

Open Access

https://doi.org/10.1186/bcr1365

Copy DOI

Abstract

IntroductionSeveral genetic risk models for breast and ovarian cancer have been developed, but their applicability to specific populations has not been evaluated. We used data from French-Canadian families to evaluate the mutation predictions given by the BRCAPRO and BOADICEA models. We also used this data set to estimate the age-specific risks for breast and ovarian cancer in BRCA1 and BRCA2 mutation carriers.MethodsA total of 195 families with multiple affected individuals with breast or ovarian cancer were recruited through the INHERIT (INterdisciplinary HEalth Research International Team on BReast CAncer susceptibility) BRCAs research program. Observed BRCA1 and BRCA2 mutation status was compared with predicted carrier probabilities under the BOADICEA and BRCAPRO models. The models were assessed using Brier scores, attributes diagrams and receiver operating characteristic curves. Log relative risks for breast and ovarian cancer in mutation carriers versus population risks were estimated by maximum likelihood, using a modified segregation analysis implemented in the computer program MENDEL. Twenty-five families were eligible for inclusion in the BRCA1 penetrance analysis and 27 families were eligible for the BRCA2 penetrance analysis.ResultsThe BOADICEA model predicted accurately the number of BRCA1 and BRCA2 mutations for the various groups of families, and was found to discriminate well at the individual level between carriers and noncarriers. BRCAPRO over-predicted the number of mutations in almost all groups of families, in particular the number of BRCA1 mutations. It significantly overestimated the carrier frequency for high predicted probabilities. However, it discriminated well between carriers and noncarriers. Receiver operating characteristic (ROC) curves indicate similar sensitivity and specificity for BRCAPRO and BOADICEA. The estimated risks for breast and ovarian cancer in BRCA1 and BRCA2 mutation carriers were consistent with previously published estimates.ConclusionThe BOADICEA model predicts accurately the carrier probabilities in French-Canadian families and may be used for counselling in this population. None of the penetrance estimates was significantly different from previous estimates, suggesting that previous estimates may be appropriate for counselling in this population.

Highlights

Several genetic risk models for breast and ovarian cancer have been developed, but their applicability to specific populations has not been evaluated
BRCAPRO over-predicted the number of mutations in almost all groups of families, in particular the number of BRCA1 mutations
In the present study we used data from French-Canadian families included in the INHERIT program to evaluate the mutation risk prediction models BOADICEA and BRCAPRO [14,16] and to estimate the breast and ovarian cancer risks conferred by BRCA1 and BRCA2 mutations

Summary

Introduction

Several genetic risk models for breast and ovarian cancer have been developed, but their applicability to specific populations has not been evaluated. We used data from FrenchCanadian families to evaluate the mutation predictions given by the BRCAPRO and BOADICEA models We used this data set to estimate the age-specific risks for breast and ovarian cancer in BRCA1 and BRCA2 mutation carriers. Approximately 80% of these founders still have descendants in Quebec today, and they account for the major part of the contemporary French-Canadian gene pool [21,22]. Founder mutations in both BRCA1 and BRCA2 genes have been characterized in French-Canadian high-risk breast/ovarian cancer families [23,24,25,26]

Methods

Results

Discussion

Conclusion