High penetrances of BRCA1 and BRCA2 mutations confirmed in a prospective series

Pål Møller,Lovise Mæhle,Christoffer Jonsrud,Jaran Apold,Trond Ludvigsen,Anita Vabø,Neal Clark,Lars F Engebretsen

doi:10.1186/1897-4287-8-2

Abstract

Penetrances of BRCA1 and BRCA2 mutations have been derived from retrospective studies, implying the possibility of ascertainment biases to influence the results.We have followed women at risk for breast and/or ovarian cancer for two decades, and report the prospectively observed age-related annual incidence rates to contract breast or ovarian cancer for women with deleterious BRCA1 or BRCA2 mutations based on 4830 observation years. Patients were grouped according to mutation, age and having/not having had previous cancer.In women not having had previous cancer and aged 40-59 years, the annual incidence rate to contract breast or ovarian cancer in those having the most frequent BRCA1 founder mutations was 4.0%, for women in this age group and with less frequent BRCA1 mutations annual incidence rate was 5.9%, and for women with BRCA2 mutations 3.5%.The observed figures may be used for genetic counseling of healthy mutation carriers in the respective age groups. The results may indicate that less frequent BRCA1 mutations have higher penetrances than BRCA1 founder mutations.

Highlights

Mutations in the two genes BRCA1 and BRCA2 may cause breast or ovarian cancer
Through 4830 follow-up years 147 among them were diagnosed as having breast and/or ovarian cancer, arriving at an overall annual incidence rate irrespective of age to be 3.0%
These 870 were fractionated into three groups: a) the four BRCA1 founder mutations for which we have previously reported retrospective cumulative incidence rates, b) other BRCA1 mutations, and c) BRCA2 mutations

Summary

Introduction

Mutations in the two genes BRCA1 and BRCA2 may cause breast or ovarian cancer. Estimates on penetrances have been based on retrospective studies and have arrived at diverging results.Retrospective reports include the possibility of presenting the selection criteria as results [1]. Estimates on penetrances have been based on retrospective studies and have arrived at diverging results. Some studies tested one affected proband and calculated on number of affected close relatives [2,3]. In such studies, prevalences of close relatives to be mutation carriers, as well as age of onset of disease in the relatives, is related to ascertainment of the proband (age, complete or incomplete ascertainment), and the reported results reflect assumptions on these factors. Others reported findings based on mutation testing in extended families to avoid some of these confounders and arrived at higher penetrance estimates [4,5,6,7]. Reports including prospective series are limited [8,9,10]

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Conclusion