Analysis of cancer risk and BRCA1 and BRCA2mutation prevalence in the kConFab familial breast cancer resource

Jennifer Leary ,Michael Gattas,Heather Thorne,Graham J. Mann ,Gulietta M. Pupo ,Sandra Picken,Eric Haan,Graham G. Giles ,Graeme Suthers,John L. Hopper ,Rosemary L. Balleine ,Phyllis Butow ,Clare L. Scott ,Amanda B. Spurdle ,Kelly‐Anne Phillips ,Christine L. Clarke ,Georgia Chenevix-Trench,Judy Kirk,Christobel Saunders,Kathy Tucker,Eveline Niedermayr,Gerda M Evans,Jack Goldblatt,Geoffrey J. Lindeman ,Sián Fereday,Edward Edkins

doi:10.1186/bcr1377

Abstract

IntroductionThe Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) is a multidisciplinary, collaborative framework for the investigation of familial breast cancer. Based in Australia, the primary aim of kConFab is to facilitate high-quality research by amassing a large and comprehensive resource of epidemiological and clinical data with biospecimens from individuals at high risk of breast and/or ovarian cancer, and from their close relatives.MethodsEpidemiological, family history and lifestyle data, as well as biospecimens, are collected from multiple-case breast cancer families ascertained through family cancer clinics in Australia and New Zealand. We used the Tyrer-Cuzick algorithms to assess the prospective risk of breast cancer in women in the kConFab cohort who were unaffected with breast cancer at the time of enrolment in the study.ResultsOf kConFab's first 822 families, 518 families had multiple cases of female breast cancer alone, 239 had cases of female breast and ovarian cancer, 37 had cases of female and male breast cancer, and 14 had both ovarian cancer as well as male and female breast cancer. Data are currently held for 11,422 people and germline DNAs for 7,389. Among the 812 families with at least one germline sample collected, the mean number of germline DNA samples collected per family is nine. Of the 747 families that have undergone some form of mutation screening, 229 (31%) carry a pathogenic or splice-site mutation in BRCA1 or BRCA2. Germline DNAs and data are stored from 773 proven carriers of BRCA1 or BRCA1 mutations. kConFab's fresh tissue bank includes 253 specimens of breast or ovarian tissue – both normal and malignant – including 126 from carriers of BRCA1 or BRCA2 mutations.ConclusionThese kConFab resources are available to researchers anywhere in the world, who may apply to kConFab for biospecimens and data for use in ethically approved, peer-reviewed projects. A high calculated risk from the Tyrer-Cuzick algorithms correlated closely with the subsequent occurrence of breast cancer in BRCA1 and BRCA2 mutation positive families, but this was less evident in families in which no pathogenic BRCA1 or BRCA2 mutation has been detected.

Highlights

Introduction The Kathleen Cuningham FoundationConsortium for Research into Familial Breast Cancer is a multidisciplinary, collaborative framework for the investigation of familial breast cancer
A high calculated risk from the Tyrer-Cuzick algorithms correlated closely with the subsequent occurrence of breast cancer in BRCA1 and BRCA2 mutation positive families, but this was less evident in families in which no pathogenic BRCA1 or BRCA2 mutation has been detected
We demonstrate that the TyrerCuzick algorithm effectively predicted breast cancer occurrence in women unaffected at the time of recruitment if they were in a family carrying a BRCA1 or BRCA2 mutation, though not otherwise

Summary

Introduction

Introduction The Kathleen Cuningham FoundationConsortium for Research into Familial Breast Cancer (kConFab) is a multidisciplinary, collaborative framework for the investigation of familial breast cancer. The original expectation was that carriers of these mutations would have very high (>80%) lifetime risks of breast cancer Such dramatic effects seem to be confined to families with six or more cases of breast cancer or with a combination of breast, ovarian and male breast cancers. Mutation carriers from multiple-case families constitute cohorts in which hypotheses about the role of potential modifying genes and non-genetic risk factors can be tested. Such analyses need to be complemented by population-based studies so that estimates of the prevalence, attributable fraction, and risk of breast cancer can be made for individuals who have not been selected on the basis of a strong family history [4]

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Conclusion