Risk Estimation as a Decision-Making Tool for Genetic Analysis of the Breast Cancer Susceptibility Genes

Article type: Research Article

Authors: Chang-Claude, Jenny | Becher, Heiko | Caligo, Maria | Eccles, Diana | Evans, Gareth | Haites, Neva | Hodgson, Shirley | Møller, Pål | Weber, Bernhard H.F. | Stoppa-Lyonnet, Dominique

Affiliations: Deutsches Krebsforschungszentrum, Division of Epidemiology, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany | Department of Oncology, University of Pisa, via Roma 57, 56126 Pisa, Italy | Wessex Clinical Genetic Services, Princess Ann Hospital, Coxford Road, Southampton SO16 5YA, UK | Clinical Genetic Services, St. Mary's Hospital, Oxford Road, Manchester M13 0JH, UK | Department of Medicine and Therapeutics, University of Aberdeen, Foresterhill, AB25 2ZD, UK | Genetics Centre, Guy's Hospital, St. Thomas Street, London SE1 9RT, UK | Unit of Medical Genetics, The Norwegian Radium Hospital, 0310 Oslo, Norway | Institut für Humangenetik, 97074 Würzburg, Germany | Service de Génétique Oncologique, Institut Curie, rue d'Ulm 26, 75231 Paris, France

Note: [] Correspondence: Dr. Jenny Chang-Claude, Deutsches Krebsforschungszentrum, Division of Epidemiology, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany, Tel.: +49 6221 422373, Fax: + 49 6221 422203, E-mail: j.chang-claude@dkfz-heidelberg.de

Abstract: For genetic counselling of a woman on familial breast cancer, an accurate evaluation of the probability that she carries a germ-line mutation is needed to assist in making decisions about genetic-testing. We used data from eight collaborating centres comprising 618 families (346 breast cancer only, 239 breast or ovarian cancer) recruited as research families or counselled for familial breast cancer, representing a broad range of family structures.  Screening was performed in affected women from 618 families for germ-line mutations in BRCA1 and in 176 families for BRCA2 mutations, using different methods including SSCP, CSGE, DGGE, FAMA and PTT analysis followed by direct sequencing.  Germ-line BRCA1 mutations were detected in 132 families and BRCA2 mutations in 16 families.  The probability of being a carrier of a dominant breast cancer gene was calculated for the screened individual under the established genetic model for breast cancer susceptibility, first, with parameters for age-specific penetrances for breast cancer only [7] and, second, with age-specific penetrances for ovarian cancer in addition [20].  Our results indicate that the estimated probability of carrying a dominant breast cancer gene gives a direct measure of the likelihood of detecting mutations in BRCA1 and BRCA2.  For breast/ovarian cancer families, the genetic model according to Narod et al. [20] is preferable for calculating the proband's genetic risk, and gives detection rates that indicate a 50% sensitivity of the gene test.  Due to the incomplete BRCA2 screening of the families, we cannot yet draw any conclusions with respect to the breast cancer only families.

Keywords: genetic counselling, genetic risk assessment, familial breast cancer

Journal: Disease Markers, vol. 15, no. 1-3, pp. 53-65, 1999