Several genes have been identified which strongly predispose to breast cancer, giving rise to high-risk families. The two most salient ones are BRCA1 on 17q12-q21, and BRCA2 on 13q12-q13. The gene sequence of BRCA1 was recently elucidated and direct mutation screening is now feasible. BRCA2 has not yet been isolated, but its location on chromosome 13 is accurately defined by polymorphic DNA markers. The main objective of this proposal for a Concerted Action is to generate large well-defined data sets by means of specific data calls, which are powerful enough to address important questions in relation to gene mapping, genetic heterogeneity, the spectrum of cancer risks associated with different mutations, the effect of programmes of intervention for individuals at risk, and the use of genetic data from tumours for prognosis and management of patients.
We expect to have assessed the genetic basis of the breast cancer predisposition in at least 350 families (250 BRCA1; 100 BRCA2). For BRCA1, this will allow the study of genotype-phenotype correlation's, and mutation-type specific cancer risks. For BRCA2, associated cancer risks and penetrance can be estimated. In the cohort of carrier women, the effect of known risk factors for breast cancer, such as parity and age at menarche, will be evaluated. In an attempt to identify genetic modifiers of the risk, polymorphism association studies will be performed in this cohort for a number of candidate genes. To investigate whether inherited breast cancer is a distinct entity relative to non-familial breast cancer, various somatic genetic changes, which occur frequently in sporadic breast tumours, will be characterised in at least 300 breast tumours from BRCA1- and BRCA2-linked families. In addition, their histopathology as well as several prognostic factors will be compared with sporadic breast cancer. We expect to identify a number of high-risk families that are not linked to BRCA1 or BRCA2, which will be employed to localise BRCA3.
EUROBCLC will maintain a database of studies of population-based series conducted by the Consortium members. Systematic studies will be undertaken to determine the prevalence of BRCA12-mutations among defined clusters of breast cancer, e.g., among 2,500 women unselected for family history and 200 sister-sister, or mother-daughter pairs.
Finally, at EUROBCLC-meetings, experiences related to social, psychological, ethical, and organisational aspects of predictive gene testing for BRCA1 (and later, BRCA2), will be exchanged. Possibly this will lead to the formulation of specific projects once genetic testing is underway in a number of countries. We can already envisage for example, the collation of data about - provision of genetic services, uptake of genetic testing, management of individuals at risk - which will almost certainly differ markedly between countries.