Breast cancer tends to cluster in families, an affected first-degree relative roughly doubles the risk and ~10% of all breast cancer cases occur in a family setting indicative of segregation of an inherited autosomal dominant allele, where genetic testing is available (BRCA Lab). Germline deleterious mutations in two major susceptibility genes BRCA1 and BRCA2 constitute high-risk (~10fold) alleles and account for 2-3% of all breast cancer, whereas high-risk alleles in other genes are very rare. Evidence is emerging of rare alleles in additional genes conferring a modest (2-3fold) risk and of more common alleles associated with a low (1.1-1.3x) but multiplicative risk, suggesting that breast cancer susceptibility may be largely polygenic and not confined to familial disease. It has been estimated that ~50% of all breast cancer will occur in the 12% of the population at highest risk, implying that targeted preventive efforts in a risk-population may become possible (COGS). Our research is also focused on functional characterization of unclassified variants in BRCA1 and BRCA2 (ENIGMA), genetic modifiers of BRCA1 and BRCA2 germline mutations (CIMBA) and on gene-environment interactions influencing susceptibility (WECARE).
Predisposing factors affect not only risk but also the pattern of somatically acquired mutations and thereby tumor biology, prognosis and response to therapy. This is true for high-risk BRCA mutations but also low-risk alleles may influence tumor phenotype. Both BRCA1 and BRCA2 have a function in homologous recombination mediated dsDNA break repair and a dysfunction may be therapeutically targeted, e.g. by means of synthetic lethality. Thus, a BRCA-like tumor phenotype may become a biomarker for selection of cases to be screened for inherited risk but also for choice of optimal treatment, one of the topics of the SCAN-B study. Our research aims to describe the tumor biology of familial and non-familial breast cancer by microarray- and massively parallel sequencing-based profiling of tumor genomes, epigenomes and transcriptomes, partly in collaboration with the ICGC, in order to understand disease etiology and improve the clinical management and outcome of patients (CREATE Health).