CELLULAR BIOLOGY OF BREAST CANCER, FOCUSING ON GENOMIC AND CLINICOPATHOLOGICAL EVENTS IN CARRIERS OF A BRCA2 FOUNDER MUTATION

Like other cancer types, breast cancer is considered to be a genetic disease. While the majority of genetic changes are somatic, a minority are in germline. About 10-20% of breast cancer is thought to be due to a germline mutation in high-penetrance genes, where the major focus has been on BRCA1 and BRCA2. Hereditary differs from sporadic breast cancer with respect to phenotype, chromosomal gains and losses, somatic mutations and expression pattern. TP53 pathways are altered in carriers of BRCA1 and BRCA2 mutations, and BRCA1 carcinomas frequently carry TP53 mutations. There is strong evidence that genomic instability has a role in breast cancer pathogenesis, particularly in hereditary breast cancer, and possibly a role in sensitivity and resistance to therapy. Some of the germline mutations are defined as founder mutations. Founder mutations permit analysis of a large number of cases, and provide more accurate information on penetrance, expression, and genetic and environmental modifiers of risk. Population studies are also valuable due to the possibilities for evaluating clinicopathological data in a group of patients who have the same mutation. In Iceland a rare founder mutation has been detected in BRCA1, and a frequent founder mutation has been detected in BRCA2. In addition to population-based studies on genetics and clinicopathology, an extensive analysis of somatic changes in tumours of BRCA2 founder mutation carriers has been made. As the Icelandic carriers of BRCA mutations all have the same alteration, this can be considered an ideal model population to analyze the influences of somatic mutations acquired during carcinogenesis and tumor progression and effects of low-penetrance modifier genes. This information can be useful in understanding the role played by these genes in the incidence of breast cancer, in order to target genetic testing, provide individual risk assessment, and design better therapeutic strategies. The evidence of differences in susceptibility and in age of onset among carriers of a specific mutation makes it easier to define the role and importance of risk-modifying factors, leading to improved disease management.