Role of BRCA1 and BRCA2 mutations in pancreatic cancer

Abstract

Germline mutations in the tumour suppressor genes breast cancer antigen gene (BRCA)1 and BRCA2 have been proven to portend a drastically increased lifetime risk of breast and ovarian cancers in the individuals who carry them. A number of studies have shown that the third most common cancer associated with these mutations is pancreatic cancer. BRCA1/2 mutations are characterised by "allelic" or "phenotypic" heterogeneity, in that they demonstrate differing cancer expressivity between and within pedigrees that segregate their mutations. If the same mutation is present in all our cells, why do some families with a given mutation display predominantly breast cancer? Why do other lineages show a preponderance of ovarian cancer? And why would some families have members who develop mostly or exclusively pancreatic cancer--a cancer that occurs more commonly in men and that lacks consistent evidence for a hormonal basis to its aetiology--which is clearly the case for breast and ovarian cancer? The answer is that other modifying genetic and environmental factors must interact to preferentially incite carcinogenesis in one organ over another. We are just beginning to elucidate what these factors are.