A theory for the tissue specificity of BRCA1/2 related and other hereditary cancers

Abstract

Women who inherit a defective BRCA1 or BRCA2 gene have risks for breast and ovarian cancer that are so high and seem so selective that many mutation carriers choose to have prophylactic surgery. There has been much conjecture to explain such apparently striking tissue specificity. All these suggestions share the assumption that some disabled function of normal tumor suppressor genes leads to a tissue specific cancer response. Here the idea is proposed and tested that major determinants of where BRCA1/2 hereditary cancers occur are related to tissue specificity of the cancer pathogen, the agent that causes chronic inflammation or the carcinogen. The target tissue may have receptors for the pathogen, become selectively exposed to an inflammatory process or to a carcinogen such as during digestion, metabolism or elimination. An innate genomic deficit in a tumor suppressor gene impairs normal responses to these extrinsic challenges and exacerbates the susceptibility to disease in organ targets. This hypothesis also fits data for several tumor suppressors beyond BRCA1/2. A major advantage of this model is that it suggests there may be some options in addition to prophylactic surgery.