Diagnostic algorithm for identification of individuals with hereditary predisposition to breast cancer.

Breast cancer originates from genetic and environmental factors leading to accumulation of mutations in both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). Incidence of breast cancer cases rises dramatically with ageing. Approximately 90% of breast cancers are sporadic while the remaining 10% are inheritable. BRCA1 and BRCA2 mutations are associated with a greatly increased risk for development of hereditary breast cancer (HBC). Besides BRCA mutations, enhanced production of ROS and accumulation of mitochondrial DNA mutations in mitochondria of post mitotic cells are a contributory factor to human aging. In this review, a model for predisposition to HBC incorporating the BRCA mutation, mtDNA4977 mutation, ER and TP53 was developed. Our model shows that germ-line point BRCA mutations transmitted from ancestors accelerated the somatic oxygen damages and mtDNA mutations leading to phenotypic expression of premature aging and breast cancer. Also, a diagnostic algorithm targeted at active identification of hereditary breast cancer was developed and introduced into clinical practice by diagnosis of founder BRCA mutation, mitochondrail common deletion and clinical parameters.