The Functional Hallmarks of Cancer Predisposition Genes

The canonical model for hereditary cancer predisposition is a cancer predisposition gene (CPG) that drives either one or both of two fundamental hallmarks of cancer, defective genomic integrity and deregulated cell proliferation, ultimately resulting in the accumulation of mutations within cells. Thus, the genes most commonly associated with cancer-predisposing genetic syndromes are tumor suppressor genes that regulate DNA repair (eg, BRCA1, BRCA2, MMR genes) and/or cell cycle (eg, APC, RB1). In recent years, however, the spectrum of high-penetrance CPGs has expanded considerably to include genes in non-canonical pathways such as oncogenic signaling, metabolism, and protein translation. We propose here that, given the variety of pathways that may ultimately affect genome integrity and cell proliferation, the model of cancer genetic predisposition needs to be expanded to account for diverse mechanisms. This synthesis calls for modeling and multiomic studies applying novel experimental and computational approaches to understand cancer genetic predisposition.