Hereditary cancer syndromes

Abstract

Hereditary cancer syndromes (HCSs) are arguably the most frequent category of Mendelian genetic diseases, as at least 2% of presumably healthy subjects carry highly-penetrant tumor-predisposing pathogenic variants (PVs). Hereditary breast-ovarian cancer and Lynch syndrome make the highest contribution to cancer morbidity; in addition, there are several dozen less frequent types of familial tumors. The development of the majority albeit not all hereditary malignancies involves two-hit mechanism, i.e. the somatic inactivation of the remaining copy of the affected gene. Earlier studies on cancer families suggested nearly fatal penetrance for the majority of HCS genes; however, population-based investigations and especially large-scale next-generation sequencing data sets demonstrate that the presence of some highly-penetrant PVs is often compatible with healthy status. Hereditary cancer research initially focused mainly on cancer detection and prevention. Recent studies identified multiple HCS-specific drug vulnerabilities, which translated into the development of highly efficient therapeutic options.

Keywords: Hereditary cancer syndromes; Germline pathogenic variants; Cancer predisposition; Cancer treatment; Next-generation sequencing

Core Tip: There are many reviews describing particular types of hereditary cancer syndromes (HCSs) (e.g., hereditary breast-ovarian cancer, Lynch syndrome, Li-Fraumeni syndrome, etc.). However, for the last 15-20 years there were no publications providing a general overview on familial cancers. Our paper describes mechanisms underlying genetic cancer predisposition, lists major types of HCSs, and comments on therapeutic advances in the management of hereditary tumors.