LAUSR

Somatic and germline mutations are traditionally viewed as separate entities. Yet, it is well established that germline variants (either inherited or occurring spontaneously) can influence cancer risk - i.e. cancer predisposition syndromes. In this presentation, I will discuss the reverse (but complementary) concept and propose that de novo germline mutations in the RTK/RAS/MAPK pathway occur recurrently because they confer a selective advantage to testicular stem cells, leading to the formation of ‘mole-like’ mutant clones in the ageing testis. This universal mechanism called ‘selfish selection’ relies on principles akin to oncogenesis and explains the paternal age-effect and high birth prevalence observed for several Mendelian disorders, including Noonan (PTPN11), Costello (HRAS), Apert (FGFR2) syndromes and achondroplasia (FGFR3). I will describe the strategies we have developed to show that the human testis is a repository of pathogenic de novo mutations and that selfish ‘moles’ are prevalent in older men’s testes. Our data show that the male germline is particularly vulnerable to dysregulation of the RTK/RAS/MAPK pathway. Importantly, because the germline provides a source of heritable material (unlike somatic tissues), this phenomenon has implications that extend far beyond the individual in whom it takes place, and is predicted to affect disease prevalence, genome heterogeneity and evolution of our species. This process illustrates another facet of the fascinating biology of the RAS/MAPK pathway. Citation Format: Anne Goriely. Somatic predisposition to germline mutations in the RTK/RAS/MAPK pathway [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr IA18.