Abstract PL02-01: The pathogenesis of cancer susceptibility due to inherited DNA repair defects

Abstract

Abstract The landscapes of somatic mutation in the genomes of normal human cells have, until recently, been poorly described compared with those of cancer cells. However, advances in technology are now changing this picture and are enabling exploration of the earliest stages of cancer development. In this talk, the patterns of somatic mutation found in normal colorectal epithelial cells are outlined and serve as a backdrop to understanding the pathogenesis of colorectal cancer susceptibility syndromes. Multiple mutational signatures are present in normal colorectal epithelial cells indicating that multiple mutational processes are operative in them during the course of life. Some of these mutational signatures are ubiquitous, present in every colorectal epithelial cell, with mutations generated at constant rates throughout life. Others are sporadic, found only in some cells or in some people, with mutations generated in bursts. Some are of endogenous origins whereas others are caused by exogenous exposures. Several inherited colorectal cancer predisposition syndromes are known to be mediated by DNA repair deficiencies that ultimately generate elevated somatic mutation rates. The results presented here show that in some of these syndromes all normal colorectal cells, and probably all cells in the body, have markedly elevated somatic mutation rates throughout life with mutational signatures not found in healthy individuals. Conversely, in other syndromes normal cells have normal mutation rates with standard mutational signatures but a small minority of cells acquire elevated mutation rates during the course of life. In both scenarios only a small proportion of cells with elevated mutation rates ever become adenomas or carcinomas. The results elucidate the different ways in which elevated somatic mutation rates due to DNA repair deficiencies lead to cancer and potentially offer a new modality contributing to clinical management of colorectal cancer susceptibility. They also provide a new perspective on the role of somatic mutations in ageing. Citation Format: Michael R. Stratton. The pathogenesis of cancer susceptibility due to inherited DNA repair defects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr PL02-01.