Germline Mutations in Oncogene-Induced Senescence Pathways Are Associated With Multiple Sessile Serrated Adenomas

Abstract

Background & Aims Little is known about the genetic factors that contribute to development of sessile serrated adenomas (SSAs). SSAs contain somatic mutations in BRAF or KRAS early in development. However, evidence from humans and mouse models indicates that these mutations result in oncogene-induced senescence (OIS) of intestinal crypt cells. Progression to serrated neoplasia requires cells to escape OIS, via inactivation of tumor suppressor pathways. We investigated whether individuals with multiple SSAs carry germline loss-of-function mutations (nonsense and splice-site) in genes that regulate OIS – the p16–Rb and ATM–ATR DNA damage response pathways. Methods Through bioinformatic analysis of the literature, we identified a set of genes that function at main nodes of the p16–Rb and ATM–ATR DNA damage response pathways. We performed whole-exome sequencing of 20 unrelated individuals with multiple SSAs; most had features of serrated polyposis. We compared sequences with those from 4300 individuals, matched for ethnicity (controls). We also used an integrative genomics approach to identify additional genes involved in senescence mechanisms. Results We identified mutations in genes that regulate senescence (ATM, PIF1, TELO2, XAF1, and RBL1) in 5/20 individuals with multiple SSAs (odds ratio [OR]=3.0; 95% confidence interval [CI], 0.9–8.9; P=.04). In 2 individuals, we found nonsense mutations in RNF43, indicating that it is also associated with multiple serrated polyps (OR=460; 95% CI, 23.1– 16384; P=6.8×10−5). In knockdown experiments with pancreatic duct cells exposed to ultraviolet light, RNF43 appeared to function as a regulator of ATM–ATR DNA damage response. Conclusions We associated germline loss-of-function variants in genes that regulate senescence pathways with the development of multiple SSAs. We identified RNF43 as a regulator of the DNA damage response, and associated nonsense variants in this gene with high risk of developing SSAs.

Association Between Screen-Detected Gallstone Disease and Cancer in a Cohort Study

“…58 A number of mutations in genes resulting in oncogene-induced senescence have also been associated with sessile serrated adenomas. 59 These mechanisms could be considered in future searches of gallstone formation mechanisms.…”

Genetics and Genetic Testing in Hereditary Colorectal Cancer

“…Although one study reported germline mutations in genes in the "oncogene-induced senescence" pathway, 52 and Cowden Syndrome and biallelic MutYH mutations have been reported in some individuals meeting WHO criteria for serrated polyposis, 53 clinical genetic testing has a low yield.…”

Serrated and Non-Serrated Precursor Lesions of Colorectal Cancer

“…BRAF mutations have been identified in the majority of lesions, but mutations in the KRAS gene also occur [54]. Very recently, germline mutations in genes that regulate senescence pathways (ATM, PIF1, TELO2, XAF1, and RBL1) have been associated with the occurrence of multiple SSA/Ps and the serrated polyposis syndrome [55], but data are still limited.…”