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.
Objective-The withdrawal of cerivastatin involved an uncommon but serious adverse reaction, rhabdomyolysis. The bimodal response--rhabdomyolysis in a small proportion of users--points to genetic factors as a potential cause. We conducted a case-control study to evaluate genetic markers for cerivastatin-associated rhabdomyolysis.Methods-The study had two components: a candidate gene study to evaluate variants in CYP2C8, UGT1A1, UGT1A3, and SLCO1B1; and a genome-wide association (GWA) study to identify risk factors in other regions of the genome. 185 rhabdomyolysis cases were frequency matched to statin-using controls from the Cardiovascular Health Study (n=374) and the Heart and Vascular Health Study (n=358). Validation relied on functional studies.Results-Permutation test results suggested an association between cerivastatin-associated rhabdomyolysis and variants in SLCO1B1 (p = 0.002), but not variants in CYP2C8 (p = 0.073) or the UGTs (p = 0.523). An additional copy of the minor allele of SLCO1B1 rs4149056 (p.Val174Ala) was associated with the risk of rhabdomyolysis (OR: 1.89, 95% CI: 1.40 to 2.56). In transfected cells, this variant reduced cerivastatin transport by 40% compared with the reference transporter (p < 0.001). The GWA identified an intronic variant (rs2819742) in the ryanodine receptor 2 gene (RYR2) as significant (p=1.74E-07). An additional copy of the minor allele of the This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.