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Published on: July 28, 2010
Germline mutations in oncogene-induced senescence pathways are associated with multiple sessile serrated adenomas
Background & Aims:
Little is known about the genetic factors that contribute to the 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 subjects 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 a bioinformatic analysis of the literature, we identified a set of genes that function at the main nodes of the p16-Rb and ATM-ATR DNA damage response pathways. We performed whole-exome sequencing of 20 unrelated subjects with multiple SSAs; most had features of serrated polyposis. We compared sequences with those from 4300 subjects 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 of 20 subjects with multiple SSAs (odds ratio, 3.0; 95% confidence interval, 0.9–8.9; P =.04). In 2 subjects,we found nonsense mutations in RNF43, indicating that it is also associated with multiple serrated polyps (odds ratio, 460; 95% confidence interval, 23.1–16,384; P = 6.8 x 10(-5)). In knockdown experiments with pancreatic duct cells exposed to UV light, RNF43 appeared to function as a regulator of ATMATRDNA 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 a high risk of developing SSAs.
Insights
Germline mutations in senescence pathways are linked to multiple sessile serrated adenomas (SSAs). RNF43 nonsense variants significantly increase SSA risk by regulating DNA damage response.
Area of Science:
- Genetics and Genomics
- Oncology
- Molecular Biology
Background:
- Sessile serrated adenomas (SSAs) develop early with BRAF/KRAS mutations, but progression requires escaping oncogene-induced senescence (OIS).
- Tumor suppressor pathways are often inactivated to facilitate serrated neoplasia progression.
- Germline genetic factors predisposing to multiple SSAs remain largely unknown.
Purpose of the Study:
- To investigate whether individuals with multiple SSAs harbor germline loss-of-function mutations in genes regulating OIS.
- To examine the roles of the p16-Rb and ATM-ATR DNA damage response pathways in SSA development.
- To identify novel genetic contributors to multiple SSA formation.
Main Methods:
- Bioinformatic literature analysis to identify key genes in senescence pathways.
- Whole-exome sequencing of 20 unrelated subjects with multiple SSAs and serrated polyposis features.
- Comparison of exome sequences with 4300 ethnically matched controls.
- Integrative genomics to identify additional senescence-related genes.
Main Results:
- Mutations in senescence-regulating genes (ATM, PIF1, TELO2, XAF1, RBL1) were found in 5 of 20 subjects with multiple SSAs (OR, 3.0; P = .04).
- Nonsense mutations in RNF43 were identified in 2 subjects, strongly associating it with multiple serrated polyps (OR, 460; P = 6.8 x 10(-5)).
- RNF43 demonstrated a role in regulating the ATM-ATR DNA damage response in knockdown experiments.
Conclusions:
- Germline loss-of-function variants in senescence pathway genes are associated with the development of multiple SSAs.
- RNF43 is identified as a novel regulator of the DNA damage response.
- Nonsense variants in RNF43 confer a significantly high risk for developing SSAs.
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