title: Germline mutations in oncogene-induced senescence pathways are associated with multiple sessile serrated adenomas.
abstract: OBJECTIVE
  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.
authors: Manish K
authors: MK
authors: Gala
authors: Yusuke
authors: Y
authors: Mizukami
authors: Long P
authors: LP
authors: Le
authors: Kentaro
authors: K
authors: Moriichi
authors: Thomas
authors: T
authors: Austin
authors: Masayoshi
authors: M
authors: Yamamoto
authors: Gregory Y
authors: GY
authors: Lauwers
authors: Nabeel
authors: N
authors: Bardeesy
authors: Daniel C
authors: DC
authors: Chung
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D018256:Adenomatous Polyps / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D051017:Apoptosis Regulatory Proteins; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D016022:Case-Control Studies; D016922:Cellular Senescence / Q000235:genetics*; D018389:Codon, Nonsense; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D004265:DNA Helicases / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D023281:Genomics; D018095:Germ-Line Mutation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D050720:Retinoblastoma-Like Protein p107 / Q000235:genetics; D017422:Sequence Analysis, DNA; D044767:Ubiquitin-Protein Ligases; D018631:ras Proteins / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D018389:Codon, Nonsense; D004268:DNA-Binding Proteins; C409823:ETV7 protein, human; D005819:Genetic Markers; D047908:Intracellular Signaling Peptides and Proteins; C117307:KRAS protein, human; D009363:Neoplasm Proteins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; C493844:RBL1 protein, human; D050720:Retinoblastoma-Like Protein p107; C417551:XAF1 protein, human; C496945:RNF43 protein, human; D044767:Ubiquitin-Protein Ligases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D004265:DNA Helicases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; C508765:PIF1 protein, human