title: A novel pit pattern identifies the precursor of colorectal cancer derived from sessile serrated adenoma.
abstract: OBJECTIVE
  Sessile serrated adenomas (SSAs) are known to be precursors of sporadic colorectal cancers (CRCs) with microsatellite instability (MSI), and to be tightly associated with BRAF mutation and the CpG island methylator phenotype (CIMP). Consequently, colonoscopic identification of SSAs has important implications for preventing CRCs, but accurate endoscopic diagnosis is often difficult. Our aim was to clarify which endoscopic findings are specific to SSAs.
  
  
  METHODS
  The morphological, histological and molecular features of 261 specimens from 226 colorectal tumors were analyzed. Surface microstructures were analyzed using magnifying endoscopy. Mutation in BRAF and KRAS was examined by pyrosequencing. Methylation of p16, IGFBP7, MLH1 and MINT1, -2, -12 and -31 was analyzed using bisulfite pyrosequencing.
  
  
  RESULTS
  Through retrospective analysis of a training set (n=145), we identified a novel surface microstructure, the Type II open-shape pit pattern (Type II-O), which was specific to SSAs with BRAF mutation and CIMP. Subsequent prospective analysis of an independent validation set (n=116) confirmed that the Type II-O pattern is highly predictive of SSAs (sensitivity, 65.5%; specificity, 97.3%). BRAF mutation and CIMP occurred with significant frequency in Type II-O-positive serrated lesions. Progression of SSAs to more advanced lesions was associated with further accumulation of aberrant DNA methylation and additional morphological changes, including the Type III, IV and V pit patterns.
  
  
  CONCLUSIONS
  Our results suggest the Type II-O pit pattern is a useful hallmark of the premalignant stage of CRCs with MSI and CIMP, which could serve to improve the efficacy of colonoscopic surveillance.
authors.affiliation: Department of Gastroenterology, Akita Red Cross Hospital, Akita, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Kimura
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Yamamoto
authors.forename: Hiro-O
authors.initials: HO
authors.lastname: Yamano
authors.forename: Hiromu
authors.initials: H
authors.lastname: Suzuki
authors.forename: Seiko
authors.initials: S
authors.lastname: Kamimae
authors.forename: Masanori
authors.initials: M
authors.lastname: Nojima
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sawada
authors.forename: Masami
authors.initials: M
authors.lastname: Ashida
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Yoshikawa
authors.forename: Ryo
authors.initials: R
authors.lastname: Takagi
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Kato
authors.forename: Taku
authors.initials: T
authors.lastname: Harada
authors.forename: Ryo
authors.initials: R
authors.lastname: Suzuki
authors.forename: Reo
authors.initials: R
authors.lastname: Maruyama
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kai
authors.forename: Kohzoh
authors.initials: K
authors.lastname: Imai
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Shinomura
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Sugai
authors.forename: Minoru
authors.initials: M
authors.lastname: Toyota
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000473:pathology*; D000368:Aged; D000704:Analysis of Variance; D016009:Chi-Square Distribution; D003113:Colonoscopy; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D010641:Phenotype; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology*; D011237:Predictive Value of Tests; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012372:ROC Curve; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins