title: Distinct molecular features of different macroscopic subtypes of colorectal neoplasms.
abstract: BACKGROUND
  Colorectal adenoma develops into cancer with the accumulation of genetic and epigenetic changes. We studied the underlying molecular and clinicopathological features to better understand the heterogeneity of colorectal neoplasms (CRNs).
  
  
  METHODS
  We evaluated both genetic (mutations of KRAS, BRAF, TP53, and PIK3CA, and microsatellite instability [MSI]) and epigenetic (methylation status of nine genes or sequences, including the CpG island methylator phenotype [CIMP] markers) alterations in 158 CRNs including 56 polypoid neoplasms (PNs), 25 granular type laterally spreading tumors (LST-Gs), 48 non-granular type LSTs (LST-NGs), 19 depressed neoplasms (DNs) and 10 small flat-elevated neoplasms (S-FNs) on the basis of macroscopic appearance.
  
  
  RESULTS
  S-FNs showed few molecular changes except SFRP1 methylation. Significant differences in the frequency of KRAS mutations were observed among subtypes (68% for LST-Gs, 36% for PNs, 16% for DNs and 6% for LST-NGs) (P<0.001). By contrast, the frequency of TP53 mutation was higher in DNs than PNs or LST-Gs (32% vs. 5% or 0%, respectively) (P<0.007). We also observed significant differences in the frequency of CIMP between LST-Gs and LST-NGs or PNs (32% vs. 6% or 5%, respectively) (P<0.005). Moreover, the methylation level of LINE-1 was significantly lower in DNs or LST-Gs than in PNs (58.3% or 60.5% vs. 63.2%, P<0.05). PIK3CA mutations were detected only in LSTs. Finally, multivariate analyses showed that macroscopic morphologies were significantly associated with an increased risk of molecular changes (PN or LST-G for KRAS mutation, odds ratio [OR] 9.11; LST-NG or DN for TP53 mutation, OR 5.30; LST-G for PIK3CA mutation, OR 26.53; LST-G or DN for LINE-1 hypomethylation, OR 3.41).
  
  
  CONCLUSIONS
  We demonstrated that CRNs could be classified into five macroscopic subtypes according to clinicopathological and molecular differences, suggesting that different mechanisms are involved in the pathogenesis of colorectal tumorigenesis.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Konda
authors.affiliation: Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Konishi
authors.affiliation: Department of Pathology, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Toshiko
authors.initials: T
authors.lastname: Yamochi
authors.affiliation: Department of Biostatistics, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Yoichi M
authors.initials: YM
authors.lastname: Ito
authors.affiliation: Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Hisako
authors.initials: H
authors.lastname: Nozawa
authors.affiliation: Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tojo
authors.affiliation: Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Shinmura
authors.affiliation: Department of Hospital Pharmaceutics, Showa University School of Pharmacy, Tokyo, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Kogo
authors.affiliation: Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Katagiri
authors.affiliation: Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Yutaro
authors.initials: Y
authors.lastname: Kubota
authors.affiliation: Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Muramoto
authors.affiliation: Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Yano
authors.affiliation: Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Kihara
authors.affiliation: Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Teppei
authors.initials: T
authors.lastname: Tagawa
authors.affiliation: Clinical Collaborating laboratory, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Makino
authors.affiliation: Department of Pathology, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takimoto
authors.affiliation: Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Michio
authors.initials: M
authors.lastname: Imawari
authors.affiliation: Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yoshida
mesh_terms: D000236:Adenoma / Q000145:classification / Q000235:genetics* / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058534:Class I Phosphatidylinositol 3-Kinases; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology*; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
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