title: Genetic instability, CpG island methylator phenotype, and proliferative activity are distinct differences between diminutive and small tubular adenoma of the colorectum.
abstract: It is recommended that small (6-10 mm) lesions be treated with endoscopic resection (ER), whereas diminutive (≤5 mm) lesions are not currently an indication for ER according to the Japanese guidelines. The aim of this study was to evaluate the molecular alterations, and therefore treatment indications, in diminutive versus small tubular adenoma (TA). We prospectively analyzed genetic instability, including microsatellite instability and loss of heterozygosity, methylation status, KRAS/BRAF mutations, and Ki-67 staining in 96 TAs without a villous component. Although no microsatellite instability was identified in either diminutive or small TAs, genetic instability was seen in small TAs (9.1%) but not diminutive TAs (P = .04). In addition, the low-level CpG island methylator phenotype (CIMP-L) was more frequently observed in small TAs (31.8%) than in diminutive TAs (P = .01). Thus, genetic instability and CIMP-L were associated with small TAs, and only CIMP-L was an independent predictive marker for small TAs (odds ratio, 3.29; P = .03). Intriguingly, the Ki-67 proliferative index tended to be higher in small TAs than in diminutive TAs (P = .06) and higher in TAs with CIMP-L than in those without CIMP (P = .08). KRAS mutations were seen in codon 12 in 5.2% of TAs, but no BRAF gene mutations were found. As the molecular events and proliferative activity for the progression may increase from diminutive to small TAs, small TAs should be treated with ER, whereas a "predict, resect, and discard" strategy may be acceptable in most diminutive lesions except flat and depressed-type lesions, in keeping with the current strategy in the West.
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Nando
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan. Electronic address: watarij@hyo-med.ac.jp.
authors.forename: Jiro
authors.initials: J
authors.lastname: Watari
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Chiyomi
authors.initials: C
authors.lastname: Ito
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Hara
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Yamasaki
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Okugawa
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kondo
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Kono
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Tozawa
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Tomita
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Ohda
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Oshima
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Fukui
authors.affiliation: Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Nagahide
authors.initials: N
authors.lastname: Matsubara
authors.affiliation: Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Tomita
authors.affiliation: Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Hirota
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Miwa
mesh_terms: D000236:Adenoma / Q000737:chemistry / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D018256:Adenomatous Polyps / Q000737:chemistry / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D001706:Biopsy; D049109:Cell Proliferation; D003111:Colonic Polyps / Q000737:chemistry / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D003113:Colonoscopy; D015179:Colorectal Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D018899:CpG Islands; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D018450:Disease Progression; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis; D019656:Loss of Heterozygosity; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011446:Prospective Studies; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D047368:Tumor Burden
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D019394:Ki-67 Antigen; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras)
keywords: BRAF; Colorectal tubular adenoma; CpG island methylator phenotype; Genetic instability; KRAS