title: MUC5AC/β-catenin expression and KRAS gene alteration in laterally spreading colorectal tumors.
abstract: OBJECTIVE
  To clarify differences in mucin phenotype, proliferative activity and oncogenetic alteration among subtypes of colorectal laterally spreading tumor (LST).
  
  
  METHODS
  LSTs, defined as superficial elevated lesions greater than 10 mm in diameter with a low vertical axis, were macroscopically classified into two subtypes: (1) a granular type (Gr-LST) composed of superficially spreading aggregates of nodules forming a flat-based lesion with a granulonodular and uneven surface; and (2) a non-granular type (NGr-LST) with a flat smooth surface and an absence of granulonodular formation. A total of 69 LSTs, comprising 36 Gr-LSTs and 33 NGr-LSTs, were immunohistochemically stained with MUC2, MUC5AC, MUC6, CD10 (markers of gastrointestinal cell lineage), p53, β-catenin and Ki-67 antibodies, and examined for alteration in exon 1 of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and exon 15 of v-raf murine sarcoma viral oncogene homologue B1 (BRAF) by polymerase chain reaction followed by direct sequencing.
  
  
  RESULTS
  Histologically, 15 Gr-LST samples were adenomas with low-grade dysplasia (LGD), 12 were high-grade dysplasia (HGD) and 9 were adenocarcinomas invading the submucosa (INV), while 12 NGr-LSTs demonstrated LGD, 14 HGD and 7 INV. In the proximal colon, MUC5AC expression was significantly higher in the Gr-type than the NGr-type. MUC6 was expressed only in NGr-LST. MUC2 or CD10 did not differ. P53 expression demonstrated a significant stepwise increment in progression through LGD-HGD-INV with both types of LST. Nuclear β-catenin expression was significantly higher in the NGr-type. Ki-67 expression was significantly higher in the Gr-type in the lower one third zone of the tumor. In proximal, but not distal colon tumors, the incidence of KRAS provided mutation was significantly higher in the Gr-type harboring a specific mutational pattern (G12V). BRAF mutations (V600E) were detected only in two Gr-LSTs.
  
  
  CONCLUSIONS
  The two subtypes of LST, especially in the proximal colon, have differing phenotypes of gastrointestinal cell lineage, proliferation and activation of Wnt/β-catenin or RAS/RAF/extracellular signal-regulated kinase signaling.
authors.affiliation: Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Kosaburo
authors.initials: K
authors.lastname: Nakae
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mitomi
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Saito
authors.forename: Michiko
authors.initials: M
authors.lastname: Takahashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Morimoto
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hidaka
authors.forename: Naoto
authors.initials: N
authors.lastname: Sakamoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Yao
authors.forename: Sumio
authors.initials: S
authors.lastname: Watanabe
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000236:Adenoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016158:Genes, p53; D006801:Humans; D007420:Intestine, Large / Q000473:pathology; D055271:Mucin 5AC / Q000235:genetics / Q000378:metabolism*; D055262:Mucin-2 / Q000235:genetics / Q000378:metabolism; D055272:Mucin-6 / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D051176:beta Catenin / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; C524625:MUC2 protein, human; C524678:MUC5AC protein, human; C524734:MUC6 protein, human; D055271:Mucin 5AC; D055262:Mucin-2; D055272:Mucin-6; D011518:Proto-Oncogene Proteins; D051176:beta Catenin; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: Adenoma-carcinoma sequence; Colon; Direct sequencing; Immunohistochemistry; Laterally spreading tumor; Mucin core protein; v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; β-catenin