Original Article
Copyright ©2012 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Oct 21, 2012; 18(39): 5551-5559
Published online Oct 21, 2012. doi: 10.3748/wjg.v18.i39.5551
MUC5AC/β-catenin expression and KRAS gene alteration in laterally spreading colorectal tumors
Kosaburo Nakae, Hiroyuki Mitomi, Tsuyoshi Saito, Michiko Takahashi, Takashi Morimoto, Yasuhiro Hidaka, Naoto Sakamoto, Takashi Yao, Sumio Watanabe
Kosaburo Nakae, Takashi Morimoto, Yasuhiro Hidaka, Naoto Sakamoto, Sumio Watanabe, Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
Kosaburo Nakae, Hiroyuki Mitomi, Tsuyoshi Saito, Michiko Takahashi, Takashi Morimoto, Yasuhiro Hidaka, Takashi Yao, Department of Human Pathology, Juntendo University School of Medicine, 1-1-19 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Author contributions: Nakae K, Mitomi H, Yao T and Watanabe S designed research; Nakae K, Takahashi M, Morimoto T and Hidaka Y performed research; Mitomi H, Saito T and Sakamoto N analyzed data; Nakae K and Mitomi H wrote the paper.
Supported by A grant-in-aid for General Scientific Research from the Ministry of Education, Science, Sports and Culture to Hiroyuki Mitomi, No. 21590394; and to Tsuyoshi Saito, No. 23590434, Tokyo, Japan
Correspondence to: Hiroyuki Mitomi, MD, PhD, Department of Human Pathology, Juntendo University School of Medicine, Motomachi building 3F, 1-1-19 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. hmitomi@juntendo.ac.jp
Telephone: +81-3-58021037 Fax: +81-3-38121056
Received: January 19, 2012
Revised: May 18, 2012
Accepted: May 26, 2012
Published online: October 21, 2012
Abstract

AIM: 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.

CONCLUSION: 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.

Keywords: Laterally spreading tumor, Mucin core protein, Colon, β-catenin, Immunohistochemistry, v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog, Direct sequencing, Adenoma-carcinoma sequence