PLoS ONE (Jan 2014)

Distinct molecular features of different macroscopic subtypes of colorectal neoplasms.

  • Kenichi Konda,
  • Kazuo Konishi,
  • Toshiko Yamochi,
  • Yoichi M Ito,
  • Hisako Nozawa,
  • Masayuki Tojo,
  • Kensuke Shinmura,
  • Mari Kogo,
  • Atsushi Katagiri,
  • Yutaro Kubota,
  • Takashi Muramoto,
  • Yuichiro Yano,
  • Yoshiya Kobayashi,
  • Toshihiro Kihara,
  • Teppei Tagawa,
  • Reiko Makino,
  • Masafumi Takimoto,
  • Michio Imawari,
  • Hitoshi Yoshida

DOI
https://doi.org/10.1371/journal.pone.0103822
Journal volume & issue
Vol. 9, no. 8
p. e103822

Abstract

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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).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.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).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.