Distinct Molecular Features of Different Macroscopic Subtypes of Colorectal Neoplasms

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

来源：PLos One, 2014, 9(8): e103822.

DOI：10.1371/journal.pone.0103822

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). %26lt;br%26gt;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. %26lt;br%26gt;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%26lt;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%26lt;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%26lt;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%26lt;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). %26lt;br%26gt;Conclusion: 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.

• 出版日期2014-8-5