Abstract
BackgroundColorectal 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).MethodsWe 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.ResultsS-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).ConclusionWe 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.
Highlights
Colorectal cancer (CRC) can develop via various molecular pathways
No significant differences in the clinicopathological features were observed between all colorectal neoplasms (CRNs) and those with high-grade dysplasia (HGD)/submucosal cancer (T1 cancer)
The frequency of TP53 mutation was higher in depressed neoplasms (DNs) than polypoid neoplasms (PNs) or laterally spreading tumors (LSTs)-Gs (DNs vs. PNs, P = 0.0066; DNs vs. LST-Gs, P = 0.0038, respectively)
Summary
Colorectal cancer (CRC) can develop via various molecular pathways. Most CRCs develop over a long period of time through a multistep process called the adenoma-carcinoma sequence [1]. The process of colorectal carcinogenesis often begins with the inactivation of the APC/b-catenin signaling pathway (the Vogelstein model), followed by KRAS and TP53 mutations [2]. Serrated adenomas (SAs), sessile serrated adenoma/polyps (SSA/Ps), have been described as the immediate precursors for CRCs that develop via an alternative pathway consisting of the CpG island methylator phenotype (CIMP) and BRAF mutations [3,4]. CIMP cancers may develop either via a mutator (microsatellite instability; MSI) pathway, or via a pathway that leads to microsatellite stability (MSS) [5]. 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)
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