Distinct Molecular Features of Different Macroscopic Subtypes of Colorectal Neoplasms

Abstract

<div><p>Background</p><p>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).</p><p>Methods</p><p>We evaluated both genetic (mutations of <i>KRAS</i>, <i>BRAF</i>, <i>TP53</i>, and <i>PIK3CA</i>, 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.</p><p>Results</p><p>S-FNs showed few molecular changes except <i>SFRP1</i> methylation. Significant differences in the frequency of <i>KRAS</i> 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 <i>TP53</i> 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). <i>PIK3CA</i> 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 <i>KRAS</i> mutation, odds ratio [OR] 9.11; LST-NG or DN for <i>TP53</i> mutation, OR 5.30; LST-G for <i>PIK3CA</i> mutation, OR 26.53; LST-G or DN for LINE-1 hypomethylation, OR 3.41).</p><p>Conclusion</p><p>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.</p></div