Distinct Molecular Features of Different Macroscopic Subtypes of Colorectal Neoplasms

<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

Macroscopic subtypes in colorectal tumorigenesis.

<p>Precursor lesions can progress to cancer through the acquisition of epigenetic or genetic changes. Tumors from each subtype exhibit different characteristics, including their underlying molecular and genetic defects. However, whether small flat-elevated neoplasms can progress to other subtypes of CRNs remains unknown. PN, Polypoid neoplasm; LST-G, granular type laterally spreading tumor; LST-NG, non-granular type laterally spreading tumor; S-FN, small flat-elevated neoplasm; DN, depressed neoplasm.</p

Clinicopathological and molecular characteristics among different macroscopic subtypes of CRNs.

<p>*, P values were calculated by Chi-square test or Kruskal-Wallis test. PN, polypoid neoplasm; LST-G, granular type laterally spreading tumor; LST-NG, non-granular type LST; DN, depressed neoplasm; proximal, cecum, ascending and transverse colon; distal, descending and sigmoid colon, and rectum; LGD, low grade dysplasia; HGD, high grade dysplasia; MSI-H, high frequency microsatellite instability; CIMP, CpG island methylator phenotype; Mut+, presence of mutation; Mut-, absence of mutation.</p

Clinicopathological features of colorectal neoplasms.

<p>*, all cases were submucosal cancers. Proximal, cecum, ascending and transverse colon; distal, descending and sigmoid colon, and rectum; LGD, low grade dysplasia; HGD, high grade dysplasia; PN, polypoid neoplasm; LST-G, granular type laterally spreading tumor; LST-NG, non-granular type LST; S-FN, small flat-elevated neoplasm; DN, depressed neoplasm; NA, not applicable.</p