Distinct Molecular Features of Different Macroscopic Subtypes of Colorectal Neoplasms

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.

Mutational profiles of different macroscopic subtypes of colorectal adenoma reveal distinct pathogenetic roles for KRAS, BRAF and PIK3CA

“…Previous studies for these tumors showed no mutations in KRAS and high frequencies of p53 expression by immunohistochemistry [ 37 ]. Through PCR-based pyrosequencing, Konda et al have reported that mutation in KRAS and BRAF occurred in 16% and 11% of depressed colorectal neoplasms respectively [ 39 ]. There was a discrepancy between this study and ours.…”

The Features of Colorectal Tumors in a Patient with Li-Fraumeni Syndrome

“…This is in contrast to familial adenomatous polyposis, in which the tumors are pedunculated or semi-pedunculated. Recently, Konda et al reported that the frequency of TP53 mutations was higher in LST-NGs and depressed neoplasms than in polypoid neoplasms, while K-ras mutations were less frequent (12). Furthermore, some reports have noted that the frequency of K-ras mutations is lower in LST-NG than in LST-G and polypoid adenomas.…”

Functional Characterization and Drug Response of Freshly Established Patient-Derived Tumor Models with CpG Island Methylator Phenotype

“…CpG island DNA methylation occurs early in malignant transformation [ 2 ] and consequently results in silencing of normal tumor-suppressor function and cancer formation, independent of (physiological) age-related methylation. The CIMP subtype exists with and without MSI, both showing distinct morphologic, molecular and most importantly, clinical characteristics [ 3 ]. MSI-high/CIMP + tumors, related to BRAF V600E mutations and MLH1 promoter methylation, are usually associated with low cancer-specific mortality, mostly due to their natural immunogenicity [ 3 ].…”

“…The CIMP subtype exists with and without MSI, both showing distinct morphologic, molecular and most importantly, clinical characteristics [ 3 ]. MSI-high/CIMP + tumors, related to BRAF V600E mutations and MLH1 promoter methylation, are usually associated with low cancer-specific mortality, mostly due to their natural immunogenicity [ 3 ]. By contrast, CIMP without MSI is independently related to significantly worse outcome [ 3 – 5 ].…”

“…MSI-high/CIMP + tumors, related to BRAF V600E mutations and MLH1 promoter methylation, are usually associated with low cancer-specific mortality, mostly due to their natural immunogenicity [ 3 ]. By contrast, CIMP without MSI is independently related to significantly worse outcome [ 3 – 5 ]. The unique molecular signature includes a high frequency of KRAS mutations (>60%) and usually less extensive promoter methylation (designated as "CIMP-Low” vs. CIMP-High in MSI + tumors) [ 6 – 8 ].…”