e15737 Background: Colon adenocarcinoma is biologically heterogeneous and is commonly summarized using binary tumor sidedness. While clinically convenient, this framework may obscure more granular anatomic variation, particularly within the proximal colon. We examined whether key molecular phenotypes vary across specific proximal colonic segments using uniformly annotated phenotype data from The Cancer Genome Atlas (TCGA). Methods: Colon adenocarcinoma cases from the TCGA-COAD cohort with annotated anatomic tumor location were evaluated. Analyses were restricted to proximal colonic segments (cecum, ascending colon, hepatic flexure, transverse colon). To ensure uniform comparability across molecular features, analyses were limited to tumors with complete annotation for all evaluated phenotypes, including hypermutation status, mismatch repair (MMR) protein loss by immunohistochemistry, MLH1 silencing, and CpG island methylator phenotype (CIMP). Differences in age at diagnosis across segments were assessed using one-way analysis of variance (ANOVA). Segment-level differences in molecular phenotypes were assessed using chi-square testing. Age- and stage-adjusted analyses were performed using regression models to evaluate whether observed segment-level differences persisted after adjustment. Results: The final analytic cohort included 68 proximal colon tumors with complete molecular phenotype annotation. Age at diagnosis did not differ significantly across proximal colonic segments (one-way ANOVA, p = 0.15), and pathologic stage distribution was similar across segments (χ² = 5.25, p = 0.81). In unadjusted analyses, segment-level heterogeneity was observed for hypermutation (χ² = 9.34, p = 0.025) and MLH1 silencing (χ² = 8.10, p = 0.044), with prevalence increasing from the cecum to the ascending colon and peaking at the hepatic flexure, followed by lower prevalence in the transverse colon. CIMP-high status (χ² = 5.69, p = 0.13) and MMR protein loss (χ² = 2.47, p = 0.48) did not demonstrate statistically significant segment-level differences. After adjustment for age, the association between segment and hypermutation was attenuated to trend level (p = 0.059). In contrast, after adjustment for pathologic stage, segment-level differences in hypermutation (p = 0.041) and MLH1 silencing (p = 0.039) remained statistically significant. Conclusions: Colon adenocarcinoma exhibits clinically relevant molecular heterogeneity within the proximal colon that is not captured by binary sidedness classifications. Hypermutation status and MLH1 silencing vary significantly across proximal colonic segments independent of tumor stage, with enrichment at the hepatic flexure. These findings support a more granular, segment-based model of colon cancer biology and suggest that anatomic factors unique to specific proximal segments may contribute to observed molecular heterogeneity.
Osmani et al. (Thu,) studied this question.