Early vs late onset primary colon adenocarcinoma: Gene expression dependent overall survival in chemotherapy treated TCGA-COAD patients.

Abstract

233 Background: Early-onset (EO, <50y) and late-onset (LO, ≥50y) colorectal cancers differ biologically and prognostically. APC, PTEN, TP53, and BRAF are commonly mutated genes that drive prognosis in colorectal adenocarcinoma. Whether varied tumor RNA expression of these genes significantly affects overall survival (OS) differently between EO and LO in chemotherapy-treated colon adenocarcinoma is unclear. Methods: Clinical and STAR RNA expression counts data of 423 TCGA-COAD patients receiving chemotherapy for primary colon adenocarcinoma were collected. STAR counts were TMM-normalized and log₂-CPM transformed. Each gene’s expression was stratified into quartiles (Q1–Q4). OS associations were estimated using univariate and multivariate Cox models with EO vs LO age group, sex, and race as covariates. Kaplan–Meier analyses with pairwise log-rank comparisons supported quartile effects. Results: There were 58 (13.7%) EO and 365 (86.3%) LO patients. In multivariable models adjusted for age, sex, and race, we observed non-linear, gene-specific associations with OS. APC: higher expression associated with markedly worse OS (Q4 vs Q1 HR 20.2, 95% CI 8.83–46.1; p<0.001; Q2 HR 2.79, 1.75–4.45; p<0.001). PTEN: A Q2 protective (HR 0.30, 0.19–0.49; p<0.001), but Q3 harmful (HR 2.01, 1.16–3.48; p=0.013) U-shape pattern. TP53: high expression harmful (Q4 HR 2.95, 1.74–5.00; p<0.001) while Q3 was protective (HR 0.55, 0.32–0.97; p=0.038). BRAF: Q3 was protective (HR 0.30, 0.15–0.60; p<0.001). Age of onset: LO was consistently associated with significantly worse OS vs EO across gene-specific models (HR ~11.0–28.5), indicating strong baseline hazard differences by age group. Sex: male sex conferred significantly higher hazard (HR ~2.2–2.9; p<0.001). Race effects were non-significant. Conclusions: In chemotherapy-treated colon adenocarcinoma, age of onset is a major prognostic survival factor and, after adjustment, APC, PTEN, TP53, and BRAF expression show distinct, non-linear relationships with OS. Signals include APC-linked risk at high expression, PTEN U-shape, TP53 worse outcome at high expression with mid expression level protection, and BRAF mid-quartile protection. At the quartile level, there are distinct gene expression prognostic differences between EO and LO patients which must be further explored in future studies.