Comparative genomic profiling of early-onset and late-onset colorectal cancer

Abstract

Objective: The increasing incidence of early-onset colorectal cancer (EO-CRC) has raised the question of whether these tumors exhibit different molecular characteristics from late-onset colorectal cancer (LO-CRC). We aimed to compare the somatic genomic profiles of EO-CRC and LO-CRC. Materials and Methods: Clinical and genomic data of patients diagnosed with colon adenocarcinoma, colorectal adenocarcinoma, and rectal adenocarcinoma from the AACR Project GENIE Cohort v20.0 database were retrospectively evaluated. Patients were divided into two groups based on age at diagnosis: early-onset (<50 years) and late-onset (≥50 years). The groups were compared in terms of demographic characteristics, number of mutations, altered genome fraction, and gene mutation frequencies. Multiple-testing correction was performed using the Benjamini–Hochberg method in the main analysis, genes with a mutation frequency ≥5% in at least one group were focused on. Results: A total of 23,410 samples from 22,142 patients were evaluated. TP53 (74.62% vs. 69.53%), APC (70.20% vs. 65.82%), and TCF7L2 (14.61% vs. 12.27%) mutations were more frequent in the EO-CRC group, while BRAF (7.16% vs. 13.55%) and RNF43 (6.98% vs. 10.80%) mutations were more frequent in the LO-CRC group (all q<0.01). Additionally, AXIN2, PLCG2, AMER1, MSH3, MGA, SOX9, and SPEN mutations were found to be significantly more frequent in the LO-CRC group. Conclusion: There are significant differences in somatic genomic profiles between early-onset and late-onset colorectal cancers. The more frequent occurrence of TP53, APC, and TCF7L2 mutations in EO-CRC, and BRAF and RNF43 mutations in LO-CRC, suggests that the relative contribution of molecular pathways involved in colorectal carcinogenesis may differ according to age. However, these findings do not support the evaluation of EO-CRC as a completely separate molecular disease based solely on age.