# Characterization of the mutational landscapes in Japanese patients with early-onset colorectal cancer from comprehensive genomic profiling data

## TL;DR

This study compares genomic differences in early-onset and late-onset colorectal cancer in Japanese patients, finding specific mutations more common in younger patients.

## Contribution

Identifies distinct genomic alterations in early-onset CRC, suggesting potential therapeutic targets in Japanese patients.

## Key findings

- EoCRC patients had higher frequencies of SMAD4, FLT3, and CDK8 alterations compared to LoCRC patients.
- Cell cycle pathway alterations were significantly enriched in the EoCRC group.
- SMAD4 mutations were associated with poor prognosis in both EoCRC and LoCRC groups.

## Abstract

The incidence of early-onset colorectal cancer (EoCRC), defined as a CRC diagnosed in individuals younger than 50 years, has been increasing globally. The clinicopathological differences between EoCRC and late-onset CRC (LoCRC: diagnosed in individuals older than 50 years) are suggestive of distinct genomic landscapes. The aim of this study was to assess the differences in genomic alterations in Japanese patients with EoCRC and LoCRC from multiple institutions across Hokkaido using comprehensive genomic profiling data.

The patient’s background, CRC location, pathological findings, clinical stage at presentation, prognosis, and genomic alterations of the EoCRC and LoCRC groups were compared.

A total of 317 CRC patients were analyzed, including 61 with EoCRC and 256 with LoCRC. Right-sided CRC and differentiated histology were significantly less common in the EoCRC group. There was no significant difference in the median survival duration between the two groups. Genomic profiling revealed significantly higher frequency of SMAD4, FLT3, and CDK8 alterations in EoCRC patients compared to LoCRC patients (p = 0.016, p = 0.023, and p = 0.035, respectively). Cell cycle pathway alterations were also significantly enriched in the EoCRC group (p = 0.003). Additionally, SMAD4 mutations were associated with poor prognosis in both groups.

SMAD4, FLT3, and CDK8 alterations were significantly more prevalent in EoCRC patients, suggesting that these genes likely contribute to the distinct molecular pathogenesis of EoCRC, and may also serve as potential therapeutic targets. Further studies are warranted to elucidate their biological significance and explore their potential in the development of targeted therapies for Japanese patients with EoCRC.

The online version contains supplementary material available at 10.1007/s10147-025-02889-w.