# Genomic characterization of colorectal tumors: insights into significantly mutated genes, pathways, and survival outcomes

## TL;DR

This study identifies 57 significantly mutated genes in colorectal cancer, including 9 new ones, and finds that BRAF p.V600E mutations are linked to worse survival.

## Contribution

The study reports 9 previously unreported significantly mutated genes in colorectal cancer and provides survival associations for BRAF p.V600E and key pathways.

## Key findings

- 57 significantly mutated genes were identified in colorectal cancer, including 9 not previously reported.
- BRAF p.V600E mutations were strongly associated with poorer disease-specific survival, especially in non-hypermutated tumors.
- Four pathways (TP53/ATM, RTK/RAS, TGF-beta, and WNT) showed statistically significant associations with survival.

## Abstract

Identifying significantly mutated genes in tumors aids in understanding disease etiology and survival and may aid in the discovery of new drug targets. We aimed to detect and characterize mutated genes from a large, well-characterized group of colorectal cancers.

In tumor and paired normal samples from 6,111 colorectal patients, we sequenced 199 genes identified from whole exome sequencing of over 1,100 tumors. Analyses focused on non-silent mutations. We classified significantly mutated genes after stratification by hypermutation status, and estimated associations of mutated genes/pathways with disease-specific (DS)-survival using Cox regression, adjusting for age, sex, mutation burden, hypermutation status, and study while accounting for multiple comparisons (n = 4,874).

We identified 57 genes that were significantly mutated in colorectal cancer, including 9 that were not previously reported. Among individual genes, only BRAF p.V600E mutations were significantly associated with poorer survival after correction for multiple testing (HR 1.96, P = 2.07 × 10− 10), with a more pronounced association among those with non-hypermutated tumors (HR 2.24, P = 1.79 × 10− 12). We also observed statistically significant associations with survival for four mutated pathways: TP53/ATM (HR 1.24, P = 7.96 × 10− 4), RTK/RAS (HR 1.33, P = 3.81 × 10− 6), TGF-beta (HR 1.25, P = 1.85 × 10− 3), and WNT (HR 0.81, P = 2.52 × 10− 03).

We identified 9 significantly mutated genes, some of which are known drug targets. Among individual genes, only the BRAF p.V600E mutation was significantly associated with DS-survival, suggesting a limited survival impact from mutations driving colorectal cancer development.

The online version contains supplementary material available at 10.1186/s12885-025-15440-x.