Differences in Somatic Mutations Between Early-Onset and Late-Onset Colorectal Cancer: A Systematic Review and Meta-Analysis
5 affiliations
- 1Department of Colorectal Surgery, Singapore General Hospital, Singapore 169608, Singapore
- 2Health Services Research Unit, Singapore General Hospital, Singapore 169608, Singapore
- 3Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore 138672, Singapore
- 4Department of Sarcoma, Peritoneal and Rare Tumors (SPRinT), Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, Singapore 168583, Singapore
- 5Division of Medical Oncology, National Cancer Centre Singapore, Singapore 168583, Singapore
Abstract
Background: Early-onset colorectal cancer (EOCRC, diagnosed <50 years) is increasing globally and presents with advanced clinicopathological features, yet its mutational landscape compared to late-onset CRC (LOCRC) remains poorly defined. Methods: We systematically searched PubMed and Embase (January 2016–December 2025) for studies comparing somatic mutations between EOCRC and LOCRC. Two reviewers independently screened 1880 records; 43 studies met inclusion criteria. Two public datasets (TCGA, China PanCancer) were also included. Meta-analyses were conducted using random-effects models with Review Manager. Subgroup analysis was restricted to microsatellite-stable (MSS) tumors. Meta-regression evaluated study-level differences in tumor sidedness and stage distribution as sources of heterogeneity. The primary outcome was odds ratios (OR) for mutations in 10 driver genes. Results: Among 154,982 participants, 33,937 (21.9%) had EOCRC. In the overall analysis, EOCRC showed higher frequencies of TP53 (OR 1.13), SMAD4 (OR 1.15), and PTEN mutations (OR 1.77), and lower frequencies of APC (OR 0.73), KRAS (OR 0.94), and BRAF mutations (OR 0.69). In MSS-restricted analysis, differences persisted for TP53, SMAD4, APC, and KRAS, whereas PTEN and BRAF differences became non-significant. Additionally, NRAS (OR 0.74) and PIK3CA mutations (OR 0.89) were less frequent in MSS-EOCRC. Meta-regression showed that study-level differences in left-sided tumor distribution were associated with lower relative BRAF mutation frequency in EOCRC (β = −5.08, 95% CI −7.66 to −2.49, p < 0.001). Conclusions: EOCRC exhibits a different mutational profile with higher TP53 and SMAD4 and lower APC and KRAS mutations. These findings highlight the need for further research into alternative mechanisms of CRC carcinogenesis among younger adults.
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BibTeX
@article{chen2026differences,
title = {{Differences in Somatic Mutations Between Early-Onset and Late-Onset Colorectal Cancer: A Systematic Review and Meta-Analysis}},
author = {Hui Lionel Raphael Chen and Jun Yan Ian Wee and Jun Kiat Thaddaeus Tan and Wei Ming Aaron Seah and Anders Jacobsen Skanderup and Chin-Ann Johnny Ong and Han Chong Toh and Kwong-Wei Emile Tan and Bee Huat Iain Tan},
journal = {Cancers},
year = {2026},
month = oct,
doi = {10.3390/cancers18193225},
url = {https://europepmc.org/article/PMC/PMC13664542},
note = {CC BY},
}
RIS
TY - JOUR
TI - Differences in Somatic Mutations Between Early-Onset and Late-Onset Colorectal Cancer: A Systematic Review and Meta-Analysis
AU - Hui Lionel Raphael Chen
AU - Jun Yan Ian Wee
AU - Jun Kiat Thaddaeus Tan
AU - Wei Ming Aaron Seah
AU - Anders Jacobsen Skanderup
AU - Chin-Ann Johnny Ong
AU - Han Chong Toh
AU - Kwong-Wei Emile Tan
AU - Bee Huat Iain Tan
PY - 2026
DA - 2026/10/01
JO - Cancers
DO - 10.3390/cancers18193225
UR - https://europepmc.org/article/PMC/PMC13664542
AB - Background: Early-onset colorectal cancer (EOCRC, diagnosed <50 years) is increasing globally and presents with advanced clinicopathological features, yet its mutational landscape compared to late-onset CRC (LOCRC) remains poorly defined. Methods: We systematically searched PubMed and Embase (January 2016–December 2025) for studies comparing somatic mutations between EOCRC and LOCRC. Two reviewers independently screened 1880 records; 43 studies met inclusion criteria. Two public datasets (TCGA, China PanCancer) were also included. Meta-analyses were conducted using random-effects models with Review Manager. Subgroup analysis was restricted to microsatellite-stable (MSS) tumors. Meta-regression evaluated study-level differences in tumor sidedness and stage distribution as sources of heterogeneity. The primary outcome was odds ratios (OR) for mutations in 10 driver genes. Results: Among 154,982 participants, 33,937 (21.9%) had EOCRC. In the overall analysis, EOCRC showed higher frequencies of TP53 (OR 1.13), SMAD4 (OR 1.15), and PTEN mutations (OR 1.77), and lower frequencies of APC (OR 0.73), KRAS (OR 0.94), and BRAF mutations (OR 0.69). In MSS-restricted analysis, differences persisted for TP53, SMAD4, APC, and KRAS, whereas PTEN and BRAF differences became non-significant. Additionally, NRAS (OR 0.74) and PIK3CA mutations (OR 0.89) were less frequent in MSS-EOCRC. Meta-regression showed that study-level differences in left-sided tumor distribution were associated with lower relative BRAF mutation frequency in EOCRC (β = −5.08, 95% CI −7.66 to −2.49, p < 0.001). Conclusions: EOCRC exhibits a different mutational profile with higher TP53 and SMAD4 and lower APC and KRAS mutations. These findings highlight the need for further research into alternative mechanisms of CRC carcinogenesis among younger adults.
SN - 2072-6694
ER -