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. 2025 Sep;10(9):105756.
doi: 10.1016/j.esmoop.2025.105756. Epub 2025 Sep 1.

Early-onset colorectal cancer patients exhibit a distinct molecular fingerprint: insights from a large-scale NGS study of 1209 patients

A Pretta  1 , V Nasca  2 , F Marmorino  3 , R Intini  4 , P Ziranu  5 , G Randon  2 , M Carullo  3 , K Cerma  4 , C Donisi  5 , C Damonte  2 , A Taravella  3 , C Gaiani  6 , G Pretta  7 , V Pusceddu  5 , I Montroni  2 , P Ciracì  3 , A De Rosa  6 , F Bergamo  4 , S Lonardi  4 , C Cremolini  3 , F Pietrantonio  2 , M Scartozzi  5
Affiliations

Early-onset colorectal cancer patients exhibit a distinct molecular fingerprint: insights from a large-scale NGS study of 1209 patients

A Pretta et al. ESMO Open. 2025 Sep.

Abstract

Background: Early-onset colorectal cancer (EO-CRC, ≤50 years of age) exhibits unique clinical and biological characteristics when compared with average-onset CRC (AO-CRC), but its overall molecular profile is still not well studied.

Materials and methods: We retrospectively analysed 1209 patients with metastatic CRC profiled using FoundationOne® CDx, a clinically validated next-generation sequencing assay targeting 324 cancer-related genes. Patients were classified as EO-CRC (n = 298) or AO-CRC (n = 911). Genomic alterations, including amplifications, deletions, and point mutations, were compared between the groups. Overall survival (OS) was assessed through 1 : 1 propensity-score-matched cohorts adjusted for key clinical and molecular covariates.

Results: Patients with EO-CRC showed a unique genomic profile marked by a higher incidence of MYC, RAD21, GNAS, and MAPK1 amplifications. They also experienced CDKN2B loss and recurrent mutations, including APC∗, NRAS Q61L, PIK3CA, and TP53 G266V. These variations were statistically significant, indicating different oncogenic pathways. When comparing matched analyses, patients with EO-CRC had notably poorer OS than those with AO-CRC: 35 months versus 41 months in the overall matched group (P = 0.0326), 35 months compared with 44 months among Eastern Cooperative Oncology Group performance status 0 patients (P = 0.0026), and 27 months versus 44 months in the RAS/BRAF-mutated subgroup (P = 0.0024).

Conclusions: Patients with EO-CRC show a distinctive and biologically aggressive molecular profile, marked by significant changes in genes associated with cell proliferation and responses to environmental stress. These observations support the classification of EO-CRC as a potentially distinct clinical entity and suggest that personalised treatment strategies tailored to age-related molecular profiles warrant further investigation.

Keywords: early-onset colorectal cancer; metastatic colorectal cancer; molecular profiling; next-generation sequencing; precision oncology.

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Conflict of interest statement

Disclosure The authors have declared no conflicts of interest.

Figures

Figure 1
Figure 1
Heatmap illustrating the mutation frequencies of selected genes in early-onset colorectal cancer (EO-CRC) and average-onset CRC (AO-CRC) patients.
Figure 2
Figure 2
Selected gene alterations enriched in early-onset colorectal cancer (EO-CRC) compared with average-onset CRC (AO-CRC). Bar plots show the proportion and absolute number of mutated versus nonmutated cases in each group for: (A) MYC amplification (EO: 34/298, AO: 65/911), (B) RAD21 amplification (EO: 19/298, AO: 28/911), (C) PIK3CA E545K mutation (EO: 23/298, AO: 40/911), (D) APC R876∗ mutation (EO: 20/298, AO: 28/911), (E) CDKN2B loss (EO: 5/298, AO: 3/911), (F) NRAS Q61L mutation (EO: 5/298, AO: 2/911), (G) GNAS amplification (EO: 12/298, AO: 52/911), (H) TP53 G266V mutation (EO: 3/298, AO: 1/911), and (I) MAPK1 amplification (EO: 3/298, AO: 1/911).
Figure 3
Figure 3
Kaplan–Meier overall survival curves comparing early-onset colorectal cancer (EO-CRC) and average-onset CRC (AO-CRC) in the propensity-score-matched (PSM) cohort. EO-CRC patients exhibited significantly shorter overall survival compared with AO-CRC patients, despite matched clinical and molecular characteristics.
Figure 4
Figure 4
Overall survival in early-onset colorectal cancer (EO-CRC) versus average-onset CRC (AO-CRC)among patients with Eastern Cooperative Oncology Group performance status (ECOG-PS) 0. Kaplan–Meier curves show significantly worse survival for EO-CRC patients compared with AO-CRC patients, despite equivalent baseline functional status.
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