Molecular Heterogeneity in Early-Onset Colorectal Cancer: Pathway-Specific Insights in High-Risk Populations

The incidence of early-onset colorectal cancer (EOCRC), defined as diagnosis before age 50, has been rising at an alarming rate, with Hispanic/Latino (H/L) individuals experiencing the most significant increases in both incidence and mortality. Despite this growing public health concern, the molecular mechanisms driving EOCRC disparities remain poorly understood. Oncogenic pathways such as WNT, TGF-beta, and RTK/RAS are critical in colorectal cancer (CRC) progression, yet their specific roles in EOCRC across diverse populations have not been extensively studied. This research seeks to identify molecular alterations within these pathways by comparing EOCRC cases in H/L and non-Hispanic White (NHW) individuals. Furthermore, we explore the clinical significance of these findings to inform precision medicine strategies tailored to high-risk populations.

To investigate mutation frequencies in genes associated with the WNT, TGF-beta, and RTK/RAS pathways, we conducted a bioinformatics analysis using publicly available CRC datasets. The study cohort consisted of 3,412 patients, including 302 H/L and 3,110 NHW individuals. Patients were categorized based on age (EOCRC: <50 years; late-onset CRC [LOCRC]: ≥50 years) and population group (H/L vs. NHW) to assess variations in mutation prevalence. Statistical comparisons of mutation rates between groups were conducted using chi-squared tests, while Kaplan-Meier survival analysis was employed to evaluate overall survival differences associated with pathway alterations.

Notable molecular distinctions in the RTK/RAS pathway were identified between EOCRC and LOCRC among H/L patients, with EOCRC exhibiting a lower frequency of RTK/RAS alterations compared to LOCRC (66.7% vs. 79.3%, p = 0.01). Within this pathway, mutations in CBL (p < 0.05) and NF1 (p < 0.05) were significantly more prevalent in EOCRC cases (5.8% vs. 1.2% and 11.6% vs. 3.7%, respectively), whereas BRAF mutations were notably less frequent in EOCRC than in LOCRC (5.1% vs. 18.3%, p < 0.05). Comparisons between EOCRC patients from H/L and NHW populations revealed distinct pathway-specific alterations that were more common in H/L individuals. These included RNF43 mutations (12.3% vs. 6.7%, p < 0.05) in the WNT pathway, BMPR1A mutations (5.1% vs. 1.8%, p < 0.05) in the TGF-beta pathway, and multiple RTK/RAS pathway alterations, such as MAPK3 (3.6% vs. 0.7%, p < 0.05), CBL (5.8% vs. 1.4%, p < 0.05), and NF1 (11.6% vs. 6.1%, p < 0.05). Survival analysis in H/L EOCRC patients did not reveal statistically significant differences based on pathway alterations. However, in NHW EOCRC patients, the presence of WNT pathway alterations was associated with significantly improved survival outcomes, suggesting potential ethnicity-specific prognostic implications.

This study highlights the substantial molecular heterogeneity present in EOCRC, particularly among high-risk populations. H/L EOCRC patients exhibited distinct genetic alterations, with a higher prevalence of CBL, NF1, RNF43, BMPR1A, and MAPK3 mutations compared to their NHW counterparts. Additionally, RTK/RAS pathway alterations were less frequent in EOCRC than in LOCRC. Despite these molecular differences, pathway alterations did not significantly impact survival outcomes in H/L EOCRC patients. However, in NHW EOCRC patients, the presence of WNT pathway alterations was associated with improved survival. These findings emphasize the necessity for further research to clarify the molecular mechanisms driving EOCRC disparities in high-risk populations and to inform precision medicine strategies for underrepresented groups.