Molecular alterations in TP53, WNT, PI3K, TGF-Beta and RTK/RAS pathways in gastric cancer among ethnically heterogeneous cohorts
Authors: Monge Cecilia , Waldrup Brigette , Carranza Francisco G. , Velazquez-Villarreal Enrique 
Published: February 2025

Background/Objectives

Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, with significant racial and ethnic disparities in incidence, molecular characteristics, and patient outcomes. However, genomic studies focusing on Hispanic/Latino (H/L) populations remain scarce, limiting our understanding of ethnicity-specific molecular alterations. This study aims to characterize pathway-specific mutations in TP53, WNT, PI3K, TGF-Beta and RTK/RAS signaling pathways in GC and compare mutation frequencies between H/L and Non-Hispanic White (NHW) patients. Additionally, we evaluate the impact of these alterations on overall survival using publicly available datasets.

Methods

We conducted a bioinformatics analysis using publicly available GC datasets to assess mutation frequencies in TP53, WNT, PI3K, TGF-Beta and RTK/RAS pathway genes. A total of 800 patients were included in the analysis, comprising 83 H/L patients and 717 NHW patients. Patients were stratified by ethnicity (H/L vs. NHW) to evaluate differences in mutation prevalence. Chi-squared tests were performed to compare mutation rates between groups, and Kaplan-Meier survival analysis was used to assess overall survival differences based on pathway alterations among both H/L and NHW patients.

Results

Significant differences were observed in the TP53 pathway and related genes when comparing GC in H/L patients to NHW patients. TP53 mutations were less prevalent in H/L patients (9.6% vs. 19%, p = 0.03). Borderline significant differences were noted in the WNT pathway when comparing GC in H/L patients to NHW GC patients, with WNT alterations more frequent in H/L GC (8.4% vs. 4%, p = 0.08), and APC mutations significantly higher (3.6% vs. 0.8%, p = 0.05). Although alterations in PI3K, TGF-Beta and RTK/RAS pathways were not statistically significant, borderline significance was observed in genes related to these pathways, including EGFR (p = 0.07), FGFR1 (p = 0.05), FGFR2 (p = 0.05), and PTPN11 (p = 0.05) in the PI3K pathway, and SMAD4 (p = 0.08) in the TGF-Beta pathway. Survival analysis revealed no significant differences among H/L patients. However, NHW patients with TP53 and PI3K pathway alterations exhibited significant differences in overall survival, while those without TGF-Beta pathway alterations also showed a significant survival impact. In contrast, WNT pathway alterations were not associated with significant survival differences. These findings suggest that TP53, PI3K, and TGF-Beta pathway disruptions may have distinct prognostic implications in NHW GC patients.

Conclusions

This study provides one of the first ethnicity-focused analyses of TP53, WNT, PI3K, TGF-Beta and RTK/RAS pathway alterations in GC, revealing significant racial/ethnic differences in pathway dysregulation. The findings suggest that TP53 and WNT alterations may play a critical role in GC among H/L patients, while PI3K and TGF-Beta alterations may have greater prognostic significance in NHW patients. These insights emphasize the need for precision medicine approaches that account for genetic heterogeneity and ethnicity-specific pathway alterations to improve cancer care and outcomes for underrepresented populations.