👤 E I Velazquez-Villarreal

The WNT signaling pathway is a key driver of colorectal cancer (CRC) initiation and progression, particularly in early-onset CRC (EOCRC) among underserved populations. However, interrogating WNT pathway dysregulation across clinical and genomic dimensions remains technically challenging, limiting both translational insight and personalized intervention strategies. To address this gap, we developed AI-HOPE-WNT, the first conversational artificial intelligence (AI) agent purpose-built to investigate WNT signaling in CRC using natural language-driven, integrative bioinformatics. AI-HOPE-WNT employs a modular architecture combining large language models (LLMs), a natural language-to-code engine, and a backend statistical workflow interfaced with harmonized data from cBioPortal. Unlike general-purpose platforms, AI-HOPE-WNT is uniquely optimized for WNT-specific precision oncology. The tool supports mutation frequency analysis, odds ratio testing, survival modeling, and subgroup stratification by genomic, clinical, and demographic variables. To validate the platform, we recapitulated findings from two previous studies examining WNT pathway alterations in high-risk CRC populations, including mutation prevalence in RNF43 and AXIN2 and survival outcomes associated with WNT pathway status across ethnic and age subgroups. Exploratory queries further assessed treatment response, co-mutation patterns, and population-specific trends. In recapitulation analyses, AI-HOPE-WNT reproduced key trends from prior work, including improved survival in WNT-altered EOCRC and higher RNF43 mutation rates in Hispanic/Latino (H/L) populations compared to non-Hispanic White (NHW) people. Exploratory analyses revealed several novel findings. Among FOLFOX-treated EOCRC patients, APC mutations were associated with significantly different survival outcomes ( AI-HOPE-WNT is the first dedicated AI platform for WNT pathway analysis in CRC. By combining natural language interaction with automated, high-throughput bioinformatics, it democratizes access to pathway-specific precision oncology research. The platform is freely available at: https://github.com/Velazquez-Villarreal-Lab/AI-HOPE-WNT. Show less

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. 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. 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. 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. Show less

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. 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. 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%, 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. Show less

Colorectal cancer contributes to cancer-related deaths and health disparities in the Hispanic and Latino community. To probe both the biological and genetic bases of the disparities, we characterized features of colorectal cancer in terms of somatic alterations and genetic similarity. Specifically, we conducted a comprehensive genome-scale analysis of 67 Hispanic and Latino samples. We performed DNA exome sequencing for somatic mutations, somatic copy number alterations, and genetic similarity. We also performed RNA sequencing for differential gene expression, cellular pathways, and gene fusions. We analyzed all samples for 22 important CRC gene mutations, 8 gene amplifications, and 25 CRC gene fusions. Then, we compared our data from the Hispanic and Latino samples to publicly available, Non-Hispanic White (NHW) cohorts. According to our analyses, twenty-four percent of colorectal carcinomas were hypermutated when patients were of Peruvians-from-Lima-like (1KG-PEL-like) genetic similarity population from the 1000 genome project. Moreover, most of these cases occurred in patients who were less than fiay years old age at diagnosis. Excluding hypermutated tumors, approximately 55% of colon cancers and 58% of rectum cancers exhibited two similar features: 1) the paderns of genomic alterations; 2) percentage of 1KG-PEL-like. We analyzed all samples -- which had a median 1KG-PEL-like proportion of 55% -- for 22 important CRC gene mutations, 8 gene amplifications, and 25 CRC gene fusions. One notable example of a frequently observed gene mutation was SMAD4. Samples with SMAD4 alterations, which are known to support tumor growth and progression, had the highest 1KG-PEL-like proportion (63%). According to our results from risk association analyses and differential gene expression, SMAD4 alterations were significant when we compared Hispanic and Latino samples to NHW cohorts. Of the 8 drug-targetable amplifications, PIK3CA and PI3K exhibited an average 1KG-PEL-like of over 55%. Of the 25 relevant CRC gene fusions, targetable genes included ALK, FGFR1, RAF1, and PTPRK; PTPRK was observed in a sample with the highest 1KG-PEL-like proportion (95%). Using Integrative analysis, we also detected recurrent alterations in the WNT, TGFB, TP53, IGF2/PI3K, and RTK/RAS pathways. Importantly, these alterations mostly occurred in young patients with high 1KG-PEL-like. These findings highlight the potential for tailoring precision medicine therapeutics to an underrepresented population. Our study advances the molecular profiling of CRC in Hispanics and Latinos. In toto, genetic similarity appears to be an important component in understanding colorectal carcinogenesis and has the potential to advance cancer health disparities research. Show less