Colorectal cancer (CRC) has increased at an alarming rate amongst younger (< 50 years) individuals. Such early-onset colorectal cancer (EOCRC) has been particularly notable within the Hispanic/Latino population. Yet, this population has not been sufficiently profiled in terms of two critical elements of CRC -- the MYC proto-oncogene and WNT signaling pathway. Here, we performed a comprehensive multi-omics analysis on 30 early-onset and 37 late-onset CRC (≥ 50 years) samples from Hispanic/Latino patients. Our analysis included DNA exome sequencing for somatic mutations, somatic copy number alterations, and global and local genetic similarity. Using RNA sequencing, we also assessed differential gene expression, cellular pathways, and gene fusions. We then compared our findings from early-onset Hispanic/Latino patient samples with publicly available data from Non-Hispanic White cohorts. Across all early-onset patients, which had a median 1000 Genomes Project Peruvian-in-Lima-like (1KG-PEL-like) genetic similarity proportion of 60%, we identified 41 WNT pathway genes with significant mutations. Six important examples were APC, TCF7L2, DKK1, DKK2, FZD10, and LRP5. Notably, patients with mutations in DKK1 and DKK2 had the highest 1KG-PEL-like proportion (79%). When we compared the Hispanic/Latino cohort to the Non-Hispanic White cohorts, four of these key genes -- DKK1, DKK2, FZD10, and LRP5 -- were significant in both risk association analyses and differential gene expression. Interestingly, early-onset tumors (vs. late-onset) exhibited distinct somatic copy number alterations and gene expression profiles; the differences included MYC and drug-targetable WNT pathway genes. We also identified a novel WNT gene fusion, RSPO3, in early-onset tumors; it was associated with enhanced WNT signaling. This integrative analysis underscores the distinct molecular features of EOCRC cancer in the Hispanic/Latino population; reveals potential avenues for tailored precision medicine therapies; and emphasizes the importance of multi-omics approaches in studying colorectal carcinogenesis. We expect this data to help contribute towards reducing cancer health disparities. Significance:This study offers multi-omics profiling analysis of early-onset colorectal cancer (EOCRC) in an underserved community, explores the implications of MYC gene and WNT pathway alterations, and provides critical insights into cancer health disparities.

Background/Objectives: Early-onset colorectal cancer (EOCRC), defined as colorectal cancer (CRC) diagnosed before the age of 50, has been increasing in incidence, particularly among Hispanic/Latino (H/L) populations. Despite this trend, the underlying molecular mechanisms driving EOCRC disparities remain poorly understood. The MAPK and JAK/STAT pathways play critical roles in tumor progression, proliferation, and treatment response; however, their involvement in ethnicity-specific differences in EOCRC remains unclear. This study aims to characterize molecular alterations in MAPK and JAK/STAT pathway genes among EOCRC patients, focusing on differences between H/L and Non-Hispanic White (NHW) patients. Additionally, we assess whether these pathway-specific alterations contribute to survival outcomes in H/L EOCRC patients. Methods: We conducted a bioinformatics analysis using publicly available CRC datasets to assess mutation frequencies in MAPK and JAK/STAT pathway genes. A total of 3412 patients were included in the study, comprising 302 H/L patients and 3110 NHW patients. Patients were stratified by age (EOCRC: <50 years, late-onset colorectal cancer-LOCRC: ≥50 years) and 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 EOCRC patients. Results: Significant differences were observed in MAPK pathway-related genes when comparing EOCRC and LOCRC in H/L patients. NF1 (11.6% vs. 3.7%, p = 0.01), ACVR1 (2.9% vs. 0%, p = 0.04), and MAP2K1 (3.6% vs. 0%, p = 0.01) were more prevalent in EOCRC, while BRAF mutations (18.3% vs. 5.1%, p = 9.1 × 10-4) were significantly more frequent in LOCRC among H/L patients. Additionally, when comparing EOCRC in H/L patients to EOCRC in NHW patients, key MAPK pathway genes such as AKT1 (5.1% vs. 1.8%, p = 0.03), MAPK3 (3.6% vs. 0.7%, p = 6.83 × 10-3), NF1 (11.6% vs. 6.1%, p = 0.02), and PDGFRB (5.8% vs. 2.1%, p = 0.02) were significantly enriched in H/L EOCRC patients. However, no significant differences were observed in JAK/STAT pathway-related genes when comparing EOCRC and LOCRC in H/L patients, nor when comparing EOCRC in H/L vs. NHW patients. Survival analysis revealed borderline significant differences in H/L EOCRC patients, whereas NHW EOCRC patients with no alterations in the JAK/STAT pathway exhibited significant survival differences. In contrast, MAPK pathway alterations were not associated with significant survival differences. These findings suggest that MAPK and JAK/STAT pathway alterations may have distinct prognostic implications in H/L EOCRC patients, justifying further investigation into their potential role in cancer progression and treatment response. Conclusions: These findings suggest that MAPK pathway dysregulation plays a distinct role in EOCRC among H/L patients, potentially contributing to disparities in CRC development and treatment response. The higher prevalence of MAPK alterations in H/L EOCRC patients compared to NHW patients underscores the need to explore ethnicity-specific tumor biology and therapeutic targets. Conversely, the lack of significant differences in JAK/STAT pathway alterations suggests that this pathway may not play a major differential role in EOCRC vs. LOCRC within this population. Survival analysis highlighted the prognostic relevance of pathway-specific alterations. These insights emphasize the importance of precision medicine approaches that consider genetic heterogeneity and pathway-specific alterations to improve outcomes for H/L CRC patients.

Background/Objectives: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, with significant racial and ethnic disparities in incidence, tumor biology, and clinical outcomes. Hispanic/Latino (H/L) patients tend to be diagnosed at younger ages and more advanced stages than Non-Hispanic White (NHW) patients, yet the molecular mechanisms underlying these disparities remain poorly understood. Key oncogenic pathways, including RTK/RAS, TGF-beta, WNT, PI3K, and TP53, play pivotal roles in tumor progression, treatment resistance, and response to targeted therapies. However, ethnicity-specific alterations within these pathways remain largely unexplored. This study aims to compare pathway-specific mutations in HCC between H/L and NHW patients, assess tumor mutation burden, and identify ethnicity-associated oncogenic drivers using publicly available datasets. Findings from this analysis may inform precision medicine strategies for improving early detection and targeted therapies in underrepresented populations. Methods: We conducted a bioinformatic analysis using publicly available HCC datasets to assess mutation frequencies in RTK/RAS, TGF-beta, WNT, PI3K, and TP53 pathway genes. This study included 547 patients, consisting of 69 H/L patients and 478 NHW patients. Patients were stratified by ethnicity (H/L vs. NHW) to evaluate differences in mutation prevalence. Chi-squared tests were used to compare mutation frequencies, while Kaplan–Meier survival analysis assessed overall survival differences associated with pathway-specific alterations in both populations. Results: Significant differences were observed in the RTK/RAS pathway-related genes, particularly in FGFR4 mutations, which were more prevalent in H/L patients compared to NHW patients (4.3% vs. 0.6%, p = 0.02). Additionally, IGF1R mutations exhibited borderline significance (7.2% vs. 2.9%, p = 0.07). In the PI3K pathway, INPP4B alterations were more frequent in H/L patients than in NHW patients (4.3% vs. 1%, p = 0.06), while, in the TGF-beta pathway, TGFBR2 mutations were more common in H/L patients (2.9% vs. 0.4%, p = 0.07), suggesting potential ethnicity-specific variations. Survival analysis revealed no significant differences in overall survival between H/L and NHW patients, indicating that molecular alterations alone may not fully explain survival disparities and suggesting a role for additional factors such as immune response, environmental exposures, or access to targeted therapies. Conclusions: This study provides one of the first ethnicity-focused analyses of key oncogenic pathway alterations in HCC, revealing distinct molecular differences between H/L and NHW patients. The findings suggest that RTK/RAS (FGFR4, IGF1R), PI3K (INPP4B), and TGF-beta (TGFBR2) pathway alterations may play a distinct role in HCC among H/L patients, while their prognostic significance in NHW patients remains unclear. These insights emphasize the importance of incorporating ethnicity-specific molecular profiling into precision medicine approaches to improve early detection, targeted therapies, and clinical outcomes in HCC, particularly for underrepresented populations.

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 being 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.

ABSTRACT Background/Objectives This study aims to characterize PI3K and TP53 pathway alterations in Hispanic/Latino patients with early‐onset colorectal cancer (CRC), focusing on potential differences compared to non‐Hispanic White patients. Understanding these differences may shed light on the molecular basis of CRC health disparities. Methods Using cBioPortal, we conducted a bioinformatics analysis to evaluate CRC mutations within the PI3K and TP53 pathways. CRC patients were stratified by age and ethnicity: (1) early‐onset (< 50 years) versus late‐onset (≥ 50 years) and (2) early‐onset in Hispanic/Latino patients compared to early‐onset in non‐Hispanic White patients. Mutation frequencies were assessed using descriptive statistics, with chi‐squared tests comparing proportions between early‐onset Hispanic/Latino and non‐Hispanic White groups. Kaplan–Meier survival curves were generated to assess overall survival for early‐onset Hispanic/Latino patients, stratified by the presence or absence of PI3K and TP53 pathway alterations. Results Significant differences were noted when comparing early‐onset CRC in Hispanic/Latino patients to early‐onset CRC in non‐Hispanic White patients. PI3K (47.1% vs. 35.2%, p = 9.39e‐3) and TP53 (89.1% vs. 81.7%, p = 0.04) pathway alterations were more prevalent in early‐onset CRC among Hispanic/Latino patients, with AKT1 (5.1% vs. 1.8%, p = 0.03), INPP4B (4.3% vs. 1.4%, p = 0.04), and TSC1 (7.2% vs. 3.1% p = 0.03) gene alterations also significantly higher in this group. Significant differences were observed in TP53 mutations between colon adenocarcinomas (90% vs. 79.1%, p = 0.03), with higher prevalence in Hispanic/Latino patients when stratified by tumor site. No significant differences were observed between early‐onset and late‐onset CRC patients within the Hispanic/Latino cohort. Conclusions These findings highlight the distinct role of PI3K and TP53 pathway disruptions in early‐onset CRC among Hispanic/Latino patients, suggesting that pathway‐specific mechanisms may drive cancer health disparities. Insights from this study could inform the potential development of precision medicine approaches and targeted therapies aimed at addressing these disparities.

Background/Objectives: 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. Methods: 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 3412 patients, including 302 H/L and 3110 NHW individuals. The 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 the groups were conducted using chi-squared tests, while Kaplan–Meier survival analysis was employed to evaluate overall survival differences associated with pathway alterations. Results: Notable molecular distinctions in the RTK/RAS pathway were identified between EOCRC and LOCRC among the 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 the 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 the EOCRC patients from the H/L and NHW populations revealed distinct pathway-specific alterations that were more common in the 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 the H/L EOCRC patients did not reveal statistically significant differences based on pathway alterations. However, in the NHW EOCRC patients, the presence of WNT pathway alterations was associated with significantly improved survival outcomes, suggesting potential ethnicity-specific prognostic implications. Conclusions: This study highlights the substantial molecular heterogeneity present in EOCRC, particularly among high-risk populations. The 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 the H/L EOCRC patients. However, in the 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.

Abstract Introduction: Colorectal cancer (CRC) remains a significant public health challenge, representing the second leading cause of cancer-related mortality in the United States. Although mortality rates have generally decreased, the Hispanic/Latino (H/L) population in the Los Angeles area still experiences mortality rates up to 20% higher than those of their Caucasian American counterparts. Additionally, they are often diagnosed at a younger age and with more advanced disease stages, highlighting significant disparities in CRC outcomes. Currently, there are limited studies integrating clinical and multi-omics data from H/L populations, which are crucial for understanding the implications of colorectal tumorigenesis and addressing these disparities effectively. Methods: Clinical and genomic sequencing data were obtained from 60 primary CRC Tumor/Normal (T/N) samples within the Hispanic/Latino (H/L) population in the Los Angeles area through the PE-CGS network. For comparison, we analyzed 3,578 samples from non-Hispanic Whites (NHW) obtained from public databases. Additionally, we retrieved three CRC samples with spatial transcriptomic (ST) data from the 10xGenomics database. Using Whole Exome and RNA sequencing data, we performed somatic mutations, somatic copy number alterations (SCNAs), differential gene expression, cellular pathways, gene fusions, and global & local genomic ancestry analyses. The ST data underwent analysis utilizing newly released bioinformatics tools. Clinical and genomic data were integrated. Results: In these studies, distinct Amerindian (AMR) genomic ancestry proportion, age at diagnosis, and tumor localization patterns were observed, alongside significant mutations in key genes such as APC, TP53, and KRAS. The studies revealed evident cancer heterogeneity, influenced by factors such as mutation type, microsatellite instability, tumor subsite, and ethnicity. Additionally, several previously well-defined SCNAs were detected in the majority of tumors. Comparative analysis of gene expression and cellular pathways between H/L and NHW samples revealed distinct patterns. Furthermore, we identified gene fusions that potentially contribute to oncogenic activity in CRC. Ancestry analysis pointed to a predominant AMR ancestry. Notably, distinct associations of genetic ancestry with CRC tumor clinicopathological characteristics were identified. ST analysis delineated separate cancer, immune, and stroma components within the tumors. Conclusion: Our research has explored the molecular profiling of CRC tumors in H/L patients, providing crucial insights into the characterization of CRC tumors at the DNA and RNA levels, as well as the complex clinical and genomic diversity within our target population. Additionally, it offers valuable insights into the heterogeneity of CRC tumors and the tumor microenvironment. These findings establish the groundwork for subsequent projects, potentially leading to precision medicine approaches. Citation Format: Enrique I. Velazquez-Villarreal, Brigette Waldrup, Yonatan Amzaleg, Yuxin Jin, Mackenzie Postel, Donna Loza, Serina Ovalle, Elizabeth Quino, Carmen Chavez, Julie Culver, Mariana C. Stern, Heinz-Josef Lenz, David W. Craig, John D. Carpten. Enhanced characterization of molecular attributes through multi-omics analysis and comprehensive evaluation of global and local genomic ancestry in colorectal cancer among Hispanic-Latinos [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C106.

Abstract Germline and somatic genetic testing have become cornerstones for assessing patient risk and tailoring cancer treatment, respectively, relying on the ability to distinguish pathogenic from benign variants. Typically, clinical reporting from these tests is conducted independently, serving distinct clinical objectives and audiences. However, integrating the underlying genomic data from both germline and somatic tests can enhance interpretative clarity, particularly in resolving variants of unknown significance (VUS) that lack sufficient evidence to determine pathogenicity. This ambiguity is especially problematic for non-White populations and those of non-European ancestry, where VUSs are disproportionately found, thereby limiting the scope of precision medicine and perpetuating health disparities. To assess the potential utility of an integrated model, we examined a prospective cohort of 88 self-identified Hispanic patients with colorectal cancer (CRC), performing both germline and somatic genomic analyses. We found that at least one germline VUS was identified in 44% (39/88) of participants, compared to a frequently reported rate of below 15%. By integrating tumor transcriptome data, mutational signatures, and copy number variations with traditional germline testing, we aimed to clarify VUSs and identify driver mutations. Integrating data modalities of the tumor transcriptome, mutational signatures, and copy number variations alongside traditional germline testing can help clarify VUSs and identify driver mutations. We constructed a model whereby the assessment of VUSs was based on the putative functional impact on either the DNA mutational patterns or allelic expression observed in tumor RNA. Using our integrated model, we deemed the oncogene AXIN2 VUS of one participant was likely biologically significant due to mutant-allele specific expression observed in the tumor RNA. Furthermore, we showed that 26% (10/39) of participants harbored a VUS that was very likely benign based on the tumor mutational profile and RNA expression. These included variants associated with homologous recombination in PALB2 and BRCA2 as well as genes associated with DNA repair like MLH1, PMS2, POLE and POLD1. Among patients with VUSs in genes associated with homologous recombination deficiency (HRD), none exhibited HRD via copy number analyses. Conversely, of the six patients that did exhibit HRD, only one had a pathogenic variant in a gene associated with HRD (ATM). Additionally, we identified tumors with a DNA mismatch repair deficiency phenotype (high tumor mutational burden, high microsatellite instability, DNA mismatch repair deficiency mutational signature) but without a pathogenic variant in a Lynch syndrome-associated gene. Methylation analysis revealed hypermethylation of the MLH1 promoter in these cases, explaining the tumor phenotype. This finding indicates that our integrative method can accurately predict DNA mismatch repair deficiency even without a genetic alteration in a DNA mismatch repair gene. Citation Format: Jonathan Amzaleg, Julie O. Culve, Charité N. Ricker, Natalia Gutierrez, Yuxin Jin, Brigette Waldrup, Carmen Chaves, Lucia Enriquez, Joel Sanchez-Mendez, Daisy Hernandez, Bodour Salhia, Lourdes Baezconde-Garbanati, Mariana C. Stern, Enrique Velazquez Villarreal, John D. Carpten, Heinz-Joseph Lenz, David W. Craig. Integrating germline and somatic data to resolve variants of uncertain significance (VUS) in colorectal cancer (CRC) patients who self-identified as Hispanic/Latino [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C010.

Background/Objectives: One of the fastest-growing minority groups in the U.S. is the Hispanic/Latino population. Recent studies have shown how this population is being disproportionately affected by early-onset colorectal cancer (CRC). Compared to corresponding non-Hispanic White (NHW) patients, Hispanic/Latino patients have both higher incidence of disease and rates of mortality. Two well-established drivers of early-onset CRC in the general population are alterations in the WNT and TGF-Beta signaling pathways; however, the specific roles of these pathways in Hispanics/Latinos are poorly understood. Methods: Here, we assessed CRC mutations in the WNT and TGF-Beta pathways by conducting a bioinformatics analysis using cBioPortal. Cases of CRC were stratified both by age and ethnicity: (1) early-onset was defined as <50 years vs. late-onset as ≥50 years; (2) we compared early-onset in Hispanics/Latinos to early-onset in NHWs. Results: No significant differences were evident when we compared early-onset and late-onset CRC cases within the Hispanic/Latino cohort. These results are consistent with findings from large cohorts that do not specify ethnicity. However, we found significant differences when we compared early-onset CRC in Hispanic/Latino patients to early-onset CRC in NHW patients: specifically, alterations in the gene bone morphogenetic protein-7 (BMP7) were more frequent in early-onset CRC for the Hispanic/Latino patients. In addition to these findings, we observed that both NHW patients and Hispanic/Latino patients with early-onset disease had better clinical outcomes when there was evidence of WNT pathway alterations. Conversely, the absence of TGF-Beta pathway alterations was uniquely associated with improved outcomes exclusively in early-onset Hispanic/Latino patients. Conclusions: In toto, these findings underscore how the WNT and TGF-Beta pathways may act differently in different ethnic groups with early-onset CRC. These findings may set a stage for developing new therapies tailored for reducing cancer health disparities.

Abstract Introduction: Clinical factors and molecular characteristics play pivotal roles in shaping therapeutic strategies and prognoses in colorectal cancer (CRC), the second leading cause of cancer-related mortality in the United States. Despite an overall decline in mortality, the Hispanic/Latino (H/L) population in the Los Angeles area exhibits mortality rates up to 20% higher than their Caucasian American counterparts, often with diagnoses at a younger age and advanced disease stages. Few studies have utilized substantial H/L sample sizes and integrated comprehensive clinical and multi-omics data to conduct integrative translational analysis of reported genomic alterations and their implications for colorectal tumorigenesis. Methods: We collected clinical, DNA, and RNA sequencing data from 36 primary CRC Tumor/Normal (T/N) samples and 82 primary CRC T/N samples within the H/L population in the Los Angeles area through the Participant Engagement and Cancer Genome Sequencing (PE-CGS) Network and the Oncology Research Information Exchange Network (ORIEN), respectively. Additionally, we retrieved two CRC samples with spatial transcriptomic (ST) data from the 10xGenomics database. This data underwent Whole Exome and RNA sequencing analysis. Furthermore, we conducted global and local genomic ancestry analyses to establish correlations between self-ancestral identification and the five main superpopulations. ST data was analyzed using recently released bioinformatics tools. Clinical and genomic data were integrated. Results: In these studies, distinct age-of-onset, Amerindian (AMR), and survival patterns were observed, with significant mutations identified in key genes, including APC, TP53, KRAS, and PIK3CA. Cancer heterogeneity was evident, influenced by mutation type, microsatellite instability, subsite, and ethnicity. Ancestry analysis indicated genetic diversity, with a predominant AMR heritage and cases showcasing substantial European genetic proportions alongside AMR ancestry. Additionally, RNA sequencing has been conducted, with ongoing transcriptomic analysis in both studies, and the results are set for presentation at the annual meeting. The ST analysis generated initial maps, delineating diverse cellular populations and revealing the samples' distinct immunological and inflammatory signals. Conclusion: Our study has delved into the molecular profiling of CRC tumors among H/L patients, contributing essential insights into the DNA and RNA level characterization of CRC tumors and the multifaceted clinical and genomic heterogeneity within our aimed population. It also provides crucial insights into CRC tumor heterogeneity and the tumor microenvironment. These findings serve as the cornerstone for forthcoming sample analyses within our PE-CGS project to potentially lead to the development of personalized treatments. Citation Format: Enrique I. Velazquez Villarreal, Seeta Rajpara, Yuxin Jin, Mackenzie Postel, Brigette Waldrup, Flemming Wu, Donna Loza, Heinz-Josef Lenz, David W. Craig, John D. Carpten. Multi-omics characterization of molecular features and global-local genomic ancestry analysis of colorectal cancer in Hispanic-Latinos [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3932.

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.

Introduction: CRC is the second leading cause of cancer mortality in the United States. Clinical factors and molecular characteristics may impact therapeutics and prognosis. Scientific studies have uncovered significant aberrations, including critical genes and pathways. Despite these efforts, few studies have utilized similar sample sizes to TCGA, heterogeneous populations and integrative clinical data to compare their reported genomic changes, even though little is known about the tumor microenvironment and its significance for colorectal tumorigenesis. Methods: Clinical and DNA genomic data from 262 colorectal tumor/normal DNA samples were obtained for whole exome sequencing analysis from the Oncology Research Information Exchange Network and two colorectal tissue samples for Spatial Transcriptomics profiling from the USC colorectal cancer Moonshot project. Whole Exome Sequencing data analysis was used for identifying genetic alterations. Samples were stratified based on microsatellite instability, age group, anatomical subsites, and histological subtypes. Emphasis was given to comparing molecular characteristics among Hispanic/Latino patients since their reported higher mortality and cancer disparities. Mutation frequencies from our cohort were compared to those from the TCGA. An ongoing spatial transcriptomics analysis consists in processing two fresh-frozen tissue samples through the visium spatial gene expression library using standard short-read sequencing. Results: Tumor molecular profiling revealed 20 genes significantly mutated. We found differences in gene mutation frequencies among our samples, highlighting APC (60%), TP53 (56%), TTN (49%), and KRAS (44%) gene mutations. In comparison with TCGA data, in addition to the expected APC, TP53, PIK3CA, and KRAS mutations, we found frequent mutations in POLE and TTN. To assess the basis for the considerably different mutation rates, we evaluated MSI. Among the 262 tumors, 41 (16%) had high levels of MSI, 2 (1%) had low levels of MSI (MSI-L), and 215 (82%) were microsatellite stable (MSS). Cancer heterogeneity was reported among tumors with different characteristics such as age group, anatomical subsite, and histological subtypes. The ongoing spatial transcriptomics analysis that will be ready before the annual meeting will identify cellular populations and map immunological and inflammatory signals in the microenvironment. Conclusions: Our study reveals the impact of molecularly profiling tumors using considerable sample sizes and stratified samples in several subgroups. Our study adds important information about tumor heterogeneity and the tumor microenvironment in colorectal cancer by including our spatial transcriptomics data analysis. Citation Format: Enrique Velazquez Villarreal, Seeta Rajpara, Yuxin Jin, Jing Qian, Bohan Zhang, Brigette Waldrup, Donna Loza, Heinz-Josef Lenz, David W. Craig, John D. Carpten. Tumor molecular profiling and spatial transcriptomics to assess colorectal cancer heterogeneity and microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1515.