Assessment of MYC Gene and WNT Pathway Alterations in Early-Onset Colorectal Cancer Among Hispanic/Latino Patients Using Integrated Multi-Omics Approaches DOI Creative Commons
Francisco Carranza, Brigette Waldrup, Yuxin Jin

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 8, 2024

ABSTRACT Colorectal cancer (CRC) has increased at an alarming rate amongst younger (< 50 years) individuals. Such early-onset colorectal (EOCRC) been particularly notable within the Hispanic/Latino population. Yet, this population not sufficiently profiled in terms of two critical elements CRC -- MYC proto-oncogene and WNT signaling pathway. Here, we performed a comprehensive multi-omics analysis on 30 37 late-onset (≥ samples from patients. Our included DNA exome sequencing for somatic mutations, copy number alterations, global local genetic similarity. Using RNA sequencing, also assessed differential gene expression, cellular pathways, fusions. We then compared our findings patient with publicly available data Non-Hispanic White cohorts. Across all patients, which had median 1000 Genomes Project Peruvian-in-Lima-like (1KG-PEL-like) similarity proportion 60%, identified 41 pathway genes significant mutations. Six important examples were APC, TCF7L2, DKK1, DKK2, FZD10, LRP5. Notably, patients mutations DKK1 DKK2 highest 1KG-PEL-like (79%). When cohort to cohorts, four these key LRP5 both risk association analyses expression. Interestingly, tumors (vs. late-onset) exhibited distinct alterations expression profiles; differences drug-targetable genes. novel fusion, RSPO3, tumors; it was associated enhanced signaling. This integrative underscores molecular features EOCRC population; reveals potential avenues tailored precision medicine therapies; emphasizes importance approaches studying carcinogenesis. expect help contribute towards reducing health disparities. Significance study offers profiling underserved community, explores implications provides insights into ABSTRACT(short version) risen (<50 yrs) cases. Both its incidence higher rates mortality are especially pronounced Although well-established CRC, lack sufficient about what role play young assess how altered CRC. analyzed using approaches, including sequencing. The strategy allowed us identify between early tumors. Specifically, prevalent : , FZD10 . Unique mutational profiles linked high Peruvians-from-Lima-like These highlight need targeted address characteristics underrepresented populations.

Language: Английский

Pathway-specific genomic alterations in pancreatic cancer across diverse cohorts DOI Creative Commons
Cecilia Monge, Brigette Waldrup, Francisco J. Carranza-Chávez

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 3, 2025

Abstract Background/Objectives Pancreatic cancer (PC) is an aggressive malignancy with rising incidence and poor survival rates. While Hispanic/Latino (H/L) patients have a lower overall compared to Non-Hispanic White (NHW) patients, they are diagnosed at younger ages, often present more advanced disease, experience worse outcomes. The molecular drivers underlying these disparities remain poorly understood. Key oncogenic pathways, including TP53, WNT, PI3K, TGF-Beta, RTK/RAS, play crucial roles in tumor progression, therapy resistance, response targeted treatments. However, their ethnicity-specific alterations prognostic implications PC largely unexplored. This study aims characterize pathway-specific mutations among H/L NHW assess mutation burden, identify using publicly available datasets. findings may provide critical insights optimize precision medicine strategies enhance therapies for underrepresented populations. Methods A bioinformatics analysis was performed datasets evaluate frequencies genes associated the TP53 pathways. included 4,248 407 identified as 3,841 NHW. Patients were stratified by ethnicity differences prevalence. Chi-squared tests conducted compare rates between groups, while Kaplan-Meier based on alterations. Results Significant observed TGF-Beta pathway patients. less prevalent (18.4% vs. 24.4%, p = 8.6e-3). Additionally, related showed significant alterations, SMAD2 (1.5% 0.4%, 6.3e-3) SMAD4 (15% 19.9%, 0.02) exhibiting notable differences. Although not statistically overall, borderline significance ERBB4 (3.4% 1.8%, 0.03), ALK (2.7% 1.1%, 0.01), HRAS (1.2% 0.1%, 1.3e-4), RIT1 (0.7% 0.03) RTK/RAS pathway, well CTNNB1 (2.9% 1.3%, 0.01) WNT pathway. Survival revealed no exhibited

Language: Английский

Citations

0
Molecular Alterations in TP53, WNT, PI3K, TGF-Beta, and RTK/RAS Pathways in Gastric Cancer Among Ethnically Heterogeneous Cohorts DOI Open Access
Cecilia Monge,

Brigette Waldrup,

Francisco Carranza

et al.

Cancers, Journal Year: 2025, Volume and Issue: 17(7), P. 1075 - 1075

Published: March 23, 2025

Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, with significant racial and ethnic disparities in incidence, molecular characteristics, patient outcomes. However, genomic studies focusing on Hispanic/Latino (H/L) populations remain scarce, limiting our understanding ethnicity-specific alterations. This study aims to characterize pathway-specific mutations TP53, WNT, PI3K, TGF-Beta, RTK/RAS signaling pathways GC compare mutation frequencies between H/L Non-Hispanic White (NHW) patients. Additionally, we evaluate the impact these alterations overall survival using publicly available datasets. We conducted bioinformatics analysis datasets assess pathway genes. A total 800 patients were included analysis, comprising 83 717 NHW Patients stratified by ethnicity (H/L vs. NHW) differences prevalence. Chi-squared tests performed rates groups Kaplan-Meier was used based among both Significant observed TP53 related genes when comparing less prevalent (9.6% 19%, p = 0.03). Borderline noted WNT patients, more frequent (8.4% 4%, 0.08) APC being significantly higher (3.6% 0.8%, 0.05). Although not statistically significant, borderline significance pathways, including EGFR (p 0.07), FGFR1 0.05), FGFR2 PTPN11 0.05) PI3K SMAD4 TGF-Beta pathway. Survival revealed no exhibited survival, while those without also showed impact. In contrast, associated differences. These findings suggest that disruptions may have distinct prognostic implications provides one first ethnicity-focused analyses GC, revealing racial/ethnic dysregulation. The play critical role greater insights emphasize need for precision medicine approaches account genetic heterogeneity improve care outcomes underrepresented populations.

Language: Английский

Citations

0
Ethnicity-Specific Molecular Alterations in MAPK and JAK/STAT Pathways in Early-Onset Colorectal Cancer DOI Open Access
Cecilia Monge,

Brigette Waldrup,

Francisco Carranza

et al.

Cancers, Journal Year: 2025, Volume and Issue: 17(7), P. 1093 - 1093

Published: March 25, 2025

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

Language: Английский

Citations

0
Comparative Genomic Analysis of Key Oncogenic Pathways in Hepatocellular Carcinoma Among Diverse Populations DOI Open Access
Cecilia Monge,

Brigette Waldrup,

Francisco Carranza

et al.

Cancers, Journal Year: 2025, Volume and Issue: 17(8), P. 1309 - 1309

Published: April 13, 2025

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

Language: Английский

Citations

0
Molecular Heterogeneity in Early-Onset Colorectal Cancer: Pathway-Specific Insights in High-Risk Populations DOI Open Access
Cecilia Monge,

Brigette Waldrup,

Francisco Carranza

et al.

Cancers, Journal Year: 2025, Volume and Issue: 17(8), P. 1325 - 1325

Published: April 15, 2025

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 and mortality. Despite this growing public health concern, molecular mechanisms driving EOCRC disparities remain poorly understood. Oncogenic pathways such WNT, TGF-beta, RTK/RAS are critical (CRC) progression, yet their specific roles across diverse populations have not extensively studied. This research seeks to identify alterations within these by comparing cases H/L non-Hispanic White (NHW) individuals. Furthermore, we explore clinical significance findings inform precision medicine strategies tailored high-risk populations. Methods: To investigate mutation frequencies genes associated pathways, conducted a bioinformatics analysis using publicly available CRC datasets. study cohort consisted 3412 patients, including 302 3110 NHW patients were categorized based on (EOCRC: <50 years; late-onset [LOCRC]: ≥50 years) population group (H/L vs. NHW) assess variations prevalence. Statistical comparisons rates between groups chi-squared tests, while Kaplan–Meier survival was employed evaluate overall differences pathway alterations. Results: Notable distinctions identified LOCRC among exhibiting lower frequency compared (66.7% 79.3%, p = 0.01). Within pathway, mutations CBL (p < 0.05) NF1 significantly more prevalent (5.8% 1.2% 11.6% 3.7%, respectively), whereas BRAF notably less frequent than (5.1% 18.3%, 0.05). Comparisons from revealed distinct pathway-specific that common These included RNF43 (12.3% 6.7%, WNT BMPR1A 1.8%, TGF-beta multiple alterations, MAPK3 (3.6% 0.7%, 0.05), 1.4%, (11.6% 6.1%, Survival did reveal statistically However, presence improved outcomes, suggesting potential ethnicity-specific prognostic implications. Conclusions: highlights substantial heterogeneity present EOCRC, particularly exhibited genetic higher prevalence CBL, NF1, RNF43, BMPR1A, counterparts. Additionally, LOCRC. differences, impact outcomes patients. survival. emphasize necessity for further clarify underrepresented groups.

Language: Английский

Citations

0
Assessment of MYC Gene and WNT Pathway Alterations in Early-Onset Colorectal Cancer Among Hispanic/Latino Patients Using Integrated Multi-Omics Approaches DOI Creative Commons
Francisco Carranza, Brigette Waldrup, Yuxin Jin

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 8, 2024

ABSTRACT Colorectal cancer (CRC) has increased at an alarming rate amongst younger (< 50 years) individuals. Such early-onset colorectal (EOCRC) been particularly notable within the Hispanic/Latino population. Yet, this population not sufficiently profiled in terms of two critical elements CRC -- MYC proto-oncogene and WNT signaling pathway. Here, we performed a comprehensive multi-omics analysis on 30 37 late-onset (≥ samples from patients. Our included DNA exome sequencing for somatic mutations, copy number alterations, global local genetic similarity. Using RNA sequencing, also assessed differential gene expression, cellular pathways, fusions. We then compared our findings patient with publicly available data Non-Hispanic White cohorts. Across all patients, which had median 1000 Genomes Project Peruvian-in-Lima-like (1KG-PEL-like) similarity proportion 60%, identified 41 pathway genes significant mutations. Six important examples were APC, TCF7L2, DKK1, DKK2, FZD10, LRP5. Notably, patients mutations DKK1 DKK2 highest 1KG-PEL-like (79%). When cohort to cohorts, four these key LRP5 both risk association analyses expression. Interestingly, tumors (vs. late-onset) exhibited distinct alterations expression profiles; differences drug-targetable genes. novel fusion, RSPO3, tumors; it was associated enhanced signaling. This integrative underscores molecular features EOCRC population; reveals potential avenues tailored precision medicine therapies; emphasizes importance approaches studying carcinogenesis. expect help contribute towards reducing health disparities. Significance study offers profiling underserved community, explores implications provides insights into ABSTRACT(short version) risen (<50 yrs) cases. Both its incidence higher rates mortality are especially pronounced Although well-established CRC, lack sufficient about what role play young assess how altered CRC. analyzed using approaches, including sequencing. The strategy allowed us identify between early tumors. Specifically, prevalent : , FZD10 . Unique mutational profiles linked high Peruvians-from-Lima-like These highlight need targeted address characteristics underrepresented populations.

Language: Английский

Citations

0