Search Results (47)

Background/Objectives: Juvenile myelomonocytic leukemia (JMML) is a rare and very aggressive pediatric myelodysplastic/myeloproliferative neoplasm with molecular heterogeneity and constitutive activation of the RAS signaling pathway. The aim of this study was to identify the mutational landscape, driver genes, mutational signatures, functional pathways, and therapeutic targets of mutations that affect receptor tyrosine kinases (RTKs) and RAS pathways in JMML. Methods: We collected tumor and matched buccal swab samples from 35 patients with JMML and performed whole-exome sequencing. Variants were called using GATK-Mutect2 and annotated with ANNOVAR. Mutational profiling, co-occurrence analysis, protein domain mapping, and driver gene identification were performed using maftools and OncodriveCLUST. DGIdb was used to explore drug–gene interactions, MutationalPatterns was used for the characterization of mutational signatures, and the clusterProfiler package was used for the functional enrichment analyses. Results: Alteration of the RTK-RAS pathway was found in 77.1% of patients. PTPN11 (23%), NRAS (20%), and KRAS (14%) were the most frequently altered genes, followed by PTEN (11%) and FLT3, ROS1, FGFR4, ERBB2, and EGFR (9% each). Domain mapping of protein sequences identified the grouping of mutations within the conserved functional domains of the proteins. The alterations in receptor tyrosine kinase genes demonstrated a significant degree of co-occurrence, while the alterations in canonical JMML genes showed mutual exclusivity. PTPN11, NRAS, ROS1, and FGFR4 were top driver genes based on driver gene analysis. Functional enrichment analysis revealed significant enrichment of receptor tyrosine kinase signaling, Ras/MAPK and PI3K-AKT pathways. The mutational signatures were mostly SBS5-like, with enrichment of C>T transitions, indicative of endogenous mutational processes. Drug–gene interaction analysis identified EGFR, ALK, ROS1, ERBB2, FLT3, FGFR4, and PDGFRA as highly interconnected and potentially actionable therapeutic targets. Conclusions: These findings expand the molecular landscape of JMML and underscore the importance of aberrant RTK-RAS signaling in disease pathogenesis. The identification of recurrent and potentially druggable RTK alterations provides a rationale for future precision medicine approaches in JMML. Full article

Triple-negative breast cancer (TNBC) lacking androgen receptor (AR) expression defines quadruple-negative breast cancer (QNBC), which is characterized by younger age at diagnosis, high Ki-67 index, and high genomic instability, however a comprehensive description of the genomic characteristics remains poorly defined. A total of 54 TNBC cases were categorized as TNBC with 100% AR expression (TNBC AR-100%) or QNBC, TNBC with 0% AR expression (TNBC AR-0%). Clinical, molecular, and genomic parameters, specifically pathogenic/likely pathogenic (P/LP) variants in homologous recombination repair (HRR) and cancer-related pathways were measured and analyzed. The QNBC cohort exhibited a high homologous recombination deficiency (HRD) score and a greater overall incidence of copy number variants (CNVs). QNBC harbored a higher mutation rate in TP53 and MYC signaling pathway than TNBC AR-100% tumors. P/LP variants corresponding to the HRR, PI3K/AKT, and RTK/RAS pathways were exclusively identified in QNBC. These results suggest that, at both molecular and genomic levels, the two groups are distinct, holding QNBC tumors more aggressive characteristics, genomic instability, and particular impairments in HRR and cancer-related pathways. In terms of actionability, these differences could potentially be leveraged through different combinations of therapies. Full article

Background: Although ERα-positive breast cancer represents approximately 70% of all breast cancer diagnoses worldwide, specific prognostic biomarkers for this subtype that are capable of stratifying patients remain limited. TRIM28 (KAP1/TIF1β), which is a multifunctional E3 ubiquitin ligase and transcriptional coregulator of ERα, has been shown to play oncogenic roles in multiple malignancies. However, its prognostic significance in ERα-positive breast cancer subtype has not been explored across independent patient cohorts. Methods: Multiple bioinformatics tools were employed to assess TRIM28 mRNA expression and prognostic significance across independent patient cohorts totaling over 4000 patients. The Kaplan–Meier plotter was used to examine associations between TRIM28 expression and survival outcomes in ERα-positive breast cancer. Multivariate Cox proportional hazards regression was performed in the METABRIC dataset (n = 1356) to confirm independent prognostic value, with sensitivity analyses using alternative TRIM28 expression cutoffs and PAM50 subtype-specific subgroup analyses. Independent validation was performed using multivariate Cox regression in the TCGA-BRCA Firehose Legacy ERα-positive cohort (n = 372). Gene Set Cancer Analysis (GSCA) was used to investigate pathways associated with TRIM28-correlated genes, and Breast Cancer Gene-Expression Miner (Bc-GenExminer) was used to assess immune cell infiltration. Results: TRIM28 expression is significantly elevated in ERα-positive breast cancer compared to normal breast tissue. High TRIM28 expression (defined as the upper quartile, ≥75th percentile, of TRIM28 expression) is independently associated with worse overall survival after adjustment for tumour size, tumour mutational burden (TMB), hormone therapy status, and age, with stratification on histologic grade (HR = 1.21, 95% CI: 1.03–1.41, p = 0.0194; METABRIC, n = 1356). This finding was independently validated using multivariate Cox proportional hazards regression in the TCGA-BRCA Firehose Legacy ERα-positive cohort (n = 372; events = 56), in which high TRIM28 expression remained independently associated with worse OS after adjustment for age, T-stage, and TMB (HR = 2.02, 95% CI: 1.10–3.71, p = 0.024). PAM50 subtype-specific analyses within METABRIC additionally confirmed an independent association of high TRIM28 with worse OS in Luminal A (HR = 1.37, 95% CI: 1.08–1.74, p = 0.009), with a directionally consistent but non-significant trend in Luminal B (HR = 1.21, 95% CI: 0.93–1.58, p = 0.155). The prognostic effect was robust across alternative TRIM28 expression cutoffs. TRIM28 expression positively correlates with tumour size, histologic grade, Nottingham Prognostic Index, and TMB, and negatively correlates with immune cell infiltration and is significantly lower in patients receiving hormone therapy. Genes co-expressed with TRIM28 are enriched in cell cycle and DNA damage response activation signatures and RAS/MAPK and RTK pathway inhibition signatures. Conclusions: TRIM28 is an independent prognostic biomarker in ERα-positive breast cancer, validated across multiple independent cohorts. These findings nominate TRIM28 as a priority candidate for prospective clinical validation and targeted experimental investigation in ERα-positive breast cancer. Full article

Gastric adenocarcinomas with yolk sac tumor (YST) differentiation represent an exceptionally rare and poorly understood phenotype, characterized by the emergence of extraembryonic features within an epithelial malignancy. Their histogenesis remains debated, with increasing evidence supporting somatic lineage plasticity rather than germ cell origin. Here, we performed an integrated histopathologic and genomic characterization of three gastric adenocarcinomas with YST differentiation surgically treated at a tertiary cancer center. Histologically, all tumors showed a predominant adenocarcinoma component associated with variable YST differentiation, displaying reticular/microcystic and papillary patterns and expression of oncofetal markers, including alpha-fetoprotein (AFP) and Glypican-3. Targeted next-generation sequencing using a 523-gene panel revealed microsatellite-stable profiles with intermediate tumor mutational burden and substantial intertumoral heterogeneity. Despite gene-level variability, the detected alterations involved signaling pathways commonly implicated in epithelial tumorigenesis, including PI3K-AKT and RTK/RAS-MAPK signaling. Several recurrent alterations were identified across cases, including CCND3 variants and MDM2 copy number gains; however, their biological significance requires validation in larger cohorts. Functional enrichment analysis identified alterations involving developmental and proliferative signaling programs. Overall, these findings suggest that YST differentiation may represent a phenotypic manifestation of epithelial tumor plasticity arising within gastric adenocarcinoma and is associated with epithelial-related oncogenic programs, although broader genomic and comparative studies are required to clarify its histogenesis. This study provides preliminary molecular and histopathologic insights into this rare entity and supports the integration of molecular profiling into its diagnostic and translational management. Full article

Background/Objectives: Acute myeloid leukemia (AML) is a hematologic malignancy of substantial genetic heterogeneity that exhibits clonal growth and blocked differentiation of myeloid progenitor cells in the bone marrow (BM). Genetic alterations play a vital role in the progression, initiation, and recurrence of AML. The aim of this study was to identify the somatic mutational landscape, pathway perturbations, mutational signatures, and druggability of baseline (at diagnosis) and relapsed AML to determine possible treatment options. Methods: Between 2020 and 2026, 120 diagnostic BM or PB samples were prospectively collected from baseline (at diagnosis) AML patients at AIIMS, New Delhi. WES was conducted of 10 BM samples from five baseline (at diagnosis) and five relapsed patients with AML. Somatic variations were identified by GATK-Mutect2 and annotated by ANNOVAR. Driver genes and pathways were analyzed using Maftools, OncodriveCLUST, and clusterProfiler. Extraction of mutational signatures was performed with the help of SigProfilerExtractor, and evaluation of drug–gene interactions was carried out with the help of DGIdb. In addition, RT-PCR was performed to estimate the expression level of TET1. The recurrent TET1 variation was validated using Sanger sequencing and PCR amplification. Results: Missense mutations were the most common variant type in the cohort, and C > T transitions were the predominant nucleotide substitution pattern. There were recurrent mutations in core AML driver genes, including TET1, FLT3, and TP53, and relapsed samples demonstrated increased involvement and complexity of the signaling system. Pathway analysis revealed widespread dysregulation of carcinogenic networks, including RTK-RAS, WNT, TP53, and PI3K signaling. Mutational signature analysis identified COSMIC SBS5, SBS8, and SBS40, which are associated with mechanisms involving oxidative damage. A large number of actionable targets were identified through druggability screening, particularly involving epigenetic regulators and kinase-associated pathways. RT-PCR analysis also supported altered TET1 expression in AML samples. The TET1 A256V variant was detected and experimentally validated. Conclusions: This study highlights the somatic mutational landscape of baseline (at diagnosis) and relapsed AML and identifies recurrent driver genes, altered signaling pathways, mutational signatures, and actionable targets with possible therapeutic relevance. The integration of mutational and expression analyses further supports a potential role for TET1 in AML biology, although the functional significance of specific variants such as A256V remains uncertain. Full article

Pediatric gastrointestinal (GI) cancers are rare malignancies that differ fundamentally from their adult counterparts in molecular drivers, histology, and clinical behavior. While adult GI cancers are frequently driven by recurrent oncogenic mutations, pediatric tumors often exhibit pathway-level dysregulation involving developmental signaling networks. Among these, the RAS/MAPK pathway emerges as a central convergent axis integrating growth factor signaling, developmental programs, inflammatory cues, and post-translational regulatory mechanisms. Increasing evidence suggests that aberrant phosphorylation dynamics result from imbalanced kinase activation and phosphatase-mediated signal attenuation, which contribute to sustained MAPK signaling in pediatric GI malignancies, even in the absence of canonical RAS or RAF mutations. This review synthesizes current knowledge on RAS/MAPK signaling in pediatric GI cancers, emphasizing the role of kinase–phosphatase imbalance, signal duration, and regulatory failure in shaping oncogenic outcomes. We highlight how altered phosphorylation control may influence tumor differentiation, therapeutic responsiveness, and resistance mechanisms, and discuss emerging opportunities for targeting signaling dynamics rather than single genetic lesions. This signaling-centric framework provides a biologically grounded rationale for functional biomarker-driven precision therapy in pediatric GI malignancies. Full article

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy marked by substantial molecular heterogeneity and variable response to gemcitabine-based therapy. While KRAS mutations are nearly universal, the broader RTK-RAS and MAPK signaling architecture and its relationship to treatment response remain incompletely defined. We conducted an integrative clinical-genomic analysis of 184 PDAC tumors stratified by age at diagnosis and gemcitabine exposure, interrogating somatic alterations across curated RTK-RAS/MAPK gene sets. Conversational artificial intelligence agents (AI-HOPE-RTK-RAS and AI-HOPE-MAPK) enabled dynamic cohort construction and pathway-level analyses, with findings validated using standard statistical methods. In late-onset PDAC, ERBB2 and RET mutations were significantly enriched in gemcitabine-treated tumors. Early-onset cases demonstrated differential enrichment of CACNA2D family alterations in non-treated tumors and higher frequencies of FLNB and TP53 mutations in treated disease. Importantly, late-onset patients not treated with gemcitabine who lacked RTK-RAS or MAPK alterations exhibited significantly improved overall survival. These findings reveal age- and treatment-dependent pathway dependencies beyond canonical KRAS status and support a precision oncology framework in PDAC. Conversational AI facilitated rapid, multidimensional clinical–genomic integration to uncover clinically relevant signaling substructures. Full article

Background/Objectives: Early-onset colorectal cancer (EOCRC; diagnosed before age 50) is rising at an accelerated rate, with a disproportionate impact on underserved populations. While alterations in the receptor tyrosine kinase–RAS (RTK–RAS) signaling pathway play a fundamental role in colorectal cancer (CRC) biology, their prognostic significance in the setting of FOLFOX chemotherapy—particularly across different age groups and ancestral backgrounds—remains insufficiently characterized. We sought to characterize age-, ancestry-, and treatment-specific associations between RTK–RAS alterations and clinical outcomes using an AI-enabled precision oncology framework. Methods: We analyzed 2515 CRC cases, including 266 Hispanic/Latino (H/L) and 2249 non-Hispanic White (NHW) patients, stratified by age at onset, ancestry, and FOLFOX treatment status. Mutation frequencies were assessed using Fisher’s exact and chi-square tests, while overall survival was analyzed with Kaplan–Meier methods. The AI-HOPE and AI-HOPE–RTK–RAS conversational artificial intelligence platforms were used to integrate clinical, genomic, and treatment data via multi-parameter, natural language–based queries. Results: In early-onset Hispanic/Latino patients, ERBB2 and NF1 mutations occurred at significantly lower frequencies in FOLFOX-treated cases compared with untreated cases (p = 0.01 for both). In late-onset H/L patients, NTRK2 mutations were depleted in FOLFOX-treated tumors (p = 0.04). In untreated early-onset H/L patients, MAPK3 and NF1 mutations were enriched relative to NHW counterparts. Among early-onset NHW patients, IGF1R and ERRFI1 mutations were less frequent with FOLFOX exposure, while multiple RTK–RAS genes were reduced in FOLFOX-treated late-onset NHW patients. Survival analyses revealed worse overall survival in FOLFOX-untreated early-onset NHW patients with RTK–RAS alterations (p = 0.029), but improved survival in FOLFOX-treated late-onset NHW patients (p = 0.048). Conclusions: RTK–RAS pathway alterations demonstrate strong age-, ancestry-, and treatment-specific prognostic effects and may serve as precision biomarkers of differential chemotherapy response. AI-enabled analytics substantially accelerated integrative biomarker discovery, supporting their utility for advancing precision oncology in EOCRC. Full article

Central nervous system (CNS) tumors consist of a diverse set of malignancies that remain clinically challenging due to their biological complexity, high morbidity, and limited responsiveness to current therapies. A growing body of genomic evidence has revealed that dysregulation of the mitogen-activated protein kinase (MAPK) signaling pathway is a recurrent and unifying characteristic across many pediatric and adult CNS tumor entities. Alterations affecting upstream receptor tyrosine kinases (RTKs), RAS GTPases, RAF kinases, and other associated regulators contribute to MAPK signaling pathway hyperactivation, shaping tumor behavior, therapy response and resistance. These aberrations ranging from hotspot mutations such as BRAF V600E and oncogenic fusions like BRAF–KIAA1549 are particularly enriched in gliomas and glioneuronal tumors, highlighting MAPK signaling as a key oncogenic driver. The expanding availability of molecularly targeted compounds, including selective inhibitors of RAF, MEK and ERK, has begun to transform treatment approaches for specific molecular subtypes. However, the clinical benefit of MAPK-directed therapies is frequently limited by restricted blood–brain barrier (BBB) penetration, intratumoral heterogeneity, parallel pathway reactivation, and an immunosuppressive tumor microenvironment (TME). In this review, we synthesize current knowledge on MAPK pathway alterations in CNS tumors and evaluate the therapeutic landscape of MAPK inhibition, with emphasis on approved agents, emerging compounds, combination strategies, and novel drug-delivery technologies. We also discuss mechanisms that undermine treatment efficacy and highlight future directions aimed at integrating MAPK-targeted therapy into precision-based management of brain tumors. Full article

Pancreatic cancer (PC) is a highly aggressive malignancy with increasing incidence and poor survival. Hispanic/Latino (H/L) patients, despite having a lower overall incidence than Non-Hispanic White (NHW) patients, are often diagnosed younger and at more advanced stages, leading to worse outcomes. The molecular mechanisms underlying these disparities remain unclear. This study characterizes mutations in key oncogenic pathways—TP53, WNT, PI3K, TGF-Beta, and RTK/RAS—among H/L and NHW patients using publicly available datasets. We analyzed genomic data from 4248 PC patients (407 H/L; 3841 NHW), comparing mutation frequencies across pathways. Chi-squared tests assessed group differences, and Kaplan–Meier analysis evaluated survival outcomes by pathway alterations. TGF-Beta pathway mutations were less common in H/L patients (18.4% vs. 24.4%, p = 8.6 × 10⁻³), with notable differences in SMAD2 (1.5% vs. 0.4%, p = 6.3 × 10⁻³) and SMAD4 (15% vs. 19.9%, p = 0.02). While overall differences in other pathways were not statistically significant, several genes showed borderline significance, including ERBB4, ALK, HRAS, RIT1 (RTK/RAS), and CTNNB1 (WNT). No significant survival differences were observed in H/L patients, but NHW patients with TP53 alterations showed borderline survival associations. This study reveals ethnicity-specific pathway alterations in PC, with SMAD2, ERBB4, ALK, and CTNNB1 mutations being more frequent in H/L patients, while SMAD4 and PI3K alterations had prognostic value in NHW patients. These findings indicate the importance of incorporating ethnicity-specific molecular profiling into precision oncology for PC. Full article

Background/Objectives: The RTK-RAS signaling cascade is a central axis in colorectal cancer (CRC) pathogenesis, governing cellular proliferation, survival, and therapeutic resistance. Somatic alterations in key pathway genes—including KRAS, NRAS, BRAF, and EGFR—are pivotal to clinical decision-making in precision oncology. However, the integration of these genomic events with clinical and demographic data remains hindered by fragmented resources and a lack of accessible analytical frameworks. To address this challenge, we developed AI-HOPE-RTK-RAS, a domain-specialized conversational artificial intelligence (AI) system designed to enable natural language-based, integrative analysis of RTK-RAS pathway alterations in CRC. Methods: AI-HOPE-RTK-RAS employs a modular architecture combining large language models (LLMs), a natural language-to-code translation engine, and a backend analytics pipeline operating on harmonized multi-dimensional datasets from cBioPortal. Unlike general-purpose AI platforms, this system is purpose-built for real-time exploration of RTK-RAS biology within CRC cohorts. The platform supports mutation frequency profiling, odds ratio testing, survival modeling, and stratified analyses across clinical, genomic, and demographic parameters. Validation included reproduction of known mutation trends and exploratory evaluation of co-alterations, therapy response, and ancestry-specific mutation patterns. Results: AI-HOPE-RTK-RAS enabled rapid, dialogue-driven interrogation of CRC datasets, confirming established patterns and revealing novel associations with translational relevance. Among early-onset CRC (EOCRC) patients, the prevalence of RTK-RAS alterations was significantly lower compared to late-onset disease (67.97% vs. 79.9%; OR = 0.534, p = 0.014), suggesting the involvement of alternative oncogenic drivers. In KRAS-mutant patients receiving Bevacizumab, early-stage disease (Stages I–III) was associated with superior overall survival relative to Stage IV (p = 0.0004). In contrast, BRAF-mutant tumors with microsatellite-stable (MSS) status displayed poorer prognosis despite higher chemotherapy exposure (OR = 7.226, p < 0.001; p = 0.0000). Among EOCRC patients treated with FOLFOX, RTK-RAS alterations were linked to worse outcomes (p = 0.0262). The system also identified ancestry-enriched noncanonical mutations—including CBL, MAPK3, and NF1—with NF1 mutations significantly associated with improved prognosis (p = 1 × 10⁻⁵). Conclusions: AI-HOPE-RTK-RAS exemplifies a new class of conversational AI platforms tailored to precision oncology, enabling integrative, real-time analysis of clinically and biologically complex questions. Its ability to uncover both canonical and ancestry-specific patterns in RTK-RAS dysregulation—especially in EOCRC and populations with disproportionate health burdens—underscores its utility in advancing equitable, personalized cancer care. This work demonstrates the translational potential of domain-optimized AI tools to accelerate biomarker discovery, support therapeutic stratification, and democratize access to multi-omic analysis. Full article

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. Full article

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. Full article

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. Full article

Gliomas are a type of highly heterogeneous and invasive central nervous system tumor. Traditional treatment methods have limited efficacy, and the prognosis for patients remains poor. Recent studies have revealed the crucial roles of several abnormal signaling pathways in the pathogenesis of gliomas, including the Receptor Tyrosine Kinase/Rat Sarcoma Virus Oncogene/Phosphatidylinositol-3-Kinase (RTK/RAS/PI3K) pathway, the Wingless-Related Integration Site/β-Catenin (Wnt/β-Catenin) pathway, the Hippo/YAP (Hippo/Yes-associated protein) pathway, and the Slit/Robo (Slit Guidance Ligands/Roundabout) signaling pathway. These pathways play extremely vital roles in tumor proliferation, invasion, and treatment resistance. This article comprehensively and systematically reviews the molecular mechanisms of these signaling pathways, deeply summarizing the research progress of various treatment strategies, including targeted inhibitors, gene therapy, and nanomedicine against them. Moreover, the combination of targeted therapy and personalized treatment regimens is expected to overcome the current treatment bottleneck and provide a more favorable survival prognosis for glioblastoma patients. Full article