Search Results (123)

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

The recent identification of early-onset mutational signatures with geographic variations by Diaz-Gay et al. is a significant finding, since early-onset colorectal cancer has emerged as an alarming public health challenge in the past two decades, and the pathomechanism remains unclear. Environmental risk factors, including lifestyle and diet, are highly suspected. The identification of colibactin from Escherichia coli as a potential pathogenic source is a major step forward in addressing this public health challenge. Therefore, the following opinion manuscript aims to outline the likely onset of the pathomechanism and the critical role of acquired Piezo2 channelopathy in early-onset colorectal cancer, which skews proton availability and proton motive force regulation toward E. coli within the microbiota–host symbiotic relationship. In addition, the colibactin produced by the pks island of E. coli induces host DNA damage, which likely interacts at the level of Wnt signaling with Piezo2 channelopathy-induced pathological remodeling. This transcriptional dysregulation eventually leads to tumorigenesis of colorectal cancer. Mechanotransduction converts external physical cues to inner chemical and biological ones. Correspondingly, the proposed quantum mechanical free-energy-stimulated ultrafast proton-coupled tunneling, initiated by Piezo2, seems to be the principal and essential underlying novel oscillatory signaling that could be lost in colorectal cancer onset. Hence, Piezo2 channelopathy not only contributes to cancer initiation and impaired circadian regulation, including the proposed hippocampal ultradian clock, but also to proliferation and metastasis. Full article

Background/Objectives: The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway is a critical mediator of immune regulation, inflammation, and cancer progression. Although implicated in colorectal cancer (CRC) pathogenesis, its molecular heterogeneity and clinical significance remain insufficiently characterized—particularly within early-onset CRC (EOCRC) and across diverse treatment and demographic contexts. We present AI-HOPE-JAK-STAT, a novel conversational artificial intelligence platform built to enable the real-time, natural language-driven exploration of JAK/STAT pathway alterations in CRC. The platform integrates clinical, genomic, and treatment data to support dynamic, hypothesis-generating analyses for precision oncology. Methods: AI-HOPE-JAK-STAT combines large language models (LLMs), a natural language-to-code engine, and harmonized public CRC datasets from cBioPortal. Users define analytical queries in plain English, which are translated into executable code for cohort selection, survival analysis, odds ratio testing, and mutation profiling. To validate the platform, we replicated known associations involving JAK1, JAK3, and STAT3 mutations. Additional exploratory analyses examined age, treatment exposure, tumor stage, and anatomical site. Results: The platform recapitulated established trends, including improved survival among EOCRC patients with JAK/STAT pathway alterations. In FOLFOX-treated CRC cohorts, JAK/STAT-altered tumors were associated with significantly enhanced overall survival (p < 0.0001). Stratification by age revealed survival advantages in younger (age < 50) patients with JAK/STAT mutations (p = 0.0379). STAT5B mutations were enriched in colon adenocarcinoma and correlated with significantly more favorable trends (p = 0.0000). Conversely, JAK1 mutations in microsatellite-stable tumors did not affect survival, emphasizing the value of molecular context. Finally, JAK3-mutated tumors diagnosed at Stage I–III showed superior survival compared to Stage IV cases (p = 0.00001), reinforcing stage as a dominant clinical determinant. Conclusions: AI-HOPE-JAK-STAT establishes a new standard for pathway-level interrogation in CRC by empowering users to generate and test clinically meaningful hypotheses without coding expertise. This system enhances access to precision oncology analyses and supports the scalable, real-time discovery of survival trends, mutational associations, and treatment-response patterns across stratified patient cohorts. Full article

In November 2024, the fourth annual Symposium focusing on early-age onset cancer (EAOC) was hosted by the Colorectal Cancer Resource & Action Network (CCRAN), assembling clinicians, researchers, and patients virtually to discuss challenges in early detection and diagnosis of individuals afflicted with EAOC across tumour types. The meeting addressed the rising rates of EAOC and identified strategies to overcome barriers to timely detection and diagnosis by closing gaps in public and healthcare provider knowledge on symptoms of cancer in younger adults and reducing inequities in standard screening for younger age groups. Discussions also encompassed the various factors that serve as impediments to accessing diagnostic testing and obtaining results, as well as the critical need for access to diagnostics such as comprehensive genomic profiling (CGP), the results of which could be imperative in helping to guide clinical decisions regarding effective and well-tolerated targeted therapies. The Symposium generated key calls to action regarding increasing EAOC education and awareness among primary care providers and the public, re-evaluation of cancer screening programs’ eligibility criteria to include younger populations, and mechanisms to reduce waiting times for diagnostic testing by addressing technologist shortages and improving access to CGP through national collaborative strategies and increased funding. Full article

The rising incidence of early-onset colorectal cancer (EOCRC), particularly among underrepresented populations, highlights the urgent need for tools that can uncover clinically meaningful, population-specific genomic alterations. The phosphoinositide 3-kinase (PI3K) pathway plays a key role in tumor progression, survival, and therapeutic resistance in colorectal cancer (CRC), yet its impact in EOCRC remains insufficiently explored. To address this gap, we developed AI-HOPE-PI3K, a conversational artificial intelligence platform that integrates harmonized clinical and genomic data for real-time, natural language-based analysis of PI3K pathway alterations. Built on a fine-tuned biomedical LLaMA 3 model, the system automates cohort generation, survival modeling, and mutation frequency comparisons using multi-institutional cBioPortal datasets annotated with clinical variables. AI-HOPE-PI3K replicated known associations and revealed new findings, including worse survival in colon versus rectal tumors harboring PI3K alterations, enrichment of INPP4B mutations in Hispanic/Latino EOCRC patients, and favorable survival outcomes associated with high tumor mutational burden in FOLFIRI-treated patients. The platform also enabled context-specific survival analyses stratified by age, tumor stage, and molecular alterations. These findings support the utility of AI-HOPE-PI3K as a scalable and accessible tool for integrative, pathway-specific analysis, demonstrating its potential to advance precision oncology and reduce disparities in EOCRC through data-driven discovery. Full article

While the incidence of colorectal cancer (CRC) in patients above 50 years old has been decreasing over the last several decades, the incidence of CRC among younger patients has been increasing. Early-onset CRC (EO-CRC) is known to exhibit distinct characteristics including specific genetic mutations and modifiable risk factors, which warrants tailored screening and management approaches. This review synthesizes current insights on EO-CRC’s epidemiological, genetic, molecular, and clinical features, as well as a call for action for future research on prevention and clinical management. Full article

Colorectal cancer (CRC) is the third most common malignancy worldwide and the second leading cause of cancer-related mortality in the United States. The incidence of early-onset colorectal cancer (EOCRC) has been increasing over the past several decades. While the etiologies for this rising incidence remain unclear, genetic factors likely play an important role. DNA polymerase epsilon (POLE) mutations occur at a higher rate than average-onset colorectal cancer (AOCRC). DNA polymerase epsilon (Pol ε) is a high-fidelity, processive polymerase that is a promising target for immune checkpoint inhibitors due to its association with various human malignancies, including colorectal cancer. EOCRC remains a major area of focus, and POLE mutations leading to the high-TMB subtype constitute a potential therapeutic target. Full article

Introduction: Early-onset colorectal cancer (EOCRC) is rising rapidly, particularly among the Hispanic/Latino (H/L) populations, who face disproportionately poor outcomes. The transforming growth factor-beta (TGF-β) signaling pathway plays a critical role in colorectal cancer (CRC) progression by mediating epithelial-to-mesenchymal transition (EMT), immune evasion, and metastasis. However, integrative analyses linking TGF-β alterations to clinical features remain limited—particularly for diverse populations—hindering translational research and the development of precision therapies. To address this gap, we developed AI-HOPE-TGFbeta (Artificial Intelligence agent for High-Optimization and Precision Medicine focused on TGF-β), the first conversational artificial intelligence (AI) agent designed to explore TGF-β dysregulation in CRC by integrating harmonized clinical and genomic data via natural language queries. Methods: AI-HOPE-TGFbeta utilizes a large language model (LLM), Large Language Model Meta AI 3 (LLaMA 3), a natural language-to-code interpreter, and a bioinformatics backend to automate statistical workflows. Tailored for TGF-β pathway analysis, the platform enables real-time cohort stratification and hypothesis testing using harmonized datasets from the cBio Cancer Genomics Portal (cBioPortal). It supports mutation frequency comparisons, odds ratio testing, Kaplan–Meier survival analysis, and subgroup evaluations across race/ethnicity, microsatellite instability (MSI) status, tumor stage, treatment exposure, and age. The platform was validated by replicating findings on the SMAD4, TGFBR2, and BMPR1A mutations in EOCRC. Exploratory queries were conducted to examine novel associations with clinical outcomes in H/L populations. Results: AI-HOPE-TGFbeta successfully recapitulated established associations, including worse survival in SMAD4-mutant EOCRC patients treated with FOLFOX (fluorouracil, leucovorin and oxaliplatin) (p = 0.0001) and better outcomes in early-stage TGFBR2-mutated CRC patients (p = 0.00001). It revealed potential population-specific enrichment of BMPR1A mutations in H/L patients (OR = 2.63; p = 0.052) and uncovered MSI-specific survival benefits among SMAD4-mutated patients (p = 0.00001). Exploratory analysis showed better outcomes in SMAD2-mutant primary tumors vs. metastatic cases (p = 0.0010) and confirmed the feasibility of disaggregated ethnicity-based queries for TGFBR1 mutations, despite small sample sizes. These findings underscore the platform’s capacity to detect both known and emerging clinical–genomic patterns in CRC. Conclusions: AI-HOPE-TGFbeta introduces a new paradigm in cancer bioinformatics by enabling natural language-driven, real-time integration of genomic and clinical data specific to TGF-β pathway alterations in CRC. The platform democratizes complex analyses, supports disparity-focused investigation, and reveals clinically actionable insights in underserved populations, such as H/L EOCRC patients. As a first-of-its-kind system studying TGF-β, AI-HOPE-TGFbeta holds strong promise for advancing equitable precision oncology and accelerating translational discovery in the CRC TGF-β pathway. Full article

There has been a well-documented increase in the incidence of colorectal cancer in patients under 50 years of age. Additionally, these patients present with later-stage cancer at diagnosis compared to their over-50 counterparts. However, there is limited consensus on how the impact of this evolving epidemiology should impact existing prevention and screening tools. Recently proposed strategies include increased genetic testing, improved young patient awareness through targeted media campaigns, and initiatives to increase clinical suspicion in primary care providers. Prevention is further complicated by nuances of treating colorectal cancer in the younger population, with underexplored concerns regarding fertility, sexual health, financial impact, and extended post-treatment surveillance. This review aims to summarize the changing epidemiology of colorectal cancer in young patients, overview existing screening guidelines, and discuss challenges and opportunities surrounding prevention of early-onset colon cancer. Full article

Background/Objectives: Over the past two decades, the incidence of early-onset colorectal cancer (EoCRC) has been increasing, although its underlying causes remain unclear. Gut microbiome is known to play a role in carcinogenesis of colorectal cancer. This scoping review aims to systematically map and synthetize current evidence on gut microbiome characterization in EoCRC (vs. late-onset colorectal cancer (LoCRC) and healthy individuals), describe the methodology used, and identify knowledge gaps to inform and guide future research. Methods: This systematic scoping review followed the Joanna Briggs Institute (JBI) methodology for scoping reviews. Searches were conducted in PubMed, Web of Science, and Scopus between January and February 2025. Two reviewers independently screened and selected the studies. One reviewer extracted the relevant information, using an adapted version of the JBI template. Results: Seven studies met eligibility criteria. Compared to healthy young adults, EoCRC patients had a predominance of lower α diversity, different β diversity, and greater abundance of Flavonifractor plautii, Akkermansia muciniphila, Bacteroides, and Fusobacteria. Comparisons with LoCRC showed that EoCRC had distinct β diversity and a higher abundance in Fusobacterium, Akkermansia, Bacteroides, and Actinomyces. Only three studies correlated the microbiota composition of EoCRC with clinicopathology features and suggested positive associations between Fusobacterium abundance, rectal tumors and lower survival and Akkermansia abundance with body mass index (BMI) ≥ 25 kg/m², rectal EoCRC, and better survival. Conclusions: There is a lack of large, methodologically robust studies linking gut microbiota with clinicopathological, lifestyle, and tumor molecular features in EoCRC. Our review highlights critical knowledge gaps, the need for standardized methodologies, and key areas for future investigation. Full article

The majority of early-onset colorectal cancers (EOCRCs) are not substantiated by germline variants in the main CRC predisposition genes (the “DIGE” panel). To identify potentially novel EOCRC-specific predisposition genes, we analyzed 585 cancer pathway genes in an EOCRC patient cohort (n = 87, diagnosis ≤ 40 years, DIGE-), and compared their variant spectrum to the GnomAD cancer-free database. We identified high-impact variants (HVs) in 15 genes significantly over-represented in EOCRC. Among the 32 unrelated patients with a CRC family history (i.e., with a potentially dominant transmission pattern), 9 presented HVs in ten genes, four of which had a DNA repair function. We subsequently sequenced these 15 genes in a cohort of 82 late-onset CRCs (diagnosis ≥ 50 years, DIGE-) and found variants in 11 of these genes to be specific to EOCRC. We then screened these 11 genes in our patient database (n = 6482), which only contained 2% of EOCRCs (DIGE-), and identified two other EOCRC cases diagnosed after our cohort constitution, with HVs in RECQL4 and NUTM1. Altogether, we found that 37.5% and 18.75% of patients carrying heterozygous NUTM1 and RECQL4 HVs, respectively, in our database were diagnosed with EOCRC. Our work has identified a pattern of germline variants not previously associated with EOCRC. Full article

For a long time, D-amino acids remained unexplored in mammalian physiology. The technological advances in enantioseparation over the past 50 years have revealed that D-amino acids not only exist in human tissues and fluids but also play important roles in neurotransmission, immune regulation, and cellular proliferation. The present review provides a comprehensive assessment of the role of D-amino acids in cancer, including their endogenous and exogenous production pathways, along with the analytical methodologies used for detection and quantification, from liquid chromatography to biosensors. These methods have underlined how altered levels of D-amino acids can be helpful in early detection, progression, or response to treatment in several malignancies, including gastric, hepatic, colorectal, or breast cancer. The present review also explores how manipulation of D-amino acids can regulate cell proliferation, their mechanisms in cancer regulation, including the modulation of N-methyl-D-aspartate (NMDA) receptors and the production of hydrogen sulphide (H₂S), and the role of specific D-amino acids in cancer onset, immune defence, and protection against chemotherapy-induced toxicity. Finally, several underexplored research directions are outlined, such as potential correlations with gut microbiota composition, the impact of processed food consumption, and the integration of multiomics strategies. Full article

Background and Aims: Prior data showed an increasing incidence of early-onset colorectal cancer (EO-CRC) in the US. However, there are limited comprehensive data on recent EO-CRC incidence and mortality per different age cohorts and tumor characteristics. We aimed to evaluate EO-CRC incidence and mortality in different populations. Methods: Age-adjusted EO-CRC incidence rates were calculated from the USCS database between 2001 and 2021. Age-adjusted EO-CRC mortality rates were calculated from the NCHS database between 2000 and 2022 and the SEER database between 2004 and 2021. The age groups were 20–44 years and 45–54 years. Tumors were categorized by anatomical location (right, transverse, left, and proximal) and stage at diagnosis (early and late). The annual and average annual percentage changes (AAPC) were estimated using joinpoint regression. Age-specific pairwise comparison was conducted. Results: A total of 474,601 patients were diagnosed with EO-CRC between 2001 and 2021. The EO-CRC incidence increased in patients aged 20–44 years faster than in those aged 45–54 years (AAPC = 1.51 vs. 0.73; AAPC difference = 0.78, p = 0.001). This was most notable in proximal colon tumors (AAPC difference = 0.88, p < 0.001). While the incidence of early-stage tumors decreased in recent years across all anatomical locations, late-stage tumors increased, mostly in the proximal colon (AAPC = 2.44). A total of 147,026 patients died from EO-CRC between 2000 and 2022. Mortality increased in patients aged 20–44 years faster than in patients aged 45–54 years, who had a stable trend (AAPC difference = 0.85, p < 0.001). The increase in mortality was noted in both early- and late-stage tumors. Conclusions: Our study provides epidemiologic evidence showing an alarming increase in EO-CRC incidence and mortality among patients aged 20–44 years compared to those aged 45–54 years, which is associated with delayed diagnosis, and mostly in proximal colon tumors. Expanding screening efforts to younger populations and addressing healthcare disparities are essential for improving early detection and outcomes for younger patients. Full article

Background and Objectives: Lynch syndrome (LS), an autosomal dominant condition arising from germline mutations in mismatch repair (MMR) genes, is a major cause of hereditary early-onset colorectal cancer (CRC). Although patients diagnosed before age 50 represent a critical subgroup where Lynch syndrome might be more prevalent, data on the precise frequency, clinical outcomes, and molecular correlates remain heterogeneous across studies. This systematic review was conducted to (1) estimate the prevalence of MMR deficiency (dMMR) and confirmed LS in patients diagnosed with CRC before the age of 50, and (2) examine immunohistochemistry (IHC) mismatch repair testing patterns and associated molecular findings (BRAF mutations, MLH1 promoter hypermethylation, somatic MMR gene alterations). Methods: Following a predefined search strategy in PubMed, Scopus, and Web of Science, five relevant studies were identified (n = 5). Each study comprised patients younger than 50 who underwent IHC-based tumor screening. Data extraction covered demographic details, number of patients tested, proportion with abnormal IHC, frequency of somatic or germline MMR gene mutations, and method of classification into sporadic dMMR vs. LS. Quality assessment was performed using recommended scales for observational studies. Results: Among 5 studies totaling 960 early-onset CRC patients, the frequency of dMMR CRC ranged from 8.4% to 19.1%. The confirmed prevalence of LS among all young-onset CRC was between 5.0% and 5.9% in three studies but reached 8.9% in another and 5.1% in yet another. Across all studies, the presence of right-sided tumors and histopathological features such as tumor-infiltrating lymphocytes were more common in dMMR cancers. Incorporation of MLH1-promoter hypermethylation and/or BRAF V600E mutation testing aided discrimination of sporadic dMMR CRC from germline LS cases. Conclusions: The prevalence of LS in CRC patients younger than 50 is clinically significant, at approximately 5–9%. Routine IHC-based MMR screening is both feasible and effective for detecting LS in early-onset CRC. Further research is needed to standardize universal testing protocols, delineate the role of additional molecular assays, and ensure comprehensive genetic counseling for at-risk individuals. Full article