Search Results (184)

Background/Objectives: Early-onset colorectal cancer (EOCRC), diagnosed before age 50 years, is increasing in many populations and usually arises outside routine screening pathways. We synthesized clinical, demographic, familial, and genetic evidence relevant to risk-stratified early detection. Methods: Two core PubMed searches covering publications from 1 January 2010 through 1 June 2026 were supplemented by targeted PubMed searches and reference-list screening. The present review cited 82 journal publications and synthesized the findings qualitatively; no formal risk-of-bias assessment, certainty-of-evidence grading, or de novo quantitative pooling was performed. Results: EOCRC commonly involves the distal colon or rectum and presents with hematochezia, abdominal pain, altered bowel habits, or iron-deficiency anemia, with diagnostic intervals of several months. Screening colonoscopy in average-risk adults aged 45–49 years has a clinically relevant yield, although generally lower than in older adults, and direct evidence of reduced incidence or mortality remains limited. Risk rises with age before 50; sex and race or ethnicity provide limited, context-dependent discrimination. Family history is a consistent marker, although most cases lack documented familial aggregation. Pathogenic germline variants explain a minority, and polygenic risk scores are not established for routine practice. Conclusions: Early detection should combine timely investigation of warning signs, assessment of family history, equitable access to diagnostics, germline testing for patients with EOCRC, cascade testing, and prospective validation of population-specific models. Full article

Background/Objectives: Early-onset colorectal cancer (EOCRC), diagnosed before age 50 years, is increasing in many countries, but its causes remain uncertain. Evidence on potentially modifiable determinants is heterogeneous and vulnerable to retrospective assessment and residual confounding. We synthesized metabolic, behavioral, dietary, medication-related, clinical, and socioeconomic factors, emphasizing consistency and life-course relevance. Methods: Two core PubMed searches covering publications from 1 January 2010 through 1 June 2026 were supplemented by targeted PubMed searches and reference-list screening. The present review cited 75 journal publications and synthesized the findings qualitatively; no formal risk-of-bias assessment, certainty-of-evidence grading, or de novo quantitative pooling was performed. Results: Evidence was most consistent for excess adiposity and cardiometabolic dysfunction, with earlier and persistent exposure and cardiometabolic clustering potentially more relevant. Inflammatory bowel disease emerged as a clinically distinct high-risk condition. Sedentary behavior, smoking, and higher alcohol consumption showed recurrent but heterogeneous associations. Dietary findings varied by pattern and component: sugar-sweetened beverages and lower-quality dietary patterns showed positive associations, whereas fiber- and plant-rich diets, calcium, folate, and vitamin D showed possible inverse associations. Dietary evidence was largely retrospective and does not establish causality. Evidence for aspirin and antibiotics was limited and vulnerable to confounding, precluding causal inference. Most patterns resembled later-onset CRC. Conclusions: Current evidence does not support a wholly distinct set of environmental determinants for EOCRC. Earlier exposure, longer duration, and cumulative interaction of CRC risk factors are plausible explanations but remain incompletely tested. Evidence supports life-course primary prevention, but no single factor should determine screening eligibility in isolation. Prospective studies with repeated exposure measurement are needed. Full article

Background/Objectives: Colorectal cancer (CRC) remains a major contributor to the global oncological burden, with marked disparities in mortality and survival between Western and Eastern European countries. Romania continues to report unfavorable CRC outcomes, driven by delayed diagnosis, limited screening uptake, and heterogeneous care pathways. This study aimed to assess the 15-year institutional description of colorectal cancer case-mix in South-West Oltenia, Romania, using real-world data from a high-volume oncology referral center. Methods: We conducted a retrospective observational study including 3497 patients with newly diagnosed CRC registered between 2011 and 2025. Sociodemographic characteristics, tumor localization, stage at diagnosis, and histopathological grade were analyzed. Temporal patterns were assessed across three five-year intervals. Results: The institutional CRC case volume increased, with 434 cases recorded in 2011–2015, 1015 in 2016–2020, and 2048 in 2021–2025. Male patients accounted for 60.5% and urban residents for 60.3% of cases. Early-onset CRC was identified in 12.0% of patients, with no significant temporal trend. Rectosigmoid junction/rectal cancers represented the largest anatomical group, followed by left-sided cancers, with stable distribution across periods. Advanced stage disease was frequent, with 77.1% of patients diagnosed in stage III–IV, increasing from 67.7% to 82.0% across study intervals (p < 0.001). Histopathological grade changed significantly (p < 0.001), due to a progressive increase in unspecified grade, from 16.1% to 45.5%. Conclusions: Colorectal cancer represents a substantial institutional workload at this regional referral center, emphasizing the need for strengthened early detection strategies, optimized referral system, improved diagnostic access, and standardized pathological reporting practices. Full article

Background: Colorectal neoplasia in adults younger than 50 years has attracted increasing clinical attention because of the rising incidence of early-onset colorectal cancer. However, the clinicopathological characteristics of colorectal lesions detected in younger adults remain incompletely described. This study aimed to characterize the clinical, anatomical, and histopathological features of colorectal neoplasia in adults younger than 50 years undergoing colonoscopy. Methods: This retrospective single-center study included adults aged 18–49 years who underwent complete colonoscopy between January 2018 and December 2023. After exclusion of individuals with normal colonoscopy findings, 152 patients with at least one colorectal lesion were included. Lesions were classified as benign, advanced, or malignant according to established histopathological criteria. Demographic, endoscopic, and pathological characteristics were analyzed and compared across lesion categories. Results: Among 152 patients, 83 (54.6%) had benign lesions, 64 (42.1%) had advanced neoplasia, and 5 (3.3%) had malignant lesions. Advanced lesions were observed predominantly in individuals aged 40–49 years. Most lesions were detected in symptomatic patients undergoing clinically indicated colonoscopy. Histopathological evaluation demonstrated a higher frequency of villous/tubulovillous adenomas, sessile serrated lesions, and high-grade dysplasia among advanced lesions. Larger lesion size was strongly associated with advanced pathological features (p < 0.001). In multivariable analysis, patients aged 30–39 years had significantly lower odds of advanced or malignant neoplasia than those aged 40–49 years, whereas no independent associations were observed for sex, smoking status, alcohol use, family history of colorectal cancer, or lesion location. Conclusions: In this selected cohort of adults younger than 50 years with detected colorectal lesions undergoing clinically indicated colonoscopy, advanced neoplasia represented a substantial proportion of cases. These findings should not be extrapolated to the general population of adults younger than 50 years or to screening cohorts. Full article

Colorectal cancer (CRC) exhibits substantial heterogeneity across ancestry, age at onset, and treatment exposure. Although dysregulation of the WNT signaling pathway is a hallmark of CRC, its associations with genomic burden and survival across diverse clinical contexts remain incompletely understood. We analyzed 2562 CRC cases from AACR Project GENIE and cBioPortal, stratified by ancestry (African American [AA] and non-Hispanic White [NHW]), age at onset (early vs. late), and FOLFOX treatment status. Associations between WNT pathway alterations, genomic burden (mutation count, tumor mutational burden, and fraction of genome altered), and survival were assessed using conventional statistical methods. AI-HOPE and AI-HOPE-WNT conversational artificial intelligence platforms were used to facilitate data integration and exploratory analyses. WNT pathway alterations were highly prevalent across all subgroups and were predominantly driven by APC alterations. Late-onset CRC, particularly among NHW patients not treated with FOLFOX, exhibited higher mutation burden and enrichment of AXIN1 and AXIN2 alterations. Survival analyses demonstrated context-dependent associations between WNT alterations and outcomes. Among early-onset FOLFOX-treated patients, WNT alterations were associated with differential survival. In NHW patients, WNT alterations were linked to improved survival across multiple clinical settings, whereas associations in AA patients were more limited and context-specific. WNT pathway alterations are pervasive in CRC but exhibit ancestry-, age-, and treatment-dependent associations with genomic complexity and survival. AI-guided analyses may accelerate identification of clinically relevant subgroup-specific molecular patterns. Full article

Background: Mismatch repair deficiency (MMRd) is a central molecular determinant of colorectal cancer (CRC) biology, prognosis, and treatment response, and Universal Tumour Screening (UTS) is advocated for Lynch syndrome (LS) detection; yet real-world performance across clinical subgroups remains limited. We evaluated MMRd distribution and UTS-based LS detection in a large consecutive surgical cohort. Methods: We retrospectively analyzed 1022 consecutive CRC patients undergoing surgical resection at the University Hospital of Padua (2015–2023). MMR status was assessed by immunohistochemistry; MMRd cases underwent reflex BRAF mutation testing and, when available, MLH1 promoter methylation analysis, followed by germline multigene panel testing for suspected LS. Clinicopathological features were compared by MMR status, age at onset, and tumour location. Results: MMR testing was performed in 875 patients (85.6%), rising from 67.0% (2015–2017) to 97.4% (2021–2023). MMRd was identified in 139 tumors (15.9%) and was independently associated with age ≥ 70 years, colonic location, and stage 0–II. Of 22 patients with confirmed LS, 13 (59.1%) were newly identified through UTS; family history showed no significant univariate association with LS status and was not independently associated with MMRd after multivariable adjustment. MMRd prevalence was numerically higher in early- than late-onset CRC (20.0% vs. 15.4%), approaching significance after multivariable adjustment (OR 1.90, 95% CI 0.99–3.64; p = 0.054); hereditary syndromes were also more frequent in early-onset disease. MMRd was markedly rarer in rectal than colonic cancer (4.1% vs. 22.5%; p < 0.0001), though MMRd rectal cancers arose in younger patients. Conclusions: UTS identified a substantial proportion of LS carriers missed by age- or family-history criteria. The relationship between age and MMRd prevalence proved more nuanced than a simple comparison would suggest, reinforcing the value of universal over selective testing across the age spectrum, while MMRd rectal cancer shows a distinct younger profile relevant to immunotherapy-based organ preservation. Full article

Background/Objectives: Early-onset colorectal cancer (EOCRC), defined as colorectal cancer diagnosed before 50 years of age, is increasing worldwide and may exhibit molecular features distinct from late-onset colorectal cancer (LOCRC). This study aimed to identify EOCRC-associated genes and evaluate the functional relevance of the leading candidate. Methods: Public transcriptomic datasets were used for age-stratified candidate-gene discovery and validation. Overall survival analysis prioritized candidates, followed by loss-of-function studies and pathway-focused analyses in colorectal cancer cell lines. Results: CEMIP, NKD2, and FOXQ1 were elevated in the EOCRC groups in the discovery and integrated validation analyses. Among them, only CEMIP was significantly associated with poorer overall survival. HCT116 and HT29 cells showed relatively high endogenous CEMIP expression, and CEMIP knockdown reduced relative viable cell biomass and migration in wound-healing and Transwell assays. CEMIP-associated transcripts were enriched in several pathways, including Hedgehog, Wnt/β-catenin, and TGF-β signaling. In TCGA colon adenocarcinoma samples, CEMIP correlated most strongly with PTCH1; however, the correlations with other Hedgehog components were weak or absent. CEMIP silencing decreased PTCH1 and GLI1 transcripts while increasing SMO, suggesting a coordinated but non-linear relationship. Conclusions: CEMIP is an EOCRC-associated candidate biomarker and a functional contributor to colorectal cancer cell viability and migration. Its relationship with PTCH1-related Hedgehog signaling is exploratory and warrants direct mechanistic validation. Full article

Purpose: This study aimed to determine the optimal temporal threshold for distinguishing “early” from “late” liver metastasis in patients who developed liver metastasis after colorectal cancer (CRC) surgery, and to evaluate whether KRAS and BRAF^V600E mutations, along with other clinicopathological factors, are associated with the timing of liver metastasis. Methods: This retrospective study utilized clinical and pathological data from patients who developed liver metastasis after radical CRC surgery at two centers from 2019 to 2023. X-tile software was used to identify the optimal temporal threshold. Logistic regression analysis was applied to determine if KRAS/BRAF^V600E mutations and other potential factors are independently associated with the time to onset of liver metastasis. Results: X-tile analysis identified 11 months post-surgery as the optimal cutoff for distinguishing early metachronous liver metastasis (EMLM) from late metachronous liver metastasis (LMLM), classifying 114 cases into the EMLM group and 72 into the LMLM group. Comparative analysis indicated statistically significant differences between the two groups in lymphovascular tumor emboli, perineural invasion, and postoperative adjuvant therapy (p < 0.05). Logistic regression analysis revealed that neither KRAS mutation (OR, 1.185; 95% CI: 0.641–2.190; p = 0.587) nor BRAF^V600E mutation (OR, 2.836; 95% CI: 0.302–26.642; p = 0.363) was independently associated with the timing of liver metastasis. In contrast, postoperative adjuvant therapy showed a statistical association with a likelihood of LMLM (OR, 0.253; 95% CI: 0.105–0.611; p = 0.002). Conclusions: This study identified 11 months post-CRC surgery as the optimal cutoff for differentiating EMLM versus LMLM. In this cohort, no statistically significant association was observed between KRAS/BRAF^V600E mutations and the timing of liver metastasis, whereas postoperative adjuvant therapy was statistically correlated with the likelihood of LMLM. This stratification may guide personalized surveillance strategies and provide valuable insights for future mechanistic investigations into the temporal heterogeneity of post-surgical liver metastasis. However, the interpretation and generalization of the findings require external validation in prospective cohorts. Full article

Background/Objectives: Early-onset colorectal cancer (EO-CRC) incidence continues to rise globally, yet age-stratified risk data for adults under 45 remain limited. Methods: This retrospective, single-center, colonoscopy-based cohort study included 3959 examinees aged 18–44 at Peking University International Hospital (2023–2024) and used Joinpoint regression to identify age inflection points for polyp detection rates. Case–control analysis with Least Absolute Shrinkage and Selection Operator (LASSO)-penalized logistic regression assessed metabolic risk factors for adenoma and serrated polyps in the 40–44 stratum. Results: Detection rates for polyps, adenomas, and serrated lesions all rose with age (p < 0.001). From the youngest (18–29) to the oldest (40–44) group, the polyp detection rate increased 2.6-fold, the adenoma detection rate (ADR) 4.3-fold, and the serrated lesion detection rate 2.0-fold. Joinpoint regression revealed an ADR inflection at age 33 (annual percentage change (APC): +0.51% → +1.27%), a high-risk adenoma (HRA) inflection at age 39 (APC: +0.14% → +0.77%), and an advanced-neoplasia inflection also at age 39 (APC: +0.20% → +0.81%). Across age strata, adenoma and advanced-neoplasia detection rates were comparable between asymptomatic screening and symptomatic examinees from age 35 onward (40–44 ADR 20.5% vs. 21.6%), whereas symptomatic examinees had higher rates in the youngest strata. In exploratory cross-sectional analyses within the 40–44 group, total cholesterol (odds ratio, OR = 1.47) and body mass index (BMI) (OR = 1.05) showed associations with adenoma, without establishing causality, with BMI elevation conferring risk only in women (p for interaction = 0.018). Conclusions: Adenoma risk accelerates at 33 and high-risk lesions escalate at 39, providing age-stratified risk benchmarks for adults under 45 in a predominantly symptomatic Chinese cohort. These inflection points warrant prospective validation in asymptomatic screening populations. Full article

Early-onset colorectal cancer is increasing, making reproductive health an increasingly relevant survivorship issue. While immune checkpoint inhibitors have altered the management of deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) colorectal cancer, their implications for reproductive-age women remain insufficiently defined. We performed a focused narrative review, structured in line with the SANRA framework, to clarify this specific clinical domain. Immunotherapy may reshape female oncofertility counseling through two distinct mechanisms: direct reproductive uncertainty, including established endocrine toxicities and hypothesized, but currently unproven, direct gonadal effects; and indirect pathway-modifying effects, such as the potential avoidance of pelvic radiotherapy or radical surgery in selected patients with locally advanced dMMR/MSI-H rectal cancer. Anatomical organ preservation should not be automatically equated with functional fertility preservation. The key clinical message is that reproductive counseling should not be restricted to historically gonadotoxic chemotherapy. Instead, early multidisciplinary guidance should explicitly distinguish CRC-specific evidence from extrapolated or theoretical concerns, integrate fertility preservation strategies when clinically feasible, and address pelvic and sexual health, contraception, washout, endocrine follow-up, and future pregnancy planning. Until prospective CRC-specific reproductive data become available, immunotherapy should not be presented as either reproductively neutral or fertility-preserving. Full article

Early-onset colorectal cancer (EOCRC) is increasing disproportionately among Hispanic/Latino (H/L) populations and demonstrates substantial molecular and clinical heterogeneity. Although Wingless/Integrated (WNT) pathway alterations are among the most common genomic events in colorectal cancer, their prognostic significance in the context of contemporary systemic therapies, including Bevacizumab, remains incompletely understood. We conducted an integrative clinical–genomic analysis of colorectal cancer cohorts stratified by age at diagnosis, ancestry, and Bevacizumab exposure, interrogating somatic alterations across curated WNT signaling pathway genes. Conversational artificial intelligence agents (AI-HOPE and AI-HOPE-WNT) enabled dynamic cohort construction, treatment-specific subgroup analyses, and pathway-level interrogation through natural language-driven clinical–genomic integration. WNT pathway alterations, predominantly involving APC, were highly prevalent across all cohorts; however, their distribution and clinical associations demonstrated strong treatment-, ancestry-, and age-dependent variability. Bevacizumab-treated tumors exhibited lower mutation frequencies in several WNT regulators, including RNF43, AXIN1/2, TCF7L2, and AMER1, suggesting potential biologic interaction or treatment-related selective pressure. Importantly, WNT pathway alterations were associated with improved overall survival in H/L EOCRC and Non-Hispanic White (NHW) late-onset colorectal cancer, but with worse survival in NHW EOCRC, highlighting distinct ancestry- and age-specific prognostic effects. These findings support the role of the WNT pathway dysregulation as a disparity-aware biomarker framework in colorectal cancer and demonstrate the utility of conversational AI systems for scalable multidimensional clinical–genomic integration in precision oncology. Full article

Background: The incidence of early-onset colorectal cancer (EOCRC) is rising, yet the relative contribution of metabolic, inflammatory, and laboratory abnormalities remains incompletely defined. Objectives: We compared these associations between EOCRC and late-onset colorectal cancer (LOCRC) while addressing the possibility that some laboratory abnormalities may reflect occult cancer rather than antecedent risk. Methods: We conducted a matched case–control study using the TriNetX US Network. Adults diagnosed with CRC between 2010 and 2023 were identified as EOCRC (18–49 years) or LOCRC (50–75 years). Patients with prior malignancy, inflammatory bowel disease, hereditary or familial CRC risk, or prior colectomy were excluded. Three separate analyses were performed. First, a direct EOCRC-versus-LOCRC comparison evaluated gastrointestinal symptoms during the 6 months preceding diagnosis. Second, EOCRC and LOCRC were each compared with their respective matched cancer-free controls to assess clinical, metabolic, and laboratory features during the 24 months preceding diagnosis. When multiple laboratory values were available, the most recent value preceding the index date was used. Conditional logistic regression estimated adjusted odds ratios with 95% confidence intervals, with Bonferroni correction applied for multiple comparisons. Results: The direct matched EOCRC-versus-LOCRC comparison included 7752 patients with CRC, comprising 2584 with EOCRC and 5168 with LOCRC. EOCRC more frequently presented with rectal bleeding, abdominal pain, diarrhea, iron-deficiency anemia, and weight loss. Rectal tumors were more common in EOCRC, whereas proximal tumors were more common in LOCRC. In separate control-based analyses, 3217 patients with EOCRC and 12,112 patients with LOCRC were compared with 6434 and 24,336 matched cancer-free controls, respectively. The strongest independent features associated with EOCRC were severe obesity (aOR 2.61), microcytosis (aOR 2.29), low ferritin (aOR 2.11), and elevated C-reactive protein (aOR 1.87). Similar but generally attenuated associations were observed in LOCRC. In adjusted EOCRC-versus-LOCRC analyses, obesity (aOR 1.38), metabolic syndrome (aOR 1.41), and MASH (aOR 1.22) remained more closely associated with EOCRC. Conclusions: EOCRC is associated with a distinct clinical–metabolic phenotype, with more pronounced metabolic, inflammatory, and hematologic abnormalities than LOCRC. These findings should be interpreted as hypothesis-generating prediagnostic associations, not as validated predictors or causal risk factors. Full article

The fifth annual pan-tumour Early Age Onset Cancer (EAOC) Symposium, held in November 2025 and organized by the Colorectal Cancer Resource & Action Network (CCRAN), convened clinicians, researchers, policymakers, patients, and caregivers to address the rising incidence of cancers in individuals under 50 years. In addition to discussions around diagnostic and therapeutic advances for patients with late-stage disease, content centered on addressing critical gaps along the EAOC care continuum, including (i) diagnostic delays related to limited awareness and suboptimal primary care pathways, (ii) screening eligibility criteria for colorectal cancer (CRC) that no longer reflect current disease epidemiology, and (iii) insufficient age-appropriate infrastructure to meet the EAOC population’s unique unmet needs with respect to psychosocial support, fertility counseling, financial navigation, and survivorship planning. The symposium generated consensus recommendations such as the embedding of EAOC education into medical training curricula to increase the index of suspicion of EAOC in primary care, lowering the CRC screening age to 45 years to match this population’s rising disease incidence, and expanding multidisciplinary adolescent and young adult (AYA) and EAOC programs—including through the use of virtual models—to ensure that patients receive coordinated, comprehensive, equitable and age-appropriate care across the country. Full article

Background: The incidence of early-onset colorectal cancer (EOCRC) has increased worldwide and now represents approximately 10% of colorectal cancers in high-income countries. EOCRC is frequently associated with advanced pathological features, although its clinical behavior and optimal management remain incompletely defined. Methods: We performed a retrospective single-center study including 88 consecutive patients aged ≤50 years who underwent curative-intent colorectal cancer resection between January 2019 and December 2023 at a tertiary referral center. Perioperative outcomes, pathological characteristics, and recurrence patterns were analyzed. Results: The median age was 44 years, and 67% of tumors were located in the colon. Pathological nodal involvement (pN+) was observed in 47.7% of patients, with a high prevalence of adverse features including perineural invasion (62.5%), tumor budding (17.0%), and tumor deposits (15.9%). Minimally invasive surgery was performed in 79% of patients and was associated with shorter hospital stay without increased postoperative morbidity (19.3%). During a median follow-up of 31.3 months [IQR 21.6–44.6], recurrence occurred in 40 patients (45.5%) and was predominantly distant (75.0%). Among patients with recurrence, 21 (52.5%) underwent surgical reintervention, most commonly hepatic and pulmonary resections. Rectal cancer was associated with higher rates of stoma formation and major postoperative complications compared to colon cancer. Conclusions: EOCRC is characterized by a high prevalence of adverse pathological features and a substantial rate of distant recurrence. However, a relevant proportion of recurrences remains amenable to surgical treatment in selected patients. Management in a specialized tertiary center allows achievement of high-quality surgical outcomes and supports an aggressive multidisciplinary approach. Full article

Background/Objectives: Colorectal cancer (CRC) is relatively uncommon in individuals under 40 years of age; however, its rising incidence is a growing concern. This study aimed to investigate clinicopathologic features, genetic alterations, and protein expression patterns in early-onset colorectal cancer (EOCRC) to better understand the underlying mechanisms and prognostic factors. Methods: We retrospectively analyzed 18 patients diagnosed with EOCRC (<40 years) at our institution between 2018 and 2023. Next-generation sequencing (NGS) and immunohistochemistry (IHC) were used to assess genomic alterations and protein expression profiles. Clinicopathologic data were correlated with molecular findings and outcomes. Results: The cohort included ten females and eight males (mean age, 32.7 years; range, 17–38 years). Tumors most frequently arose in the rectum (56%) and were predominantly high stage (T3–T4, 67%) and moderately differentiated (78%). Lymphovascular invasion occurred in 50% of cases, and lymph node metastasis in 39%. Most tumors were microsatellite stable (MSS, 89%) and mismatch repair–proficient; two cases (11%) were MSI-high with germline MMR mutations. Among 17 patients who underwent NGS, the most frequent mutations involved KRAS (35%), APC (24%), TP53 (18%), and SMAD4 (18%). Notably, SMAD4 protein downregulation by IHC was observed in 67% of cases, including 60% of SMAD4 wild-type tumors. Loss of SMAD4 expression was significantly associated with lymph node metastasis (p = 0.037) and poor survival (p = 0.045). Conclusions: SMAD4 alteration—on both the genetic and protein levels—is common in EOCRC and is significantly correlated with aggressive clinicopathologic features and worse prognosis. Full article