Early-Onset Colorectal Cancer: From Epidemiologic Shift to Life-Course Carcinogenesis and Age-Attuned Care

Early-Onset Colorectal Cancer: Epidemiology, Molecular Drivers, and Implications for Screening and Treatment

Current evidence on early-onset colorectal cancer epidemiology, biology, clinical presentation, screening, and treatment is summarized, and emerging directions including liquid biopsy, artificial intelligence, and microbiome-based strategies are highlighted.

Announcing The Lancet Regional Health—Europe series on the alarming surge of early-onset colorectal cancer: a multidisciplinary call to action

The rising incidence of early-onset colorectal cancer (EOCRC), defined as a diagnosis in adults younger than 50 years, has emerged as a critical global public health challenge. 1 While colorectal cancer (CRC) rates in older populations have stabilized or declined due to successful screening programs, the incidence among younger adults is surging at an unprecedented rate. 2 Projections suggest that by 2030, one-third of all colo-rectal cancers will be diagnosed in individuals under the age of 50. 3 This “unprecedented tumor epidemic” might be driven by a significant birth cohort effect, suggesting that generational shifts in environmental exposures, lifestyle factors, such as obesity, westernized diets, antibiotic usage, and potentially associated alterations in the microbiome are reshaping the epidemiological landscape of CRC. 4 The rising incidence of EOCRC has prompted increasing scientific attention, though substantial knowledge gaps still remain. No specific etiologic factors have been clearly identified, limiting our understanding of disease biology and hindering the development of effective prevention tools and tailored management strategies. Although EOCRC shows distinct clinical and pathological features, clear associations with specific molecular alterations have not yet been demonstrated. As a result, no obvious molecular targets have emerged so far to support the development of dedicated targeted therapies. Moreover, EOCRC affects individuals during the most productive years of life, adding complexity to their clinical management. Patients face a broad range of unmet needs including fertility, relationships, career, and long-term survivorship, which are often insufficiently addressed within current care models. The higher prevalence of hereditary cancer

Emerging exposure-driven accelerated colorectal carcinogenesis: a model with implications for screening colonoscopy effectiveness.

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide, with its burden projected to rise. Screening average-risk individuals is recommended because several strategies reduced CRC incidence and mortality. While overall CRC incidence and mortality have stabilised or declined in many developed regions, rates increase in low- and middle-income countries, alongside a global surge in early-onset CRC (EOCRC). The previous shift toward earlier-stage diagnosis has reversed, with rising distal and rectal tumours, despite these being more amenable to prevention by screening. Even when performed with highest quality, guideline-concordant screening and surveillance cannot fully prevent CRC and post-colonoscopy CRC (PCCRC). These patterns suggest that current slowly progressing precursor-based models of tumourigenesis may not fully explain all emerging CRC phenotypes. We propose that sporadic microsatellite-stable EOCRC and a subset of PCCRC represent sentinel manifestations of a broader, under-recognised process of exposure-related accelerated carcinogenesis. In this conceptual model, environmental and lifestyle exposures may promote subclinical inflammation, immune dysregulation, microbiome disruption and epigenetic remodelling, thereby compressing the timeline from early mutational events to overt tumourigenesis. We postulate that cumulative exposures converge to create biologically permissive tissue states that enable accelerated malignant transition, either through shortened, subtle precursor phases or directly from dysplastic mucosa. We introduce oncoembryonic reprogramming as a potential molecular mechanism linking exposure-driven mucosal remodelling to accelerated tumour progression and malignant competence. This proposed model may help explain why some CRCs are not prevented by conventional precursor-based strategies and could have relevant implications for risk stratification, screening strategies and translational targeting.

Shaping the future of early-onset colorectal cancer prevention.

P1.036. Early-Onset Gastric Cancer (EOGC): A Meta-Analysis of Risk Factors, Clinicopathological Features, and Survival Outcomes

Esophageal Cancer: Other Early onset gastric cancer (EOGC), defined as diagnosis before 55 years, represents a growing global health challenge. Although traditionally rare, its incidence is rising and now constitutes the second most common early onset gastrointestinal malignancy after colorectal cancer. EOGC has been hypothesised to reflect distinct biology, yet risk factors, clinicopathological features and survival outcomes remain poorly synthesised. We aimed to evaluate global evidence on EOGC and, where possible, compare findings with late onset gastric cancer to determine whether EOGC represents a distinct clinical entity with implications for earlier diagnosis and targeted prevention strategies. A systematic review and meta-analysis was conducted according to PRISMA guidelines. PubMed, Embase and Scopus were searched from inception to 20 June 2025. After deduplication, titles, abstracts and full texts were screened for eligibility. Studies were included if they reported EOGC (<55 years) as a distinct cohort and provided extractable data on risk factors, clinicopathological characteristics or overall survival. Comparative late-onset cohorts were included when available. Case reports, reviews, studies without age stratification, mixed-malignancy cohorts and studies lacking sufficient numerical data were excluded. Non-English studies were excluded unless reliable translation was possible. Effect estimates were extracted or calculated, and pooled using random-effects models. Heterogeneity was assessed using I2 statistics. Survival proportions were synthesised where comparable time points could be extracted. Ninety-one studies comprising 30,067 EOGC patients were included. EOGC showed a significant female predominance globally (53.3% vs 46.7%; p < 0.0001), and women were more likely to have EOGC than late-onset disease (OR 1.50, 95% CI 1.45–1.56). Significant associations were identified for Helicobacter pylori (OR 4.12, 2.37–7.18), family history (OR 4.02, 3.03–5.36), high salt intake (OR 2.06, 1.44–2.94) and obesity (OR 1.81, 1.58–2.07), while smoking and alcohol were not associated. Diffuse-type and signet-ring morphology were prominent (38.9%). EOGC more frequently presented at advanced stage than late-onset cancer (52.5% vs 45.9%; p < 0.0001). Pooled overall survival was 78.0% at 1 year, 51.1% at 3 years and 43.0% at 5 years, with no significant difference compared with late-onset disease (OR 1.08, 0.39–2.97; p = 0.88). Distal gastric cancers predominated across all global regions, but the highest burden of proximal tumours was observed in East and South-East Asia. EOGC exhibits a distinct clinicopathological and risk-factor profile, characterised by strong associations with H. pylori, family history, high-salt diet and obesity, alongside a high burden of diffuse and signet-ring histology. Despite younger age, advanced-stage presentation is common and long-term survival remains poor, with outcomes comparable to older adults. These findings indicate that youth does not confer prognostic advantage and support the need for targeted prevention, earlier recognition and tailored research efforts focused on gastric cancer in younger populations.

Understanding the Rising Incidence of Early-Onset Colorectal Cancer: Life-Course Determinants and Opportunities for Primary Prevention

Simple Summary Colorectal cancer diagnosed before age 50 is becoming more common in many countries, although the reasons remain uncertain. This review examined 75 publications on lifestyle, metabolic, clinical, medication-related, and social factors associated with early-onset disease. The clearest associations involved excess body weight and poor metabolic health. Physical inactivity, smoking, alcohol consumption, and dietary patterns showed less consistent associations, while inflammatory bowel disease emerged as a clinical risk condition. Evidence on medications and social conditions was limited. Many of these factors influence colorectal cancer at older ages; their relevance to earlier-onset disease may depend on when exposure begins, its duration, and how exposures interact over time. The findings support prevention throughout the life course with healthier food and activity environments, tobacco control, reduced harmful alcohol use, and better metabolic health. However, observational evidence does not establish that any single factor causes early-onset colorectal cancer or should independently determine screening eligibility.