From Mutation to Prognosis: AI-HOPE-PI3K Enables Artificial Intelligence-Agent Driven Integration of PI3K Pathway Data in Colorectal Cancer Precision Medicine

e15520 Background: Colorectal cancer (CRC) is a significant public health concern, with disparities based on race, gender, and socioeconomic status increasingly recognized. The incidence of early-onset CRC (EOCRC) is rising, highlighting the need for detailed examination of disparities in EOCRC compared to late-onset CRC (LOCRC). This study utilizes the NIH All of Us database to explore these disparities. Methods: We conducted a cross-sectional analysis of 266,520 participants from the NIH All of Us Registered Tier Dataset v7. CRC cases were identified based on at least two recorded diagnoses in electronic health records. Participants were categorized into EOCRC if diagnosed before age 50 and LOCRC if diagnosed at age 50 or above. We compared demographic and socioeconomic variables, including gender, race/ethnicity, income, education, and smoking status, between the groups, using questionnaire responses. Statistical analyses were performed using R. Results: The average age at diagnosis was 42.1 years for EOCRC patients and 63.7 years for LOCRC patients. The EOCRC group had a higher proportion of females (57.8%) compared to the LOCRC group (49.2%, p = 0.006). Whites constituted the majority in both categories, but Hispanics were significantly more represented in the EOCRC group (21.1%) compared to the LOCRC group (11.1%, p < 0.001). Individuals with a higher income (more than $100,000 per year) were more prevalent in the EOCRC group (29.9%) than in the LOCRC group (17.7%, p < 0.001). There was no significant difference in education levels between the two groups (p = 0.52). A history of smoking 100 or more cigarettes was less common in EOCRC patients (32.8%) than LOCRC patients (48.1%, p < 0.001). Conclusions: This analysis highlights significant disparities in racial and gender representation as well as income level. Despite observed differences between the two groups, Hispanics, females, and higher income alone may not explain the only influencing factors as other cofounders, like insurance level, may have impacted the result. Cigarette exposure was more prevalent in the LOCRC group, which may represent a stronger environmental influence on CRC within this group. These findings highlight the need for further research to understand the underlying causes of these disparities and to develop targeted interventions. By addressing these disparities, we can move towards more equitable outcomes across all populations. [Table: see text]

The proportion of early onset colorectal cancer (EOCRC) is alarming in adults, including in African Americans (AA). To investigate differences between EOCRC compared to late-onset colorectal cancer (LOCRC) among AA patients. This retrospective study reviewed demographic, clinical presentations, colonoscopy, and pathology reports of patients at Howard University Hospital from 1959 to 2023. The study included 176 EOCRC cases (< 45years) and 2034 LOCRC cases (> 45years). Both EOCRC and LOCRC groups were predominantly AA (> 80%) with slightly more females (53%) than males. The mean age was 38years for EOCRC and 66years for LOCRC cases. EOCRC cases increased as a proportion of total detected CRC cases since 2010 (over 13%) after several decades of just above 6%. Family history of CRC in first degree relatives was higher among EOCRC (15.5% vs.3.4% in LOCRC patients, p < 0.01). Symptoms at presentation were prevalent in both EOCRC (93.8%) and LOCRC (92.6%). EOCRC patients exhibited higher incidence of abdominal pain (23.3% vs. 17.2%, p = 0.05) and changes in bowel habits (24.4% vs. 14%, p < 0.01) compared to LOCRC patients. Other symptoms such as melena, hematochezia, and weight loss were less prevalent in EOCRC patients. Comorbidities like hypertension (HTN), diabetes mellitus (DM), and inflammatory bowel disease (IBD) were less frequent among EOCRC patients. EOCRC was primarily observed in the sigmoid and rectosigmoid regions (p = 0.02). Metastasis at index colonoscopy was more prevalent with EOCRC compared to LOCRC (p = 0.04), with a higher proportion of patients at stage 3 cancer (p < 0.05). Significant differences were noted in the timeline for undergoing surgery after the diagnosis of colorectal cancer, with EOCRC patients taking longer than LOCRC patients (p = 0.03). Presentation of EOCRC over LOCRC increased proportionally in our cohort since 2010 and is associated with family history, and symptoms such as abdominal pain and change in bowel habits. Likely because of age at presentation, there are less comorbidities among EOCRC patients who predominantly present in the outpatient setting, and more likely diagnosed with advanced stage lesions that are predominantly sigmoid or rectosigmoid. These findings are similar to observations seen in the general population with EOCRC, albeit African American patients have commonly had earlier age presentation of CRC than White American patients.

Background/Objectives:Early-onset colorectal cancer (EOCRC), defined as colorectal cancer (CRC) diagnosed before the age of 50, has been increasing in incidence, particularly among Hispanic/Latino (H/L) populations. Despite this trend, the underlying molecular mechanisms driving EOCRC disparities remain poorly understood. The MAPK and JAK/STAT pathways play critical roles in tumor progression, proliferation, and treatment response; however, their involvement in ethnicity-specific differences in EOCRC remains unclear. This study aims to characterize molecular alterations in MAPK and JAK/STAT pathway genes among EOCRC patients, focusing on differences between H/L and Non-Hispanic White (NHW) patients. Additionally, we assess whether these pathway-specific alterations contribute to survival outcomes in H/L EOCRC patients.Methods:We conducted a bioinformatics analysis using publicly available CRC datasets to assess mutation frequencies in MAPK and JAK/STAT pathway genes. A total of 3,412 patients were included in the study, comprising 302 H/L patients and 3,110 NHW patients. Patients were stratified by age (EOCRC: <50 years, late-onset colorectal cancer –LOCRC: ≥50 years) and 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 EOCRC patients.Results:Significant differences were observed in MAPK pathway-related genes when comparing EOCRC and LOCRC in H/L patients. NF1 (11.6% vs. 3.7%, p = 0.01), ACVR1 (2.9% vs. 0%, p = 0.04), and MAP2K1 (3.6% vs. 0%, p = 0.01) were more prevalent in EOCRC, while BRAF mutations (18.3% vs. 5.1%, p = 9.1e-4) were significantly more frequent in LOCRC among H/L patients. Additionally, when comparing EOCRC in H/L patients to EOCRC in NHW patients, key MAPK pathway genes such as AKT1 (5.1% vs. 1.8%, p = 0.03), MAPK3 (3.6% vs. 0.7%, p = 6.83e-3), NF1 (11.6% vs. 6.1%, p = 0.02), and PDGFRB (5.8% vs. 2.1%, p = 0.02) were significantly enriched in H/L EOCRC patients. However, no significant differences were observed in JAK/STAT pathway-related genes when comparing EOCRC and LOCRC in H/L patients, nor when comparing EOCRC in H/L vs. NHW patients. Survival analysis revealed borderline significant differences in H/L EOCRC patients, whereas NHW EOCRC patients with no alterations in the JAK/STAT pathway exhibited significant survival differences. In contrast, MAPK pathway alterations were not associated with significant survival differences. These findings suggest that MAPK and JAK/STAT pathway disruptions may have distinct prognostic implications in H/L EOCRC patients, justifying further investigation into their potential role in cancer progression and treatment response.Conclusions:These findings suggest that MAPK pathway dysregulation plays a distinct role in EOCRC among H/L patients, potentially contributing to disparities in CRC development and treatment response. The higher prevalence of MAPK alterations in H/L EOCRC patients compared to NHW patients underscores the need to explore ethnic-specific tumor biology and therapeutic targets. Conversely, the lack of significant differences in JAK/STAT pathway alterations suggests that this pathway may not play a major differential role in EOCRC vs. LOCRC within this population. Survival analysis highlighted the prognostic relevance of pathway-specific disruptions. These insights emphasize the importance of precision medicine approaches that consider genetic heterogeneity and pathway-specific alterations to improve outcomes for H/L CRC patients.

The incidence of colorectal cancer (CRC) in individuals under the age of 50 has increased. Liver metastasis (LM) is the most common metastasis in CRC patients and is associated with a poor prognosis. This study aimed to use public databases to identify the risk factors for LM in early-onset colorectal cancer (EOCRC) patients and develop a nomogram to quantify the risk of LM. We retrospectively collected data of EOCRC patients diagnosed from 2010 to 2015 in the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate logistic analysis were used to screen and validate the risk factors for LM in EOCRC patients, and a nomogram was established based on these factors. Calibration curve, area under the receiver operating curve (AUC), and decision curve analysis (DCA) were developed to evaluate the accuracy of the model. A total of 2567 EOCRC patients were included and randomly divided into a training set (n = 1797) and a validation set (n = 770) at a ratio of 7:3. Univariate and multivariate analyses showed that N stage, pretreatment CEA, bone metastasis, and lung metastasis were independent risk factors. The AUCs of the training set and validation set were 0.7958 and 0.7653, respectively, and the calibration curve also demonstrated good accuracy and predictive ability. DCA indicated that it was more clinically relevant than the traditional TN staging. We constructed a Random Forest model, and calculated the SHapley Additive exPlanations (SHAP) values to determine variables importance and visualize the results. We developed a nomogram to predict the risk of LM in EOCRC patients, and the model was internally validated with good accuracy and reliability. It can assist doctors in risk assessment and clinical decision-making.

There has been a global increase in early-onset colorectal cancer (EOCRC), yet there has been very limited exploration of its impact in Indonesia. This study aimed to determine the clinicopathologic characteristics and the overall survival (OS) of EOCRC compared with those of average-onset colorectal cancer (AOCRC). Medical records were retrospectively reviewed from all patients presenting with colorectal cancer (CRC) at Dr Sardjito General Hospital (Yogyakarta, Indonesia) between 2016 and 2019. Sociodemographic, clinicopathologic, and treatment variables were extracted. t Tests were used to compare characteristics of EOCRC and AOCRC patient groups. The Cox proportional hazards regression model was used to analyze age and other potential prognostic factors. The total population (N = 1,276) comprised EOCRC (n = 149; 11.7%) and AOCRC (n = 1,127; 88.3%) patients. EOCRC patients were more likely to have a higher education level, be single, have out-of-pocket insurance, be underweight, and have signet ring histology (all P values <.05), compared with AOCRC patients. EOCRC and AOCRC groups had a comparable estimated 5-year OS of 34.2% and 36.9%, respectively. In multivariable analyses, performance status (Eastern Cooperative Oncology Group), hemoglobin level, cancer stage, and treatment intention were independent prognostic factors for OS (all P values <.05). To our knowledge, this first major study of EOCRC in Indonesia highlights its role in the overall burden of CRC and its connection with social determinants of health. Patients with EOCRC are more commonly underweight and generally have a higher proportion of signet ring histology than AOCRC, yet OS in both groups is similar. Future research is required to identify risk factors to inform the content and focus of public health education activities, alongside delineating the biology and causes of early and average onset of the disease.

ObjectiveThe incidence of early-onset colorectal cancer (EO-CRC) is steadily increasing. Here, we aimed to characterise the interactions between gut microbiome, metabolites and microbial enzymes in EO-CRC patients and evaluate their...

BackgroundThe incidence of early-onset colorectal cancer (EoCRC), defined as a CRC diagnosed in individuals younger than 50 years, has been increasing globally. The clinicopathological differences between EoCRC and late-onset CRC (LoCRC: diagnosed in individuals older than 50 years) are suggestive of distinct genomic landscapes. The aim of this study was to assess the differences in genomic alterations in Japanese patients with EoCRC and LoCRC from multiple institutions across Hokkaido using comprehensive genomic profiling data.MethodsThe patient’s background, CRC location, pathological findings, clinical stage at presentation, prognosis, and genomic alterations of the EoCRC and LoCRC groups were compared.ResultsA total of 317 CRC patients were analyzed, including 61 with EoCRC and 256 with LoCRC. Right-sided CRC and differentiated histology were significantly less common in the EoCRC group. There was no significant difference in the median survival duration between the two groups. Genomic profiling revealed significantly higher frequency of SMAD4, FLT3, and CDK8 alterations in EoCRC patients compared to LoCRC patients (p = 0.016, p = 0.023, and p = 0.035, respectively). Cell cycle pathway alterations were also significantly enriched in the EoCRC group (p = 0.003). Additionally, SMAD4 mutations were associated with poor prognosis in both groups.ConclusionsSMAD4, FLT3, and CDK8 alterations were significantly more prevalent in EoCRC patients, suggesting that these genes likely contribute to the distinct molecular pathogenesis of EoCRC, and may also serve as potential therapeutic targets. Further studies are warranted to elucidate their biological significance and explore their potential in the development of targeted therapies for Japanese patients with EoCRC.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10147-025-02889-w.

Early-onset colorectal cancer (EOCRC), defined as that diagnosed before the age of 50, accounts for 10–12% of all new colorectal cancer (CRC) diagnoses. Epidemiological data indicate that EOCRC incidence is increasing, despite the observed heterogeneity among countries. Although the cause for such increase remains obscure, ≈13% (range: 9–26%) of EOCRC patients carry pathogenic germline variants in known cancer predisposition genes, including 2.5% of patients with germline pathogenic variants in hereditary cancer genes traditionally not associated with CRC predisposition. Approximately 28% of EOCRC patients have family history of the disease. This article recapitulates current evidence on the inherited syndromes that predispose to EOCRC and its familial component. The evidence gathered support that all patients diagnosed with an EOCRC should be referred to a specialized genetic counseling service and offered somatic and germline pancancer multigene panel testing. The identification of a germline pathogenic variant in a known hereditary cancer gene has relevant implications for the clinical management of the patient and his/her relatives, and it may guide surgical and therapeutic decisions. The relative high prevalence of hereditary cancer syndromes and familial component among EOCRC patients supports further research that helps understand the genetic background, either monogenic or polygenic, behind this increasingly common disease.

Introduction: Obesity is commonly characterized by high levels of internal (visceral) adiposity. Visceral adipose tissue (VAT) is highly metabolically active and secretes proteins and metabolites in paracrine and endocrine signaling pathways. The phenotype of tumor-adjacent VAT may be an unexplored factor for risk and progression of early-onset colorectal cancer (EOCRC). Thus, we aimed to identify transcriptomic differences in tumor-adjacent visceral adipose tissue (VAT) in patients with EOCRC (&amp;lt;50 years at diagnosis) vs. those diagnosed with later-onset colorectal cancer (LOCRC; &amp;gt;50 years at diagnosis). Methods: VAT samples were collected from 332 patients with stage 0-III colorectal cancer enrolled in the ColoCare Study and recruited at Huntsman Cancer Institute (Utah), Heidelberg University Hospital (Germany), University of Tennessee Health Science Center (Tennessee), and Moffitt Cancer Center (Florida). Patients in our study were treatment naïve. VAT tissue was collected 1-3 cm from the colorectal tumor during surgery. VAT transcriptomes were measured with bulk RNA sequencing. Participants were classified as EOCRC vs. LOCRC. Normalized differentially expressed genes were identified (DESeq2), with analyses adjusted for sex, body mass index (BMI), study site, and tumor stage. Gene set enrichment analysis (GSEA) identified enriched pathways within the 2025 Hallmark gene sets. Significance was assessed using false discovery rate (FDR) p-adj&amp;lt;0.05. We replicated our analyses, adjusting for tumor site (colon vs. rectal), to account for potential differences by anatomical subgroup. Results: Patients with EOCRC (n=45, average age: 41±9 years) had higher disease stages compared to LOCRC patients (n=287, average age: 66±10 years) (EOCRC: 64% Stage III vs LOCRC: 39% Stage III) and similar BMI (EOCRC: 28.8±7.0 kg/m2 vs. LOCRC: 28.5±5.9 kg/m2). GSEA revealed 5 significantly enriched gene sets (FDR p-adj&amp;lt;0.05) in VAT when comparing EOCRC to LOCRC patients. VAT of EOCRC patients exhibited upregulation of immune pathways (Interferon Alpha Response, Interferon Gamma Response, TNFA Signaling via NF- κB), and fibrosis Hallmark pathways (Epithelial Mesenchymal Transition) (Normalized Enrichment Score (NES) &amp;gt;1.5, p-adj&amp;lt;0.05). Additionally, the VAT of patients with EOCRC showed upregulation of the glycolysis gene set relative to LOCRC (NES&amp;gt;1.5, p-adj&amp;lt;0.05). These pathways remained significantly enriched regardless of tumor site adjustment. Conclusions: VAT of patients with EOCRC displays a differential gene expression landscape relative to LOCRC patients, suggesting enhanced immune, fibrotic, and metabolic activity. These findings suggest that tumor-adjacent VAT physiology may be a relevant factor of the tumor-microenvironment in EOCRC progression. Citation Format: Victoria M. Bandera, Patricia Erickson, Caroline Himbert, Elaine M. Glenny, Tengda Lin, Sheetal Hardikar, Aik Choon Tan, Jennifer Ose, Victoria Damerell, Christy Warby, Olena Aksonova, Chris Stubben, David Nix, Kenneth Boucher, Peter Schirmacher, Ildiko Strehli, Megan Mclaws, Alejandro Sanchez, Jolanta Jedrzkiewicz, Lyen C. Huang, Vaia Florou, Jessica N. Cohan, Alexander Brobeil, Hans-Ulrich Kauczor, Christoph Kahlert, Meghana Karchi, Elizabeth H. Wood, Doratha A. Byrd, Erin M. Siegel, Adetunji T. Toriola, David Shibata, Christopher I. Li, Jane C. Figueiredo, Biljana Gigic, Jatin Roper, Stephen Hursting, Cornelia M. Ulrich. Tumor-adjacent visceral adipose tissue displays an altered transcriptomic landscape in early-onset colorectal cancer patients: Results from the ColoCare Study [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(23_Suppl):Abstract nr PR007.

Simple SummaryColorectal cancer (CRC) screening by immuno-fecal occult blood tests (iFOBTs) begins at age 50 in average-risk persons. However, the incidence of early-onset CRC has risen; of the cases, at least half are sporadic CRC without a family history. The authors of this study found a high percentage of de novo germline mutation in young sporadic CRC patients, as well as in sporadic colorectal polyp and control groups. All the mutated genes contribute to various DNA-repair pathways, hinting that a loss of genomic integrity play a crucial role in the development of CRC. The early identification of cancer-susceptible individuals by multigene panels in younger individuals who may be missed under current iFOBT screening could contribute to preventing CRC.Given recent increases in the proportion of early-onset colorectal cancer (CRC), researchers are urgently working to establish a multi-gene screening test for both inherited and sporadic cancer-susceptible individuals. However, the incidence and spectrum of germline mutations in young sporadic CRC patients in East Asian countries and, especially, in sporadic polyp carriers and normal individuals are unknown. Peripheral blood samples were collected from 43 colonoscopy-proved normal controls and from 50 polyp patients and 49 CRC patients with no self-reported family history of cancer. All participants were under 50 years old. Next-generation sequencing with a panel of 30 CRC-associated susceptibility genes was employed to detect pathogenic germline mutations. The germline mutation carrier rates were 2.3%, 4.0%, and 12.2% in the normal, polyp, and cancer groups, respectively. A total of seven different mutations in six DNA repair pathway-related genes (MLH1, BRCA1, BRCA2, CHEK2, BLM, and NTHL1) were detected in nine participants. One frameshift mutation in BRCA2 and one frameshift mutation in the CHEK2 gene were found in a normal control and two colorectal polyp patients, respectively. One young sporadic CRC patient carried two heterozygous mutations, one in MLH1 and one in BRCA1. Three mutations (MLH1 p.Arg265Cys, MLH1 p.Tyr343Ter and CHEK2 p.Ile158TyrfsTer10) were each found in two independent patients and were considered “founder” mutations. This is the first report to demonstrate high percentage of germline mutations in young sporadic colorectal polyp, CRC, and general populations. A multi-gene screening test is warranted for the proactive identification of cancer-predisposed individuals.

Background. Colorectal cancer (CRC) incidence rates have increased in younger individuals worldwide. A recent US study reported increases among both non- Hispanic whites (NHW) and non-Hispanic blacks (NHB), but did not consider other racial/ethnic groups. Thus, we examined the most recent CRC rates for the US by age, race/ethnicity, and anatomic location. Methods. Age-standardized incidence rates (ASR, per 100,000) of CRC were calculated for 2001-2002 through 2015-2016 using the US Cancer Statistics Database, which includes data from the National Program of Cancer Registries and the Surveillance, Epidemiology, and End Results Program. US Cancer Statistics covers the entire US population. Results were cross- classified by age (20-49 [early-onset] and 50-74 years [late-onset]), race/ethnicity (NHW, NHB, Hispanic, American Indian/Alaskan Native [AIAN], Asian/Pacific Islander [API]), and location (proximal, distal, rectal). To examine the change in ASR over time, annual percent change (APC) was calculated using joinpoint regression models. Results. Historically, NHB have had the highest rates of early-onset CRC. However, in 2015-2016, early-onset CRC rates were highest in AIAN (ASR=14.72), followed by NHB (ASR=13.20) and NHW (ASR=12.31). The rate of early-onset proximal colon cancer was highest in NHB (ASR=4.83), which was 62% higher than the rate in NHW (ASR=2.98). Early-onset distal colon and rectal cancer rates were highest in AIAN (ASR=3.98 and 6.43, respectively). Between 2001-2002 and 2015-2016, early-onset CRC rates significantly increased among NHWs (APC=1.62%) and AIAN (APC=3.33%). Racial disparities in incidence of early-onset CRC have decreased between NHB and NHW, due to increasing rates in NHW. Among NHW, early-onset CRC has significantly increased for all CRC locations, with the largest increase for rectal cancer (APC=2.22%). Early-onset rates of rectal cancer also significantly increased for AIAN (APC=4.38%) and Hispanics (APC=0.76%), while rates of proximal colon cancer significantly increased for AIAN (APC=2.21%). Rates of late-onset CRC have significantly decreased in all racial/ethnic groups. However, compared to NHW (ASR=82.48), late-onset CRC rates remain 32% higher in NHB (ASR=108.91) and 18% higher in AIAN (ASR=97.06). Conclusion. Early-onset CRC rates have been increasing, while late-onset CRC rates have decreased. The racial disparity between NHB and NHW in incidence of early-onset CRC has decreased, but this is due to increases in NHW—not decreases in NHB. NHB and AIAN have the highest rates of both early-and late-onset CRC. To counter these trends, research should focus on identifying predictors of early-onset CRC to determine who should be screened prior to age 50 and identify underlying causes of early-onset CRC. Further, ongoing prevention efforts must ensure access to screening colonoscopies for AIAN and NHB. Citation Format: Jessica L. Petrick, Lauren E. Barber, Shaneda Warren Andersen, Andrea A. Florio, Julie R. Palmer, Lynn Rosenberg. Racial disparities in early- and late-onset colorectal cancer incidence, 2001- 2016 [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-223.

58 Background: The incidence of early-onset colorectal cancer (EOCRC) has increased across sub-Saharan Africa, but data describing the features of EOCRC in this region is limited. We characterized the demographics, clinicopathologic features, and survival outcomes of EOCRC patients in South Africa (SA). Methods: The Colorectal Cancer in South Africa (CRCSA) study is a longitudinal cohort study that enrolled CRC patients from five academic teaching hospitals affiliated with the University of the Witwatersrand between 2016 and 2019. We excluded patients with known mismatch repair deficiency and treated patients with multiple primary tumors as distinct cases. We stratified the cohort by age at CRC diagnosis (&lt;50 vs ≥50 years) and performed a multivariable Cox proportional hazards analysis to compare overall survival (OS) between EOCRC and average-onset CRC (AOCRC). We performed a principal component analysis of self-reported diet data to identify dietary patterns and used a multivariable linear regression model to test the association of diet with age at CRC diagnosis. Results: In our cohort of 704 CRC cases, 179 were EOCRC (25.4%). EOCRC accounted for a greater proportion of CRC cases in Black patients than in non-Black patients (32.1% vs 18.4%, p &lt; 0.001). Rectal cancer accounted for 55.8% of all tumors with no difference by age at diagnosis (p = 0.737). Metastatic disease was present at diagnosis in 47.4% of EOCRC cases and 38.0% of AOCRC cases (p = 0.042). EOCRC tumors were more likely to be KRAS WT (78.6% of EOCRC vs 48.3% of AOCRC, p = 0.041), although only 10% of tumors were tested. In a multivariable Cox proportional hazards model, EOCRC was not associated with OS (adjusted HR 1.12; 95% CI 0.88-1.42). Black race (adjusted HR 1.43; 95% CI 1.13-1.81) and male gender (adjusted HR 1.46; 95% CI 1.17-1.82) were associated with worse OS. In a multivariable linear regression model, patients in the highest quartile of adherence to a Western diet were diagnosed 4.19 years earlier than those in the lowest quartile (p = 0.005). Conclusions: In SA, EOCRC and AOCRC have comparable presentations, although EOCRC is more common in Black South Africans and is more likely to present with metastatic disease. Survival outcomes are similar across age groups after adjusting for relevant factors. Increased adoption of a Western diet may contribute to the rising burden of EOCRC in SA, but larger prospective studies of lifestyle factors are needed. Multivariable Cox regression model evaluating the association of age at CRC diagnosis with overall survival in the Colorectal Cancer in South Africa (CRCSA) study (2016-2019). Hazard Ratio* (95% CI)(n = 578) Age at Diagnosis Early-Onset 1.12 (0.88-1.42) Average-Onset 1.00 Race Black 1.43 (1.13-1.81) Non-Black 1.00 Gender Male 1.46 (1.17-1.82) Female 1.00 *The model also adjusted for BMI, socioeconomic status, and stage at diagnosis (data not shown).

Tumor mutational burden.

The occurrence of colorectal cancer in those under 50 has significantly increased in recent decades. This study assesses the burden of colorectal cancer (CRC) and early-onset colorectal cancer (EO-CRC), along with associated risk factors, using data from the Global Burden of Disease (GBD) 2021, and projects incidence and mortality rates for 2031. Data on prevalence, incidence, mortality, disability-adjusted life years (DALYs), and risk factors were retrieved from the GBD 2021. The average annual percentage changes (AAPCs) were calculated using joinpoint regression analysis, and projections to 2031 were made with Autoregressive Integrated Moving Average (ARIMA) models. The number of new CRC cases globally was 2,194,143, of which EO-CRC accounted for 211,890 cases. Both CRC (AAPC 0.20) and EO-CRC (AAPC 0.99) demonstrated global increases from 1990 to 2021, with EO-CRC showing a sharper rise. The most significant increases in EO-CRC incidence, mortality, and DALYs occurred in America. Projected EO-CRC incidence and mortality rates for 2031 are 6.70 and 2.57 per 100,000 individuals, respectively. Major risk factors for CRC and EO-CRC DALYs included diets low in milk and calcium, high red meat intake, and elevated BMI. This study highlights the growing EO-CRC burden, particularly in America, emphasizing the need for targeted interventions to address dietary and lifestyle risk factors. Projections indicate a continued rise in EO-CRC incidence and mortality by 2031, underscoring the urgency for public health action to mitigate this trend. The occurrence of colorectal cancer in those under 50 has significantly increased globally from 1990 to 2021, with notable regional variations. Our study assesses the current burden of CRC and EO-CRC using data from the Global Burden of Disease 2021, identifies associated risk factors, and projects incidence and mortality trends through 2031 using ARIMA models. These findings offer a precise measurement of the EO-CRC burden and underscore the necessity of identifying and addressing at-risk people to effectively mitigate this escalating health concern.

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.