Artificial Intelligence Agent: AI-HOPE-TP53 Enables Pathway-Centric Analysis of TP53-Driven Molecular Alterations in Colorectal Cancer Precision Oncology

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.

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.

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 &lt; 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 &lt; 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 &lt; 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 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.

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.

Accurately estimating prognosis based on clinicopathologic variables could improve risk stratification for patients with early-onset colorectal cancer (EOCRC). Our primary goal was to create and validate a survival nomogram with adequate performance for predicting overall survival (OS) in patients with EOCRC. Least absolute shrinkage and selection operator (LASSO) Cox regression analysis was applied to identify clinical features statistically related to OS. Then we established and internally validated a survival nomogram based on surveillance, epidemiology and end results (SEER) database (N=23813). A cohort of 77 patients with EOCRC from Renmin Hospital of Wuhan University (RHWU) was employed to detect the external validity of the survival nomogram. Moreover, we compared the predictive accuracy of survival nomogram with TNM stage, and also compared the OS between endoscopy and surgery groups before and after propensity score matching (PSM) among EOCRC patients with early stage (Tis-T1N0M0). We selected seven informative indexes (N stage, M stage, perineural invasion, chemotherapy, surgery primary site, summary stage and tumor grade) for the construction of the survival nomogram. Then the survival nomogram exhibited good discrimination with C-index of 0.829, 0.841 and 0.796 in the SEER training, SEER validation and RHWU validation sets, respectively. Calibration curves showed good concordance between the survival nomogram predictions and actual outcomes for 1-year, 3-year and 5-year OS. Furthermore, the survival nomogram was superior to risk stratification by TNM stage in predicting OS among patients with EOCRC. Early-stage patients treated with endoscopy showed similar survival to those with surgery before and after PSM. We proposed a survival nomogram based on the extensively used parameters to precisely predict OS in EOCRC patients. This survival nomogram will contribute to aid oncologists better risk stratification and prognostication for patients with EOCRC.

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.

The current rise in early-onset colorectal cancer (EOCRC) has been attributed to a Westernized lifestyle, but a definitive lifestyle factor or genetic etiology has yet to be discovered. Still, genetic studies do show that APC mutations are initiating events in both EOCRC and later-onset CRC (LOCRC). So, a key question is why do somatic APC mutations occur at a relatively young age in EOCRC patients? Hence, we surmise that something is retarding tissue renewal in colonic crypts so that somatic mutations are retained instead of being extruded during tissue turnover. Thus, we conjecture that EOCRC involves an essential nutrient required for tissue renewal. Accordingly, we investigated vitamin A (retinol, retinoic acid), which is an essential vitamin requiring adequate dietary intake. Indeed, vitamin A is essential for tissue homeostasis because germline mutations in retinoid receptors and vitamin A deficiency during pregnancy can lead to fetal malformations. Moreover, population-based studies report vitamin A deficiency in pre-school-aged children. Consequently, young-aged individuals might be prone to cancer-initiating effects of vitamin A deficient diets. Our Goal is to determine how aberrant retinoid receptor expression might promote EOCRC development through dysregulated retinoic acid signaling. Rationale: Our previous studies show that retinoic acid (RA) signaling pathway plays an essential role in regulating cell differentiation in the colon. Moreover, we reported that CRC cells harboring mutations in RA receptors (RAR, RXR) have drug resistance to all-trans RA (ATRA). So, mutation or aberrant expression of RA receptors could lead to incomplete differentiation and promote CRC initiation. Hypothesis: Aberrant RA receptor expression leads to dysregulated RA signaling that contributes to EOCRC development. Results: Our bioinformatics analyses show that retinoid receptors are often abnormally expressed and mutated in human CRCs. We found that up to 22% of CRCs have RA receptor mutations, but mutation status did not predict patient survival. However, we did find that frequency of retinoid receptor mutation was higher (&amp;gt;2X-fold) in EOCRC (age &amp;lt; 45) compared to LOCRC. Specifically, a high frequency of somatic mutations (2x-fold) occurred in receptors for vitamin A (STRA6) and retinoic acid (RARG, PPARG) in EOCRCs. We also found RARG hypermethylation occurs frequently in EOCRCs (p&amp;lt;0.05). Conclusions Since the rate of retinoid receptor alteration was increased in EOCRCs, aberrant RA signaling may be a predisposing factor for early CRC development and contribute to the etiology of EOCRCs. Based on this view, reduced retinoid signaling could lead to incomplete differentiation which provides a mechanism that may explain how delayed tissue renewal causes retention of acquired APC mutations in colonic epithelium: Thus, we put forth the idea that aberrant vitamin A (retinol) metabolism and APC mutation-induced activation of WNT signaling are co-factors in promoting EOCRC. Citation Format: Bruce Boman, Brian Osmond, Anh Nguyen, Chi Zhang. Colonic Tissue Renewal, Retinoic Acid Signaling, Early-onset CRC [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 C004.

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...

Early-onset colorectal cancer (EOCRC) incidence is increasing in Australia. However, no Australian studies have reported on EOCRC patients' surgical management and survival patterns. A retrospective study of 111 EOCRC patients treated at the Royal Prince Alfred Hospital (RPAH), Sydney, Australia between January 2013 and December 2021 was performed. RPAH is a quaternary referral centre for pelvic exenteration (PE) and cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). Most patients had left-sided tumours (76.58%) and stage IV disease at the time of presentation (37.85%). 27.93% of patients underwent either CRS/HIPEC and PE and 72.07% of patients underwent other colorectal resections of which the most common was low anterior resection (19.82%). A stoma was fashioned in 50.54% of patients. Complications occurred in 54.95% of patients of which most were Clavien-Dindo grade II (47.54%). Absolute 1-, 3- and 5-year time intervals were 93.69%, 87.39% and 85.48%. Disease-free and overall survival were poorer in stage IV patients who had PE, followed by CRS/HIPEC then other colorectal resections (P < 0.001 and P = 0.003). Stoma formation, PE and CRS/HIPEC and minor postoperative complications were common in our EOCRC cohort. Despite this, the 5-year absolute survival rate was acceptable. Thus, an aggressive surgical approach in EOCRC patients at a quaternary referral centre may be feasible at the cost of greater postoperative morbidity. This information is imperative in the surgical consent and preoperative counselling of EOCRC patients and highlights the need for further research to assess the postoperative functional outcomes and quality of life of EOCRC patients.

Colorectal cancer incidence among individuals age younger than 50 (early-onset CRC) continues to rise with etiologies unknown. Synchronously, early-onset CRC disparities have grown more pronounced. Molecular characteristics underlying CRC disparities among young adults remain uncharacterized. In a study of 5,292 patients (1,483 early-onset; 28.0%) with CRC and clinical-grade targeted sequencing data from AACR Project GENIE, we explored tumor mutational burden (TMB) and genomic patterns of early-onset CRC by race/ethnicity using multivariable regression models adjusted for sex, histology, sequencing assay, primary sample type and TMB. In total, 9.4% of CRCs (n=500) were hypermutated (&amp;gt;17.77 mutations/Mb). Excluding the hypermutated cancers, early-onset CRCs had 5.6 mutations/Mb versus 6.2 mutations/Mb among CRCs from late-onset cases. Moreover, among young patients, Blacks (n=115), but not Asians (n=122), had significantly higher TMB compared with Whites (n=1,245) with non-hypermutated CRC (P=0.02 and 0.38, respectively). Overall, young patients with non-hypermutated CRCs had significantly higher odds of presenting with nonsilent mutations in TP53 (Odds Ratio [OR]=1.26, 95%CI: 1.08-1.47, P=0.003) and SMAD2 (OR=1.69, 95%CI: 1.19-2.40, P=0.003) versus late-onset cases after adjustment for sex, race, histology, sequencing assay, sample type and TMB. In contrast, young patients had a 40% and 44% decreased odds of presenting with KDR and FLT4 nonsilent mutations, respectively, compared with patients with late-onset non-hypermutated CRC (KDR: OR=0.60, 95%CI: 0.38-0.95, P=0.03; FLT4: OR=0.56, 95%CI: 0.33-0.94, P=0.03). Mutation heterogeneity in TGFBR2 (Cochran's Q test: P=0.003) and NOTCH1 (P=0.02) was also observed between early-onset and late-onset cases. By race, distinct genomic patterns of early-onset CRC emerged. Young Whites with non-hypermutated CRC had higher odds of presenting with SMAD2 and TP53 mutations (SMAD2: OR=1.88, 95%CI:1.28-2.78, P=0.001; TP53: OR=1.25, 95%CI:1.06-1.48, P=0.007), and decreased odds of presenting with FLT4 mutations (OR=0.56, 95%CI: 0.32-0.99, P=0.04) versus late-onset non-hypermutated CRC cases. Among Black individuals, early-onset non-hypermutated CRC cases had significantly higher odds of presenting with TGFBR2 nonsilent mutations versus late-onset cases (OR=61.37, 95%CI:2.24-1680.45, P=0.01). Young Asians had 6-fold increased odds of presenting with nonsilent mutations in NOTCH1 versus Asians with non-hypermutated late-onset CRC (OR=6.26, 95%CI:1.32-29.68, P=0.02). By race, distinct TGFBR2 (P=0.0001) and NOTCH1 (P=0.02) mutation frequencies were observed in non-hypermutated CRCs among young patients. Together, this study provides initial evidence that molecular features of early-onset CRC may differ by race/ethnicity, which could provide insight into biological mechanisms underlying early-onset CRC disparities. Citation Format: Andreana N. Holowatyj, Wanqing Wen, Timothy Gibbs, Kay M. Washington, Paulette D. Chandler, Cathy Eng, Jose Perea, Wei Zheng, Xingyi Guo. Racial differences in somatic mutations among patients with early-onset colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 101.

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.

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).

Early Onset Colorectal cancer (EOCRC) incidence is increasing at an alarming pace. An increase of 90% in colon cancer and 124% in rectal cancer is expected by 2030. Patients with EOCRC are not receiving additional attention compared to older patients despite having a unique molecular pattern, majority of cases are sporadic, and related short- and long-term treatment and disease complications. The current management and screening guidelines have been constructed from studies on late onset CRC. Plethora of studies are ongoing to understand this disease entity in order to construct a tailored prevention, detection and management plans. While waiting for a better understanding of the disease, efforts should be directed toward improving the quality of care across the cancer continuum. Here we aim to address the challenges faced by EOCRC patients across the cancer continuum. This will facilitate directing future efforts and research toward construction of a personalized and precise guidelines.