Comprehensive molecular and clinical characterization of early-onset gastrointestinal cancers: Integrating genomic landscapes with allostatic load in a safety-net cohort.

e22621 Background: The incidence of early-onset gastrointestinal cancers (EOGIC), diagnosed in individuals underage 50, is rising globally. While hereditary syndromes account for a minority of cases, the"exposome"- cumulative environmental and psychosocial stressors remains a critical butunderdefined driver, particularly in marginalized populations. This study characterizes theclinical, genomic, and Allostatic Load (AL) profiles of EOGIC patients at a minority-serving safety-net institution to elucidate the intersection of biological aggression and social determinants. Methods: We conducted a retrospective cohort study (2015–2025) of patients aged 18–50yr withhistologically confirmed GI malignancies at the University of Illinois Chicago. Allostatic Load wasquantified using a validated 10-biomarker index, and was graded by dichotomizing each markerinto high-risk quartiles and aggregating points into a cumulative score (High AL > 2). Genomic profiling was performed using the Tempus xT and xF next-generation sequencing assay. Descriptive statistics are being presented for AL burden, demographics, and somatic mutation landscapes. Results: The cohort (N = 75) was ethnically diverse (40.0% Black, 28.0% Hispanic) and socioeconomicallyvulnerable, with 68.0% relying on Medicaid/Medicare or uninsured. Patients predominantlypresented with advanced disease (52.0% Stage IV) and aggressive, poorly differentiatedhistology (37.3%). High AL at diagnosis was found in 41.3% of this cohort. The most common mutations areoutlined in table 1 and included TP53, APC, KRAS, ARID1A, and PIK3. The median CPS was < 1, MSI-Hrate was 2.7%, and median tissue TMB was 3.95 mut/MB with rare extreme TMB outliers ( > 50mut/MB) accounting for 4.5%. Conclusions: EOGIC patients in this urban safety-net setting are characterized by a dual burden of biologicallyaggressive disease and elevated physiological stress at diagnosis. Nearly half the patients exhibited high AL, reflecting substantial cumulative exposure to chronic stress in early life. Concurrently, tumors frequently presented at advanced stage with poor differentiation and molecular profiles that included frequent TP53, APC, and KRAS mutations. Additionally, these tumor exhibited an immunologically cold landscape marked by low median CPS, low MSI-H prevalence, and modest median TMB. Further study is planned on the impact of AL on molecular biology and clinical outcomes. Ten most common mutations, arranged by percentage. Gene Frequency Percent TP53 78 14.16 APC 71 12.89 KRAS 38 6.90 ARID1A 22 3.99 PIK3 10 3.44 SMAD4 17 3.09 CDKN2A 14 2.54 LRP1B 12 2.18 RB1 10 1.81