A comprehensive molecular and clinical study of patients with young-onset CRC.

235 Background: Young-onset colorectal cancer (YO-CRC), defined as colorectal cancer diagnosed in individuals under 50 years of age, has emerged as a distinct clinical entity, often presenting at advanced stages. Despite the increasing incidence, molecular and clinical underpinnings of YO-CRC remain underexplored. This study aims to characterize the clinical and molecular features of YO-CRC and to evaluate their impact on OS. Methods: We retrospectively reviewed 110 patients diagnosed with YO-CRCfrom our institution’s molecular database. All patients underwent next-generation sequencing. Demographic, clinical, and molecular data, including age, gender, race, tumor location, cancer stage, and mutation status (KRAS, NRAS, BRAF, POLE, ERBB-2/HER2, microsatellite status), were collected by reviewing electronic medical records. For OS analysis, we focused on patients diagnosed with de novo Stage 4. Cox proportional hazards regression and Kaplan-Meier survival analysis were utilized to assess the association of these factors with OS, with statistical significance determined by a p-value threshold of <0.05. Results: Among 110 patients, N=44 (40%) presented with local disease (stage 1-3), while N=66 (60%) patients presented with de novo metastatic disease at the time of diagnosis. The median age at diagnosis was 44.5 years. The cohort consisted of 64% males and 36% females, with 84% of patients identified as White. Most tumors were left-sided (77%), including the distal colon/sigmoid (44%) and rectum (33%). KRAS and BRAF mutations were present 36% and 5.5%, respectively. ERBB-2/HER2 amplification and microsatellite instability were observed in 4.5% and 6.4% respectively. Tumor mutation burden (TMB) was <10 in 57% of patients, with 14% having TMB >20. CNV analysis revealed that 14% of patients had copy gains, 12% had concurrent gains/losses, and 31% had copy losses. Among the 66 Stage 4 patients, 44% had died by the time of analysis, with a median overall survival (OS) of 43.6 months (95% CI, 28.7 - not reached). KRAS mutation was found to be significantly associated with worse survival outcomes. Cox regression analysis reveals the prognostic significance of KRAS status, with a hazard ratio (HR) of 3.52 (95% CI: 1.59-7.76, P = 0.002 < 0.05), indicating a significantly higher risk of death for KRAS-mutant YO-CRC patients. Conclusions: KRAS mutations are a key prognostic factor in YO-CRC, highlighting the need for therapeutic need to improve outcomes in this high-risk group.