Background: Young-onset colorectal cancer (YO-CRC) has emerged as a distinct clinical entity, often presenting at advanced stages. Despite the increasing incidence, the 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 reviewed 110 patients diagnosed with YO-CRC at our institution who 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 IV. 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 ap-value threshold of <0.05.Results: Among 110 patients,n= 44 (40%) presented with local disease (stage 1–3), whilen= 66 (60%) 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 in 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 66 patients with de novo metastatic disease, 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 mutations were 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), indicating a significantly higher risk of death for KRAS-mutant YO-CRC patients.Conclusions: Patients with YO-CRC are more likely to present with de novo metastatic disease and left-sided tumors with distinct molecular characteristics. KRAS mutations are a key prognostic factor in YO-CRC, highlighting the need for therapeutic interventions to improve outcomes in this high-risk group.
背景：早发性结直肠癌（YO-CRC）已成为一种独特的临床实体，常表现为晚期阶段。尽管发病率不断上升，但YO-CRC的分子和临床基础仍未得到充分探索。本研究旨在描述YO-CRC的临床和分子特征，并评估其对总生存期（OS）的影响。 方法：我们回顾了本机构接受下一代测序的110例YO-CRC患者。通过查阅电子病历收集人口统计学、临床和分子数据，包括年龄、性别、种族、肿瘤位置、癌症分期和突变状态（KRAS、NRAS、BRAF、POLE、ERBB-2/HER2、微卫星状态）。在OS分析中，我们重点关注初诊即为IV期的患者。采用Cox比例风险回归和Kaplan-Meier生存分析评估这些因素与OS的关联，统计显著性以p值<0.05为阈值。 结果：在110例患者中，n=44例（40%）表现为局部疾病（1-3期），而n=66例（60%）在诊断时即为初诊转移性疾病。诊断时的中位年龄为44.5岁。队列中男性占64%，女性占36%，84%的患者为白人。大多数肿瘤位于左侧（77%），包括远端结肠/乙状结肠（44%）和直肠（33%）。KRAS和BRAF突变分别占36%和5.5%。ERBB-2/HER2扩增和微卫星不稳定性分别占4.5%和6.4%。57%的患者肿瘤突变负荷（TMB）<10，14%的患者TMB>20。CNV分析显示，14%的患者存在拷贝数增加，12%的患者同时存在拷贝数增加/缺失，31%的患者存在拷贝数缺失。在66例初诊转移性疾病患者中，44%在分析时已死亡，中位总生存期（OS）为43.6个月（95% CI，28.7—未达到）。KRAS突变被发现与较差的生存结果显著相关。Cox回归分析揭示了KRAS状态的预后意义，风险比（HR）为3.52（95% CI：1.59–7.76，p=0.002），表明KRAS突变的YO-CRC患者死亡风险显著更高。 结论：YO-CRC患者更可能表现为初诊转移性疾病和左侧肿瘤，并具有独特的分子特征。KRAS突变是YO-CRC的关键预后因素，突显了需要治疗干预以改善这一高风险群体预后的必要性。
A Comprehensive Molecular and Clinical Study of Patients with Young-Onset Colorectal Cancer
肿瘤(癌症)患者之家