结直肠癌仍然是癌症相关死亡的第二大原因，因此需要能够预测患者对治疗的抵抗力并估计其预后的生物标志物。我们设计了一组 558 个基因，其中包含与 5-氟尿嘧啶耐药性相关的药物基因组学记录、对其他常用药物敏感性重要的基因、主要致癌驱动因素和可操作基因。我们对来自肿瘤和匹配的患者血液样本的 DNA 进行了靶向富集测序，并将结果与​​通过全身辅助化疗分层的患者预后进行了比较。每个肿瘤样本检测到的变异中位数为 18.5 个，其中 4 个被归类为具有高预测功能性效果和14.5中等效果。 APC、TP53 和 KRAS 是最常见的突变基因（分别占突变样本的 64%、59% 和 42%），其次是 FAT4（23%）、FBXW7 和 PIK3CA（均为 16%）。晚期 III 期患者比 I 期或 II 期患者更常见 APC、TP53 或 KRAS 突变。 KRAS 突变计数随年级呈增加趋势 (G1 < G2 < G3)。 APC 移码突变或 KRAS 12D 变异携带者对辅助治疗的反应较差，但这些致癌驱动因素均不具有预后价值。 ABCA13、ANK2、COL7A1、NAV3 或 UNC80 基因中任何一个体细胞突变的携带与所有患者的总生存期 (OS) 较差具有预后相关性。相比之下，对于未经治疗的患者，FLG、GLI3 或 UNC80 的突变具有相同的预后，而对于接受辅助治疗的患者，COL6A3、LRP1B、NAV3、RYR1、RYR3、TCHH 或 TENM4 的突变则具有相同的预后。第一个关联经过外部验证。在所有具有高或中度预测功能影响（每位患者中位数为 326）、> 5% 频率和基于 3 年 RFS 的阳性曼哈顿图的所有种系变异中，NFACS 中的 rs72753407、ERBB4 中的 rs34621071 和 RIF1 中的 rs2444274 与 RFS 显着相关、OS 或两者。本研究确定了几个对结直肠癌具有预后潜力的假定体细胞和种系遗传事件，应进行功能表征。© 2024。作者。

Colorectal cancer is still the second leading cause of cancer-related deaths and thus biomarkers allowing prediction of the resistance of patients to therapy and estimating their prognosis are needed. We designed a panel of 558 genes with pharmacogenomics records related to 5-fluorouracil resistance, genes important for sensitivity to other frequently used drugs, major oncodrivers, and actionable genes. We performed a target enrichment sequencing of DNA from tumors and matched blood samples of patients, and compared the results with patient prognosis stratified by systemic adjuvant chemotherapy.The median number of detected variants per tumor sample was 18.5 with 4 classified as having a high predicted functional effect and 14.5 moderate effect. APC, TP53, and KRAS were the most frequent mutated genes (64%, 59%, and 42% of mutated samples, respectively) followed by FAT4 (23%), FBXW7, and PIK3CA (16% for both). Patients with advanced stage III had more frequently APC, TP53, or KRAS mutations than those in stages I or II. KRAS mutation counts followed an increasing trend with grade (G1 < G2 < G3). The response to adjuvant therapy was worse in carriers of frameshift mutations in APC or 12D variant in KRAS, but none of these oncodrivers had prognostic value. Carriage of somatic mutations in any of the genes ABCA13, ANK2, COL7A1, NAV3, or UNC80 had prognostic relevance for worse overall survival (OS) of all patients. In contrast, mutations in FLG, GLI3, or UNC80 were prognostic in the same direction for patients untreated, and mutations in COL6A3, LRP1B, NAV3, RYR1, RYR3, TCHH, or TENM4 for patients treated with adjuvant therapy. The first association was externally validated. From all germline variants with high or moderate predicted functional effects (median 326 per patient), > 5% frequency and positive Manhattan plot based on 3-year RFS, rs72753407 in NFACS, rs34621071 in ERBB4, and rs2444274 in RIF1 were significantly associated with RFS, OS or both.The present study identified several putative somatic and germline genetic events with prognostic potential for colorectal cancer that should undergo functional characterization.© 2024. The Author(s).