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Abstract：
BACKGROUND: 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.
RESULTS: 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.
CONCLUSIONS: The present study identified several putative somatic and germline genetic events with prognostic potential for colorectal cancer that should undergo functional characterization.
RESULTS: 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.
CONCLUSIONS: The present study identified several putative somatic and germline genetic events with prognostic potential for colorectal cancer that should undergo functional characterization.
摘要：
背景：结直肠癌仍然是癌症相关死亡的第二大原因，因此需要生物标志物来预测患者对治疗的抗性并估计其预后。我们设计了一组558个基因与5-氟尿嘧啶抗性相关的药物基因组学记录，对其他常用药物敏感的重要基因，主要的oncodrivers，和可操作的基因。我们对肿瘤的DNA和患者的匹配血液样本进行了靶富集测序，并将结果与通过全身辅助化疗分层的患者预后进行比较。
结果:每个肿瘤样品中检测到的变体的中位值为18.5,其中4个被分类为具有高预测功能效应和14.5中等效应。APC,TP53和KRAS是最常见的突变基因(64%，59%,和42%的突变样本,分别)其次是FAT4(23%)，FBXW7和PIK3CA（两者均为16％）。晚期III期患者更常出现APC，TP53，或KRAS突变比那些在阶段I或II。KRAS突变计数随分级呈增加趋势(G15%的频率和基于3年RFS的积极曼哈顿图，rs72753407在NFACS,ERBB4中的rs34621071和RIF1中的rs2444274与RFS显著相关,OS或两者。
结论：本研究确定了一些推定的体细胞和种系遗传事件，这些事件具有结直肠癌的预后潜力，应进行功能表征。
结果:每个肿瘤样品中检测到的变体的中位值为18.5,其中4个被分类为具有高预测功能效应和14.5中等效应。APC,TP53和KRAS是最常见的突变基因(64%，59%,和42%的突变样本,分别)其次是FAT4(23%)，FBXW7和PIK3CA（两者均为16％）。晚期III期患者更常出现APC，TP53，或KRAS突变比那些在阶段I或II。KRAS突变计数随分级呈增加趋势(G1
结论：本研究确定了一些推定的体细胞和种系遗传事件，这些事件具有结直肠癌的预后潜力，应进行功能表征。
