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Abstract：
Colorectal cancer (CRC) is a global health concern, necessitating adjuvant chemotherapy post-curative surgery to mitigate recurrence and enhance survival, particularly in intermediate-stage patients. However, existing therapeutic disparities highlight the need for biomarker-guided adjuvant chemotherapy to achieve better CRC inhibition. This study explores the molecular mechanisms underlying the inhibition of CRC through a genome-wide association study (GWAS) focused on 5-fluorouracil (5-FU)-based adjuvant therapy in intermediate-stage CRC patients, a domain previously unexplored. We retrospectively included 226 intermediate-stage CRC patients undergoing surgical resection followed by 5-FU-based adjuvant chemotherapy. The exploration cohort comprised 31 patients, and the validation cohort included 195 individuals. Genotyping was carried out using either Axiom Genome-Wide TWB 2.0 Array Plate-based or polymerase chain reaction-based methods on genomic DNA derived from collected tissue samples. Statistical analyses involved descriptive statistics, Kaplan-Meier analyses, and Cox proportional hazard analyses. From the GWAS, potential genetic predictors, GALNT14-rs62139523 and DNMBP-rs10786578 genotypes, of 5-FU-based adjuvant therapy following surgery in intermediate-stage CRC patients were identified. Validation in a larger cohort of 195 patients emphasized the predictive significance of GALNT14-rs62139523 genotypes, especially the \"A/G\" genotype, for improved overall and progression-free survival. This predictive association remained robust across various subgroups, with exceptions for specific demographic and clinical parameters such as age < 58 years old, CEA ≤ 2.5 ng/mL, tumor diameter > 44.0 mm, and tumor-free margin ≥ 50 mm. This study identifies that the GALNT14-rs62139523 \"A/G\" genotype modulates therapeutic outcomes, establishing it as a promising biomarker for predicting favorable responses to 5-FU-based adjuvant chemotherapy in intermediate-stage CRC patients, although further investigations are needed to detail these mechanisms.
摘要：
结直肠癌（CRC）是一个全球性的健康问题，治疗后需要辅助化疗以减轻复发和提高生存率，尤其是中期患者。然而,现有的治疗差异凸显了生物标志物指导的辅助化疗以实现更好的CRC抑制的必要性.本研究通过对中期CRC患者进行以5-氟尿嘧啶（5-FU）为基础的辅助治疗的全基因组关联研究（GWAS），探讨了抑制CRC的分子机制。以前未探索的领域。我们回顾性地纳入了226例接受手术切除，然后进行基于5-FU的辅助化疗的中期CRC患者。探索队列包括31名患者，验证队列包括195名个体。使用基于公理全基因组TWB2.0阵列板的方法或基于聚合酶链反应的方法对来自收集的组织样品的基因组DNA进行基因分型。统计分析涉及描述性统计，Kaplan-Meier分析,和Cox比例风险分析。从GWAS,潜在的遗传预测因子，GALNT14-rs62139523和DNMBP-rs10786578基因型,确定了中期CRC患者手术后基于5-FU的辅助治疗。在195名患者的更大队列中进行的验证强调了GALNT14-rs62139523基因型的预测意义，尤其是“A/G”基因型，改善总体和无进展生存期。这种预测性关联在各个子组之间保持稳健，除了特定的人口统计学和临床参数，如年龄<58岁，CEA≤2.5ng/mL，肿瘤直径>44.0毫米，无瘤边缘≥50mm。这项研究确定了GALNT14-rs62139523“A/G”基因型调节治疗结果，将其确立为预测中期CRC患者对基于5-FU的辅助化疗的良好反应的有希望的生物标志物,尽管需要进一步的调查来详细说明这些机制。
