Department of Hepatology and Gastroenterology, Linkou Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan.
Liver Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan.
Int J Mol Sci. 2024 Jun 17;25(12):6642. doi: 10.3390/ijms25126642.
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, -rs62139523 and -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 -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 -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.
结直肠癌（CRC）是一个全球性的健康问题，需要在治愈性手术后进行辅助化疗，以减轻复发和提高生存率，特别是在中危期患者中。然而，现有的治疗差异突出表明需要生物标志物指导的辅助化疗，以实现更好的 CRC 抑制。本研究通过全基因组关联研究（GWAS）探索了基于 5-氟尿嘧啶（5-FU）的辅助治疗在中危期 CRC 患者中的分子机制，这是一个以前未探索的领域。我们回顾性纳入了 226 例接受手术切除并接受基于 5-FU 的辅助化疗的中危期 CRC 患者。探索队列包括 31 例患者，验证队列包括 195 例患者。使用 Axiom 基因组-wide TWB 2.0 基于阵列板或聚合酶链反应的方法对收集的组织样本中的基因组 DNA 进行基因分型。统计分析包括描述性统计分析、Kaplan-Meier 分析和 Cox 比例风险分析。从 GWAS 中，我们确定了手术切除后基于 5-FU 的辅助治疗中潜在的遗传预测因子——rs62139523 和 rs10786578 基因型。在更大的 195 例患者队列中的验证强调了 rs62139523 基因型，特别是“AG”基因型，对改善总体和无进展生存率的预测意义。这种预测相关性在各种亚组中仍然稳健，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>44.0mm 和肿瘤无残留边缘≥50mm。本研究表明，rs62139523“AG”基因型调节治疗结果，确立了它作为预测中危期 CRC 患者对基于 5-FU 的辅助化疗良好反应的有前途的生物标志物，尽管需要进一步研究来详细阐明这些机制。
