我们进行了第一项大规模全基因组关联研究，以鉴定预测结直肠癌患者在接受标准一线奥沙利铂基化疗和不含奥沙利铂的化疗中预后更好（或更差）的新型遗传变异。我们使用了两项三期试验的数据，即NCCTG N0147和NCCTG N9741，以及一个基于人群的患者队列，即DACHS。采用多变量Cox比例风险模型，包括每个SNP与治疗类型相互作用项，用于整体生存期（OS）和无进展生存期的分析。分别对每个研究进行了分析，并使用固定效应的荟萃分析方法将结果单独应用于结直肠癌III期切除患者（来自NCCTG N0147的3098例患者和来自DACHS的549例患者）和转移性结直肠癌（来自NCCTG N9741的505例患者和来自DACHS的437例患者）。我们还对已鉴定的位点进行了基因组学相关功能注释的基因为单位的分析和体外生物信息学分析。在III期结直肠癌患者中，chr22上的位点（rs11912167）与奥沙利铂基化疗后与不含奥沙利铂的化疗相比明显较差的整体生存期相关（Pinteraction < 5 × 10-8）。对于转移性结直肠癌患者，chr1（rs1234556），chr12（rs11052270）和chr15（rs11858406）上的三个位点与不同的整体生存期相关（P < 5 × 10-7）。在chr1上位于RCSD1内含区的位点，在独立队列ALGB/SWOG 80405的586例转移性结直肠癌患者中得到了重复验证（Pinteraction = 0.04）。GWA基因为单位的分析结果显示，在转移性结直肠癌中，RCSD1与不同的整体生存期相关性最显著（P = 6.6 × 10-6）。通过进一步研究其生物机制，该发现有可能用于个体化一线治疗，并改善临床结果。© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

We conducted the first large genome-wide association study to identify novel genetic variants that predict better (or poorer) prognosis in colorectal cancer patients receiving standard first-line oxaliplatin-based chemotherapy vs chemotherapy without oxaliplatin. We used data from two phase III trials, NCCTG N0147 and NCCTG N9741 and a population-based patient cohort, DACHS. Multivariable Cox proportional hazards models were employed, including an interaction term between each SNP and type of treatment for overall survival (OS) and progression-free survival. The analysis was performed for studies individually, and the results were combined using fixed-effect meta-analyses separately for resected stage III colon cancer (3098 patients from NCCTG N0147 and 549 patients from DACHS) and mCRC (505 patients from NCCTG N9741 and 437 patients from DACHS). We further performed gene-based analysis as well as in silico bioinformatics analysis for CRC-relevant functional genomic annotation of identified loci. In stage III colon cancer patients, a locus on chr22 (rs11912167) was associated with significantly poorer OS after oxaliplatin-based chemotherapy vs chemotherapy without oxaliplatin (Pinteraction  < 5 × 10-8 ). For mCRC patients, three loci on chr1 (rs1234556), chr12 (rs11052270) and chr15 (rs11858406) were found to be associated with differential OS (P < 5 × 10-7 ). The locus on chr1 located in the intronic region of RCSD1 was replicated in an independent cohort of 586 mCRC patients from ALGB/SWOG 80405 (Pinteraction  = .04). The GWA gene-based analysis yielded for RCSD1 the most significant association with differential OS in mCRC (P = 6.6 × 10-6 ). With further investigation into its biological mechanisms, this finding could potentially be used to individualize first-line treatment and improve clinical outcomes.© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.