Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Duke Cancer Institute, Duke University, Durham, North Carolina.
Clin Cancer Res. 2021 Jan 1;27(1):267-275. doi: 10.1158/1078-0432.CCR-20-2021. Epub 2020 Sep 21.
Irinotecan/5-fluorouracil (5-FU; FOLFIRI) or oxaliplatin/5-FU (FOLFOX), combined with bevacizumab or cetuximab, are approved, first-line treatments for metastatic colorectal cancer (mCRC). We aimed at identifying germline variants associated with survival in patients with mCRC treated with these regimens in Cancer and Leukemia Group B/SWOG 80405.
Patients with mCRC receiving either FOLFOX or FOLFIRI were randomized to either cetuximab or bevacizumab. DNA from peripheral blood was genotyped for approximately 700,000 SNPs. The association between SNPs and overall survival (OS) was tested in 613 patients of genetically estimated European ancestry using Cox proportional hazards models.
The four most significant SNPs associated with OS were three haplotypic SNPs between microsomal glutathione S-transferase 1 () and LIM domain only 3 (, representative HR, 1.56; = 1.30 × 10), and rs11644916 in (HR, 1.39, = 4.26 × 10). is a well-established tumor suppressor gene in colorectal cancer, and rs11644916 (G>A) conferred shorter OS. Median OS for patients with the AA, AG, or GG genotypes was 18.4, 25.6, or 36.4 months, respectively. In 90 patients with stage IV colorectal cancer from The Cancer Genome Atlas (TCGA), rs11649255 in [in almost complete linkage disequilibrium (LD) with rs11644916], was associated with shorter OS (HR, 2.24, = 0.0096). Using rs11648673 in (in very high LD with rs11644916 and with functional evidence), luciferase activity in three colorectal cancer cell lines was reduced.
This is the first large genome-wide association study ever conducted in patients with mCRC treated with first-line standard treatment in a randomized phase III trial. A common SNP in conferred worse OS and the effect was replicated in TCGA. Further studies in colorectal cancer experimental models are required.
伊立替康/5-氟尿嘧啶（5-FU；FOLFIRI）或奥沙利铂/5-FU（FOLFOX）联合贝伐单抗或西妥昔单抗，是转移性结直肠癌（mCRC）的一线治疗药物。我们旨在确定癌症和白血病组 B/SWOG 80405 中接受这些方案治疗的 mCRC 患者的生存相关的种系变异。
接受 FOLFOX 或 FOLFIRI 的 mCRC 患者被随机分配接受西妥昔单抗或贝伐单抗。外周血 DNA 进行了约 700,000 个 SNP 的基因分型。使用 Cox 比例风险模型在 613 名遗传上估计为欧洲血统的患者中，对 SNP 与总生存（OS）之间的关联进行了测试。
与 OS 最显著相关的四个 SNP 是微粒体谷胱甘肽 S-转移酶 1（）和 LIM 结构域唯一 3（之间的三个单倍型 SNP，代表 HR，1.56； = 1.30×10），和位于中的 rs11644916（HR，1.39，= 4.26×10）。是结直肠癌中一种成熟的肿瘤抑制基因，rs11644916（G>A）导致较短的 OS。AA、AG 或 GG 基因型患者的中位 OS 分别为 18.4、25.6 或 36.4 个月。在癌症基因组图谱（TCGA）中的 90 名 IV 期结直肠癌患者中，位于中的 rs11649255[与 rs11644916 几乎完全连锁不平衡（LD）]与较短的 OS 相关（HR，2.24，= 0.0096）。在三种结直肠癌细胞系中，位于中的 rs11648673[与 rs11644916 具有非常高的 LD 并具有功能证据]的活性降低。
这是首次在接受一线标准治疗的 mCRC 患者中进行的大规模全基因组关联研究，在一项随机 III 期试验中进行。位于中的一个常见 SNP 与较差的 OS 相关，并且在 TCGA 中得到了复制。需要在结直肠癌实验模型中进行进一步的研究。
