Laboratory of Experimental Oncology, Department of Oncology, University of Leuven, Leuven, Belgium; Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium.
Center for Cancer Biology, Flemish Institute for Biotechnology, Leuven, Belgium; Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven, Belgium.
Clin Genitourin Cancer. 2018 Aug;16(4):266-273. doi: 10.1016/j.clgc.2018.01.013. Epub 2018 Feb 5.
Clear-cell renal-cell carcinoma (ccRCC) is characterized by loss of a functional Von Hippel-Lindau (VHL) protein. We investigated the potential of 3 single nucleotide polymorphisms (SNPs) in VHL as biomarkers in metastatic ccRCC (m-ccRCC) patients treated with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs).
We genotyped 3 VHL SNPs in 199 m-ccRCC patients: rs1642742 T > C, rs1642743 A > G, and rs1678607 C > A. Primary end points were response rate (RR), progression-free survival (PFS), and overall survival (OS) after start of first-line TKI. RR was compared with Fisher's exact test, and PFS and OS with Kaplan-Meier analysis and multivariable Cox regression. Secondary end points were association with VHL promotor hypermethylation, VHL mutation status, VHL loss of heterozygosity, ≥ 25% sarcomatoid dedifferentiation, and expression of genes implicated in angiogenesis and immunoresponse (Fisher's exact test and unpaired t tests).
The minor alleles of rs1642742 and rs1642743, known to be in close linkage disequilibrium, were associated with poor outcome, following a recessive pattern. For the rs1642742 CC versus TT/TC genotype, OS was 11 versus 26 months (hazard ratio = 2.3; 95% confidence interval, 1.2-6.6; P = .015). For the rs1642743 GG versus AA/AG genotype, OS was 15 versus 28 months (hazard ratio = 2.6; 95% confidence interval, 1.4-5.0; P = .004). After multivariable analysis, both remained linked with poor OS (P = .018 and P = .009, respectively). There was a trend toward shorter PFS and poorer RR. Both SNPs were associated with ≥ 25% sarcomatoid dedifferentiation (P = .037 and .006, respectively). No significant results were found for rs1678607.
rs1642742 and rs1642743 are candidate biomarkers for poor OS in m-ccRCC patients receiving first-line VEGFR-TKI. They are associated with higher levels of sarcomatoid dedifferentiation.
肾透明细胞癌（ccRCC）的特征是功能性 von Hippel-Lindau（VHL）蛋白缺失。我们研究了 3 个 VHL 单核苷酸多态性（SNP）在接受血管内皮生长因子受体（VEGFR）酪氨酸激酶抑制剂（TKI）治疗的转移性 ccRCC（m-ccRCC）患者中的作为生物标志物的潜力。
我们对 199 名 m-ccRCC 患者的 3 个 VHL SNP 进行了基因分型：rs1642742 T > C、rs1642743 A > G 和 rs1678607 C > A。主要终点是一线 TKI 治疗开始后的反应率（RR）、无进展生存期（PFS）和总生存期（OS）。RR 采用 Fisher 确切检验比较，PFS 和 OS 采用 Kaplan-Meier 分析和多变量 Cox 回归。次要终点与 VHL 启动子高甲基化、VHL 突变状态、VHL 杂合性丢失、≥25%的肉瘤样去分化以及与血管生成和免疫反应相关的基因表达有关（Fisher 确切检验和未配对 t 检验）。
已知紧密连锁的 rs1642742 和 rs1642743 的次要等位基因与不良结局相关，呈隐性模式。对于 rs1642742 CC 与 TT/TC 基因型，OS 为 11 与 26 个月（危险比=2.3；95%置信区间，1.2-6.6；P=0.015）。对于 rs1642743 GG 与 AA/AG 基因型，OS 为 15 与 28 个月（危险比=2.6；95%置信区间，1.4-5.0；P=0.004）。多变量分析后，两者均与不良 OS 相关（P=0.018 和 P=0.009）。有 PFS 缩短和 RR 降低的趋势。这两个 SNP 与≥25%的肉瘤样去分化相关（P=0.037 和 P=0.006）。rs1678607 未发现显著结果。
rs1642742 和 rs1642743 是接受一线 VEGFR-TKI 治疗的 m-ccRCC 患者 OS 不良的候选生物标志物。它们与更高水平的肉瘤样去分化相关。
