von Hippel-Lindau 基因多态性与接受 VEGFR 酪氨酸激酶抑制剂治疗的转移性透明细胞肾细胞癌患者的总生存相关。
Polymorphisms in the Von Hippel-Lindau Gene Are Associated With Overall Survival in Metastatic Clear-Cell Renal-Cell Carcinoma Patients Treated With VEGFR Tyrosine Kinase Inhibitors.
机构信息
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.
出版信息
Clin Genitourin Cancer. 2018 Aug;16(4):266-273. doi: 10.1016/j.clgc.2018.01.013. Epub 2018 Feb 5.
BACKGROUND
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).
PATIENTS AND METHODS
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).
RESULTS
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.
CONCLUSION
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.
背景
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。
患者和方法
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）。
结果
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。
结论
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。
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