Smits Kim M, Schouten Leo J, van Dijk Boukje A C, Hulsbergen-van de Kaa Christina A, Wouters Kim A D, Oosterwijk Egbert, van Engeland Manon, van den Brandt Piet A
Departmens of Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.
Clin Cancer Res. 2008 Feb 1;14(3):782-7. doi: 10.1158/1078-0432.CCR-07-1753.
Inactivation of the von Hippel-Lindau (VHL) gene is considered as an early event in renal cancer tumorigenesis. The prognostic relevance of these changes, however, is not clear and previous results are contradictory. We have evaluated the influence of (epi)genetic alterations in VHL on cause-specific survival in clear-cell renal cell cancer (ccRCC) in a large, population-based group of cases.
One hundred and eighty-five cases of ccRCC, identified in the Netherlands Cohort Study on diet and cancer diagnosed in the period 1986 to 1997, were included in the analyses. Mortality information until December 2005, including causes of death, were obtained for all cases through linkage with the Central Bureau of Statistics. VHL mutations were determined with PCR single-strand conformational polymorphism and direct sequencing. VHL methylation was determined with methylation-specific PCR. Kaplan-Meier analyses and Cox proportional hazards models were used to assess associations between VHL alterations and cause-specific mortality.
Median follow-up in our population was 6 years. The frequency of loss of function mutations and methylation, separately or combined, did not differ statistically significant between different cancer stages or between tumors with different sizes. We observed no influence of loss of function mutations or methylation of the VHL gene on cause-specific mortality (hazard ratio, 1.08; 95% confidence interval, 0.69-1.68, P = 0.735) as compared with patients with a wild-type or silent mutation in VHL.
Our results indicate that (epi)genetic alterations in the VHL gene do not have prognostic value in ccRCC.
冯·希佩尔-林道（VHL）基因失活被认为是肾癌发生过程中的早期事件。然而，这些变化的预后相关性尚不清楚，先前的结果相互矛盾。我们在一个基于人群的大型病例组中评估了VHL基因（表观）遗传改变对透明细胞肾细胞癌（ccRCC）特定病因生存率的影响。
纳入了1986年至1997年期间在荷兰饮食与癌症队列研究中确诊的185例ccRCC病例进行分析。通过与中央统计局的数据链接，获取了所有病例截至2005年12月的死亡信息，包括死亡原因。采用聚合酶链反应单链构象多态性和直接测序法检测VHL基因突变。采用甲基化特异性聚合酶链反应法检测VHL基因甲基化。采用Kaplan-Meier分析和Cox比例风险模型评估VHL改变与特定病因死亡率之间的关联。
我们研究人群的中位随访时间为6年。功能丧失性突变和甲基化的频率，单独或联合出现时，在不同癌症分期或不同大小的肿瘤之间没有统计学显著差异。与VHL基因野生型或沉默突变的患者相比，我们未观察到VHL基因功能丧失性突变或甲基化对特定病因死亡率有影响（风险比，1.08；95%置信区间，0.69-1.68，P = 0.735）。
我们的结果表明，VHL基因的（表观）遗传改变在ccRCC中没有预后价值。
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