Von Hippel-Lindau (VHL) inactivation in sporadic clear cell renal cancer: associations with germline VHL polymorphisms and etiologic risk factors.
Von Hippel-Lindau (VHL) inactivation in sporadic clear cell renal cancer: associations with germline VHL polymorphisms and etiologic risk factors.
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DOI：
10.1371/journal.pgen.1002312
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发表时间：
2011-10
期刊：
影响因子：
4.5
通讯作者：
Rothman N
中科院分区：
文献类型：
--
作者：
Moore LE;Nickerson ML;Brennan P;Toro JR;Jaeger E;Rinsky J;Han SS;Zaridze D;Matveev V;Janout V;Kollarova H;Bencko V;Navratilova M;Szeszenia-Dabrowska N;Mates D;Schmidt LS;Lenz P;Karami S;Linehan WM;Merino M;Chanock S;Boffetta P;Chow WH;Waldman FM;Rothman N
肾肿瘤异质性研究利用von Hippel-Lindau VHL基因将疾病分类为分子定义的亚型，以检查与病因危险因素和预后的关系。本研究的目的是全面分析透明细胞肾肿瘤（ccRCC）中VHL失活的情况，并评估VHL失活亚群与肾癌危险因素和VHL种系单核苷酸多态性（snp）之间的关系。利用核酸内切酶扫描、亚硫酸盐处理和VHL启动子内11个CpG位点的Sanger测序，对507例散发性RCC/470例ccRCC进行了VHL遗传和表观遗传失活检测。进行了仅病例的多变量分析，以确定变异亚型与危险因素之间的关联。在86.6%的ccRCC病例中，通过肿瘤DNA序列改变或启动子甲基化，观察到VHL失活。种系VHL snp和单倍型与肿瘤组织中启动子超甲基化相关（OR = 6.10; 95% CI: 2.28-16.35, p = 3.76E-4, p-global = 8E-5）。遗传VHL失活的风险与吸烟呈负相关，因为野生型ccRCC肿瘤的比例较高[先前：OR = 0.70(0.20-1.31)，当前：OR = 0.56 (0.32-0.99)；P-trend = 0.04]。改变的发生率不因组织病理特征或职业暴露于三氯乙烯而异。具有特定VHL种系多态性的ccRCC病例更有可能通过启动子超甲基化而不是通过肿瘤DNA序列改变而使VHL失活，这表明这些snp的存在可能代表了肾组织中易发生表观遗传变异（表观遗传变异的遗传倾向）的一个例子。一部分来自当前吸烟者的肿瘤缺乏VHL改变，这可能代表了与灭活病例不同的生物学临床实体。在470例散发性透明细胞肾癌（ccRCC）病例的大型病例系列中，我们检查了von Hippel-Lindau （VHL）失活作为肿瘤异质性的生物标志物。VHL基因的种系改变在大多数VHL疾病（一种与ccRCC相关的遗传综合征）家族中被发现。在散发疾病中，高达91%的病例报告了VHL的改变。在这里，我们观察到通过遗传和表观遗传机制与ccRCC高度相关的VHL失活的高患病率。肿瘤中启动子超甲基化导致的VHL失活与遗传多态性有关，这些遗传多态性被选择来捕捉VHL位点的共同变异。在肿瘤DNA中发现了与启动子超甲基化相关的高风险单倍型。这些发现表明，这些多态性和VHL启动子超甲基化的存在可能是肿瘤组织中VHL基因表观遗传变异和潜在沉默的遗传倾向的一个例子。这一结果可能具有翻译意义，因为具有高风险单倍型的个体可能成为增加监测的目标。没有检测到VHL序列改变或表观遗传失活的吸烟者有更高的肿瘤患病率。与VHL灭活病例相比，此类肿瘤可能具有生物学特异性，预后较差。
Renal tumor heterogeneity studies have utilized the von Hippel-Lindau VHL gene to classify disease into molecularly defined subtypes to examine associations with etiologic risk factors and prognosis. The aim of this study was to provide a comprehensive analysis of VHL inactivation in clear cell renal tumors (ccRCC) and to evaluate relationships between VHL inactivation subgroups with renal cancer risk factors and VHL germline single nucleotide polymorphisms (SNPs). VHL genetic and epigenetic inactivation was examined among 507 sporadic RCC/470 ccRCC cases using endonuclease scanning and using bisulfite treatment and Sanger sequencing across 11 CpG sites within the VHL promoter. Case-only multivariate analyses were conducted to identify associations between alteration subtypes and risk factors. VHL inactivation, either through sequence alterations or promoter methylation in tumor DNA, was observed among 86.6% of ccRCC cases. Germline VHL SNPs and a haplotype were associated with promoter hypermethylation in tumor tissue (OR = 6.10; 95% CI: 2.28–16.35, p = 3.76E-4, p-global = 8E-5). Risk of having genetic VHL inactivation was inversely associated with smoking due to a higher proportion of wild-type ccRCC tumors [former: OR = 0.70 (0.20–1.31) and current: OR = 0.56 (0.32–0.99); P-trend = 0.04]. Alteration prevalence did not differ by histopathologic characteristics or occupational exposure to trichloroethylene. ccRCC cases with particular VHL germline polymorphisms were more likely to have VHL inactivation through promoter hypermethylation than through sequence alterations in tumor DNA, suggesting that the presence of these SNPs may represent an example of facilitated epigenetic variation (an inherited propensity towards epigenetic variation) in renal tissue. A proportion of tumors from current smokers lacked VHL alterations and may represent a biologically distinct clinical entity from inactivated cases. In a large case-series of 470 sporadic clear cell renal cancer (ccRCC) cases, we examined von Hippel-Lindau (VHL) inactivation as a biomarker of tumor heterogeneity. Germline alterations of the VHL gene were identified and have been found in most families with VHL disease, a hereditary syndrome associated with ccRCC. In sporadic disease, VHL alterations have been reported in up to 91% of cases. Here, we observed a high prevalence of VHL inactivation through both genetic and epigenetic mechanisms that were highly associated with ccRCC. VHL inactivation through promoter hypermethylation in tumors was associated with inherited polymorphisms selected to capture common variation across the VHL locus. A high-risk haplotype associated with promoter hypermethylation in tumor DNA was identified. These findings suggest that the presence of these polymorphisms and VHL promoter hypermethylation may represent an example of an inherited propensity toward epigenetic variation and potential silencing of the VHL gene in tumor tissue. This result could have translational implications, as individuals with the high-risk haplotype could be targeted for increased surveillance. Smokers had a higher prevalence of tumors without detectable VHL sequence alteration or epigenetic inactivation. Such tumors may be biologically distinct and have demonstrated a poorer prognosis compared to VHL inactivated cases.
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DOI：
10.1186/1745-6673-2-13
发表时间：
2007-11-12
期刊：
Journal of occupational medicine and toxicology (London, England)
影响因子：
--
作者：
Charbotel, Barbara;Gad, Sophie;Richard, Stephane
通讯作者：
Richard, Stephane
影响因子：
4.7
作者：
Hemminki, K;Jiang, YW;Lindblad, P
通讯作者：
Lindblad, P
影响因子：
30.8
作者：
Hodgson, G;Hager, JH;Gray, JW
通讯作者：
Gray, JW
影响因子：
6.1
作者：
Bruning, T;Weirich, G;Brauch, H
通讯作者：
Brauch, H
影响因子：
7.5
作者：
Hawkins, Nicholas J.;Lee, James H-F;Hitchins, Megan P.
通讯作者：
Hitchins, Megan P.