Medical and Molecular Genetics, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, UK.
Genes Chromosomes Cancer. 2011 Jul;50(7):479-88. doi: 10.1002/gcc.20865. Epub 2011 Mar 31.
Germline mutations in the VHL tumor suppressor gene cause von Hippel-Lindau (VHL) disease and somatic VHL mutations occur in the majority of clear cell renal cell carcinoma (cRCC). To compare copy number abnormalities (CNAs) between cRCC from VHL patients and sporadic cRCC cases without detectable somatic VHL mutations, we analyzed 34 cRCC with Affymetrix 250K arrays. To increase the power of the study, we then combined our results with those of a previously published study and compared CNAs in VHL and non-VHL related cRCC using the genomic identification of significant targets in cancer (GISTIC) program. In VHL, cRCC GISTIC analysis identified four statistically significant regions of copy number gain and four statistically significant regions of deletion that occurred in >10% of tumors analyzed. Sporadic cRCC without detectable VHL mutations had, on average, more copy number abnormalities than VHL cRCC though the most common regions of loss/gain (e.g., 3p and 14q loss and 5q gain) were present in both tumor sets. However, CNAs on chromosome arms 7p (gain) and 8p (loss) were only detected in VHL RCC. Although individual copy number abnormality peaks contained clear candidate cancer genes in some cases (e.g., the 3p loss peak in VHL cRCC contained only six genes including VHL), most peaks contained many genes. To date, only a minority of the candidate genes included in these peaks have been analyzed for mutation or epigenetic inactivation in cRCC but TNFRSF10C and DUSP4 map to the 8p region deleted in VHL cRCC and TP53 and HIF2A (EPAS1) mapped to CNA loss and gain peaks (chromosomes 17 and 2, respectively) detected in sporadic VHL wild-type cRCC.
VHL 肿瘤抑制基因的种系突变导致 von Hippel-Lindau（VHL）病，而体细胞 VHL 突变则发生在大多数透明细胞肾细胞癌（cRCC）中。为了比较 VHL 患者的 cRCC 和无明显体细胞 VHL 突变的散发性 cRCC 之间的拷贝数异常（CNAs），我们使用 Affymetrix 250K 阵列分析了 34 例 cRCC。为了增加研究的效力，我们将结果与之前发表的研究结果相结合，并使用基因组鉴定癌症中的显著靶标（GISTIC）程序比较 VHL 和非 VHL 相关 cRCC 中的 CNAs。在 VHL 中，cRCC 的 GISTIC 分析确定了四个具有统计学意义的拷贝数增益区域和四个具有统计学意义的缺失区域，这些区域发生在分析的肿瘤中 >10%。无明显 VHL 突变的散发性 cRCC 的拷贝数异常平均多于 VHL cRCC，尽管最常见的缺失/增益区域（例如 3p 和 14q 缺失和 5q 增益）存在于两组肿瘤中。然而，在 VHL RCC 中仅检测到染色体臂 7p（增益）和 8p（缺失）的 CNAs。尽管在某些情况下，单个拷贝数异常峰中包含明确的候选癌症基因（例如，VHL cRCC 中的 3p 缺失峰仅包含六个基因，包括 VHL），但大多数峰包含许多基因。迄今为止，在这些峰中包含的少数候选基因已被分析用于突变或表观遗传失活在 cRCC 中，但 TNFRSF10C 和 DUSP4 映射到 VHL cRCC 中缺失的 8p 区域，TP53 和 HIF2A（EPAS1）映射到 CNA 缺失和增益峰（分别为染色体 17 和 2）检测到在散发性 VHL 野生型 cRCC 中。
