Laboratory of Oncology, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Foggia, Italy.
Int J Biol Markers. 2013 Jun 28;28(2):208-15. doi: 10.5301/jbm.5000011.
Clear cell renal cell carcinoma (ccRCC) is the most common malignant neoplasm of the kidney and belongs to the few human tumors known to develop from mutations of the VHL tumor suppressor gene. VHL germline mutations are associated with hereditary ccRCCs in VHL disease. However, somatic VHL gene defects may also occur in sporadic ccRCCs. In this study, we analyzed the frequency and the spectrum of VHL gene alterations in 35 Italian patients with sporadic renal cell carcinoma (RCC). Tumor-specific intragenic VHL pathogenic mutations were detected in 38% (11/29) of the ccRCC patients and 33% (2/6) of the patients with other types of RCC. One novel 18-bp in-tandem duplication and 4 previously unreported nucleotide changes in the VHL gene were described. Microsatellite analysis showed loss of heterozygosity for at least 1 informative marker in 43% (9/21) of the ccRCCs and 50% (3/6) of the non-ccRCCs; 5 of the 13 tumors (38%) harboring VHL gene alterations also had loss of heterozygosity for at least 1 microsatellite marker. Our results confirm that somatic inactivation of the VHL gene may play a pivotal role in the tumorigenesis of sporadic ccRCCs in Italian patients and suggests that mutation analysis of the VHL gene may be helpful for discriminating sporadic, VHL-gene-related ccRCCs from those related to VHL disease.
透明细胞肾细胞癌（ccRCC）是最常见的肾脏恶性肿瘤，属于少数已知由 VHL 肿瘤抑制基因突变引起的人类肿瘤之一。VHL 种系突变与 VHL 病中的遗传性 ccRCC 相关。然而，散发性 ccRCC 也可能发生体细胞 VHL 基因缺陷。在这项研究中，我们分析了 35 名意大利散发性肾细胞癌（RCC）患者中 VHL 基因改变的频率和谱。在 38%（11/29）的 ccRCC 患者和 33%（2/6）的其他类型 RCC 患者中检测到肿瘤特异性内含子 VHL 致病性突变。描述了 1 个新的 18 碱基串联重复和 VHL 基因中 4 个以前未报道的核苷酸变化。微卫星分析显示，在 43%（9/21）的 ccRCC 和 50%（3/6）的非 ccRCC 中至少有 1 个信息性标记丢失杂合性；在 13 个携带 VHL 基因改变的肿瘤中，有 5 个（38%）至少有 1 个微卫星标记丢失杂合性。我们的结果证实，VHL 基因的体细胞失活可能在意大利患者散发性 ccRCC 的肿瘤发生中起关键作用，并表明 VHL 基因突变分析可能有助于鉴别散发性、与 VHL 基因相关的 ccRCC 与与 VHL 病相关的 ccRCC。
