Constitutional von Hippel-Lindau (VHL) gene deletions detected in VHL families by fluorescence in situ hybridization.-猫眼课题宝

DOI：

发表时间：

1999-11

期刊：

Cancer research

影响因子：

11.2

通讯作者：

中科院分区：

医学1区

文献类型：

作者：

Svetlana Pack;Berton Zbar;Evgenia Pak;David O. Ault;Jeffrey S. Humphrey;Thu Pham;K. Hurley;Robert J. Weil;Won Sang Park;I. Kuzmin;Catherine A. Stolle;G. Glenn;Lance A. Liotta;M. Lerman;R. D. Klausner;W. Linehan;Zhengping Zhuang

von Hippel-Lindau（VHL）病是一种常染色体显性遗传的癌症综合征，易患多种肿瘤类型，包括视网膜成血管细胞瘤、中枢神经系统成血管细胞瘤、肾细胞癌、胰腺囊肿和肿瘤、嗜铬细胞瘤、内淋巴囊肿瘤和附睾囊腺瘤[W. M. Linehan等人，J. Am.医学协会，273：564-570，1995; E. A. Maher和W. G.小凯林，Medicine（巴尔的摩），76：381-391，1997; W. M. Linehan和R. D. Klausner，In：B. Vogelstein和K. Kinzler（eds.），人类癌症的遗传基础，pp。455-473，McGraw-Hill，1998]。将VHL基因定位于染色体3 p25 -26，并克隆[F. Besidf等人，Science（华盛顿DC），260：1317-1320，1993]。已在大多数VHL激酶中检测到VHL基因的种系突变。报道的VHL种系突变的检测频率从39%到80%不等（J.M. Whaley等人，Am. J.哈姆。遗传学，55：1092-1102，1994;日本临床研究组，J.D.摩尔Genet.，4：2233-2237，1995; F. Chen等人，Hum. Mutat.，5：66-75，1995; E. R. Maher等人，医学遗传学杂志，33：328-332，1996; B. Zbar，癌症调查，25：219-232，1995）。最近，发现定量Southern印迹法可提高该频率（C. Stolle等人，Hum. Mutat.，12：417-423，1998）。在本研究中，我们报告使用荧光原位杂交（FISH）作为一种方法来检测和表征VHL种系缺失。我们重新检查了一组VHL患者先前显示单链构象和测序分析不港点突变的VHL基因座。我们发现宪法删除29 30 VHL患者在这组中使用粘粒和P1探针，覆盖VHL基因座。然后，我们测试了6个表型正常的后代，从这些VHL家庭的四个：两个被发现进行删除，其他四个是删除免费的。此外，VHL基因的生殖嵌合体被确定在一个家庭。总之，FISH被认为是一种简单可靠的方法来检测VHL种系缺失和实际有用的情况下，其他方法的筛选未能检测到VHL基因异常。

von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited cancer syndrome predisposing to a variety of tumor types that include retinal hemangioblastomas, hemangioblastomas of the central nervous system, renal cell carcinomas, pancreatic cysts and tumors, pheochromocytomas, endolymphatic sac tumors, and epididymal cystadenomas [W. M. Linehan et al., J. Am. Med. Assoc., 273: 564-570, 1995; E. A. Maher and W. G. Kaelin, Jr., Medicine (Baltimore), 76: 381-391, 1997; W. M. Linehan and R. D. Klausner, In: B. Vogelstein and K. Kinzler (eds.), The Genetic Basis of Human Cancer, pp. 455-473, McGraw-Hill, 1998]. The VHL gene was localized to chromosome 3p25-26 and cloned [F. Latif et al., Science (Washington DC), 260: 1317-1320, 1993]. Germline mutations in the VHL gene have been detected in the majority of VHL kindreds. The reported frequency of detection of VHL germline mutations has varied from 39 to 80% (J. M. Whaley et al., Am. J. Hum. Genet., 55: 1092-1102, 1994; Clinical Research Group for Japan, Hum. Mol. Genet., 4: 2233-2237, 1995; F. Chen et al., Hum. Mutat., 5: 66-75, 1995; E. R. Maher et al., J. Med. Genet., 33: 328-332, 1996; B. Zbar, Cancer Surv., 25: 219-232, 1995). Recently a quantitative Southern blotting procedure was found to improve this frequency (C. Stolle et al., Hum. Mutat., 12: 417-423, 1998). In the present study, we report the use of fluorescence in situ hybridization (FISH) as a method to detect and characterize VHL germline deletions. We reexamined a group of VHL patients shown previously by single-strand conformation and sequencing analysis not to harbor point mutations in the VHL locus. We found constitutional deletions in 29 of 30 VHL patients in this group using cosmid and P1 probes that cover the VHL locus. We then tested six phenotypically normal offspring from four of these VHL families: two were found to carry the deletion and the other four were deletion-free. In addition, germline mosaicism of the VHL gene was identified in one family. In sum, FISH was found to be a simple and reliable method to detect VHL germline deletions and practically useful in cases where other methods of screening have failed to detect a VHL gene abnormality.

Constitutional von Hippel-Lindau (VHL) gene deletions detected in VHL families by fluorescence in situ hybridization.

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