McGarvey T W, Maruta Y, Tomaszewski J E, Linnenbach A J, Malkowicz S B
Department of Surgery, University of Pennsylvania Medical Center and Veterans Administration Medical Center, Philadelphia 19104, USA.
Oncogene. 1998 Sep 3;17(9):1167-72. doi: 10.1038/sj.onc.1202045.
LOH analysis suggests that multiple tumor suppressor genes play a role in the development of human TCC. The human homolog of the Drosophila PTCH was recently cloned and mapped to the BCNS locus on 9q22.3, a chromosomal region commonly deleted in TCCs. We first examined the steady state mRNA transcription of the PTCH, SMOH and GLI3 genes of the HH signal transduction pathway in TCC cell lines and normal urothelium. Normal urothelium and TCC cell lines express these three genes within the PTCH signal transduction pathway. We then screened for PTCH mutations in 'hot spot' exons 6, 8, 13 and 16 by PCR/SSCP analysis of genomic DNAs from 54 TCC tumor samples and control autologous peripheral blood lymphocytes. DNA sequence analysis confirmed TCC-specific mutations in two of 54 patients (3.7%). These mutations resulted a single amino acid substitution and two frame shifts. One tumor had PTCH mutations in exon 16 as well as exon 13 and one tumor had a mutation in exon 13 alone. Both TCC tumors that contained PTCH mutations had a loss of heterozygosity at 9q. Although the PTCH protein has an unknown function in urothelial cells, the detection of the PTCH, SMOH and GLI3 transcripts in normal urothelium and TCC cell lines and rare PTCH mutations in tumor samples suggest that the HH pathway may have a role in controlling the proliferation of urothelial cells and that PTCH mutations may contribute to the development of a subset of TCCs.
杂合性缺失分析表明，多个肿瘤抑制基因在人类移行细胞癌（TCC）的发生发展中起作用。果蝇PTCH的人类同源物最近被克隆并定位于9q22.3的基底细胞痣综合征（BCNS）位点，这是TCC中常见的染色体缺失区域。我们首先检测了TCC细胞系和正常尿路上皮中HH信号转导通路的PTCH、SMOH和GLI3基因的稳态mRNA转录情况。正常尿路上皮和TCC细胞系在PTCH信号转导通路中表达这三个基因。然后，我们通过对54例TCC肿瘤样本和对照自体外周血淋巴细胞的基因组DNA进行PCR/SSCP分析，筛选了“热点”外显子6、8、13和16中的PTCH突变。DNA序列分析证实，54例患者中有2例（3.7%）存在TCC特异性突变。这些突变导致了一个氨基酸替换和两个移码突变。一个肿瘤在外显子16以及外显子13中有PTCH突变，另一个肿瘤仅在外显子13中有突变。两个含有PTCH突变的TCC肿瘤在9q均存在杂合性缺失。尽管PTCH蛋白在尿路上皮细胞中的功能尚不清楚，但在正常尿路上皮和TCC细胞系中检测到PTCH、SMOH和GLI3转录本，以及在肿瘤样本中发现罕见的PTCH突变，提示HH通路可能在控制尿路上皮细胞增殖中起作用，且PTCH突变可能有助于一部分TCC的发生发展。
