PTCH gene mutations in invasive transitional cell carcinoma of the bladder
PTCH gene mutations in invasive transitional cell carcinoma of the bladder
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DOI：
10.1038/sj.onc.1202045
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发表时间：
1998-09-03
期刊：
影响因子：
8
通讯作者：
Malkowicz, SB
中科院分区：
文献类型：
--
作者：
McGarvey, TW;Maruta, Y;Malkowicz, SB
LOH分析表明，多种肿瘤抑制基因在人类TCC的发展中发挥作用。果蝇PTCH的人类同源基因最近被克隆并定位到9q22.3的BCNS位点，这是一个在tcc中通常缺失的染色体区域。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GL13基因的稳态mRNA转录。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PCR/SSCP分析54例TCC肿瘤样本和对照自体外周血淋巴细胞的基因组dna，筛选“热点”外显子6,8,13和16的PTCH突变。DNA序列分析证实54例患者中有2例（3.7%）发生tcc特异性突变。这些突变导致单个氨基酸取代和两个框架移位。一个肿瘤在16外显子和13外显子中都有PTCH突变，一个肿瘤仅在13外显子中有突变。包含PTCH突变的两种TCC肿瘤在9q处的杂合性缺失。尽管PTCH蛋白在尿路上皮细胞中的功能未知，但在正常尿路上皮和TCC细胞系中检测到PTCH、SMOH和GL13转录本，以及肿瘤样本中罕见的PTCH突变表明，HH途径可能在控制尿路上皮细胞的增殖中起作用，PTCH突变可能有助于TCC亚群的发展。
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 GL13 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 GL13 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.