Frequently deleted loci on chromosome 9 may harbor several tumor suppressor genes in human renal cell carcinoma
Frequently deleted loci on chromosome 9 may harbor several tumor suppressor genes in human renal cell carcinoma
复制标题
DOI：
10.1016/s0022-5347(05)65927-7
复制
发表时间：
2001-09-01
影响因子：
6.6
通讯作者：
Dahiya, R
中科院分区：
文献类型：
--
作者：
Grady, B;Goharderakhshan, R;Dahiya, R
目的：9号染色体上不同位点的缺失在多种癌症中都有报道。为了确定肾细胞癌中9号染色体不同位点缺失的频率，我们分析了来自同一患者的正常肾上皮和癌的微解剖样本。材料与方法：从60例肾脏标本的正常细胞和肿瘤细胞显微切片中分离DNA，经聚合酶链反应扩增，用16个微卫星标记D9S178、D9S157、D9S274、D9S168、D9S285、D9S156、D9S1839、D9S162、IFNA、D9S736、D9S171、D9S1749、D9S273D9S270、D9S153和D9S170分析9号染色体杂合缺失情况。杂合性缺失是通过我们实验室开发的基于聚合酶链反应的技术进行分析的。结果：本研究显示肾细胞癌中9号染色体杂合性缺失的发生率很高。60例中，44例（73%）、24例（40%）和14例（23%）分别出现至少1个、至少3个和4个或更多位点的杂合性缺失。38%的病例在9p21区域DS171位点上发现主缺失，42%的病例在D9S1749位点上，14%的病例在DS270位点上发现主缺失。57%的肾癌患者存在9p21染色体缺失。其他缺失区域位于9p'0022至23号染色体上D9S157位点（37%），D9S274位点（20%），D9S168位点（27%），D9S285位点（20%），D9S156位点（12%），D9S1839位点（17%），D9S162位点（24%）。在46%的肾细胞癌病例中，9q32至33号染色体全部缺失。在22%的肾癌病例中，染色体9q32至33也显示D9S170位点缺失。当我们根据肾细胞癌分级比较9号染色体上不同位点的缺失发生率时，我们发现晚期肾细胞癌的缺失率更高。一个候选的靶肿瘤抑制基因p16 （MTS-1/CDKN2）已经在多种癌症的9p21缺失区被发现。在我们的研究中，p16蛋白在肾细胞癌样本中缺失或低表达，提示p16基因的缺失可能参与了肾细胞的癌变。结论：我们的研究表明，在肾细胞癌中，9号染色体（主要是9p21和9p22至23）杂合性缺失的发生率很高，表明这些区域可能存在几种肿瘤抑制基因。9p21和9p22 ~ 23区域其他抑癌基因的鉴定有待进一步研究。
Purpose: Loss of various loci on chromosome 9 has been reported in various cancers. To determine the frequency of deletions at different loci of chromosome 9 in renal cell carcinoma microdissected samples of normal renal epithelium and carcinoma from the same patients were analyzed.Materials and Methods: DNA was isolated from microdissected sections of normal and tumor cells of 60 renal specimens, amplified by polymerase chain reaction and analyzed for loss of heterozygosity on chromosome 9 using the 16 microsatellite markers D9S178, D9S157, D9S274, D9S168, D9S285, D9S156, D9S1839, D9S162, IFNA, D9S736, D9S171, D9S1749, D9S273D9S270, D9S153 and D9S170. Loss of heterozygosity was analyzed by a polymerase chain reaction based technique developed at our laboratory.Results: This study showed a high incidence of loss of heterozygosity on chromosome 9 in renal cell carcinoma. Of 60 cases 44 (73%), 24 (40%) and 14 (23%) showed loss of heterozygosity at a minimum of 1, at a minimum of 3 and at 4 or more loci, respectively. The main deletion was found on the 9p21 region at loci DS171 in 38% of cases, D9S1749 in 42% and DS270 in 14%. Overall deletion on chromosome 9p21 was noted in 57% of renal cancer cases. Other deleted regions were on chromosome 9p'0022 to 23 at loci D9S157 in 37% of cases, D9S274 in 20%, D9S168 in 27%, D9S285 in 20%, D9S156 in 12%, D9S1839 in 17% and D9S162 in 24%. Overall deletion at chromosome 9q32 to 33 was noted in 46% of renal cell carcinoma cases. Chromosome 9q32 to 33 also showed deletion at locus D9S170 in 22% of renal cell carcinoma cases. When we compared the incidence of deletion at various loci on chromosome 9 according to renal cell carcinoma grade, we found a higher rate of deletion in advanced grades of renal cell carcinoma. A candidate target tumor suppressor gene, p16 (MTS-1/CDKN2), has been identified within the 9p21 deleted region in various cancers. In our study the expression of p16 protein was absent or low in renal cell cancer samples, suggesting that loss of the p 16 gene may be involved in renal cell carcinogenesis.Conclusions: Our study demonstrates a high incidence of loss of heterozygosity on chromosome 9, mainly 9p21 and 9p22 to 23, in renal cell carcinoma, suggesting several putative tumor suppressor genes on these regions. The identification of other tumor suppressor genes on the 9p21 and 9p22 to 23 regions warrants further studies.