9号染色体上频繁缺失的基因座可能包含人类肾细胞癌中的多个肿瘤抑制基因。

Frequently deleted loci on chromosome 9 may harbor several tumor suppressor genes in human renal cell carcinoma.

作者信息

Grady B, Goharderakhshan R, Chang J, Ribeiro-Filho L A, Perinchery G, Franks J, Presti J, Carroll P, Dahiya R

机构信息

Department of Urology, Veterans Affairs Medical Center and University of California-San Francisco, San Francisco, CA, USA.

出版信息

J Urol. 2001 Sep;166(3):1088-92.

PMID:11490304

Abstract

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 p16 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.

摘要

目的

已有报道称多种癌症中存在9号染色体上不同位点的缺失。为确定肾细胞癌中9号染色体不同位点的缺失频率，对来自同一患者的正常肾上皮和癌组织的显微切割样本进行了分析。

材料与方法

从60例肾脏标本的正常和肿瘤细胞显微切割切片中提取DNA，通过聚合酶链反应进行扩增，并使用16个微卫星标记D9S178、D9S157、D9S274、D9S168、D9S285、D9S156、D9S1839、D9S162、IFNA、D9S736、D9S171、D9S1749、D9S273、D9S270、D9S153和D9S170分析9号染色体上的杂合性缺失。采用我们实验室开发的基于聚合酶链反应的技术分析杂合性缺失。

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。在60例病例中，分别有44例（73%）、24例（40%）和14例（23%）至少在1个、至少在3个以及4个或更多位点显示杂合性缺失。主要缺失位于9p21区域，其中DS171位点缺失的病例占38%，D9S1749位点缺失的病例占42%，DS270位点缺失的病例占14%。57%的肾癌病例中观察到9p21染色体整体缺失。其他缺失区域位于9p'0022至23，其中D9S157位点缺失的病例占37%，D9S274位点缺失的病例占20%，D9S168位点缺失的病例占27%，D9S285位点缺失的病例占20%，D9S156位点缺失的病例占12%，D9S1839位点缺失的病例占17%，D9S162位点缺失的病例占24%。46%的肾细胞癌病例中观察到9q32至33染色体整体缺失。22%的肾细胞癌病例中9q32至33染色体上的D9S170位点也显示缺失。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，发现晚期肾细胞癌的缺失率更高。在多种癌症的9p21缺失区域内已鉴定出一个候选的肿瘤抑制基因p16（MTS - 1/CDKN2）。在我们的研究中，肾细胞癌样本中p16蛋白表达缺失或较低，这表明p16基因的缺失可能参与肾细胞癌的发生。