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Frequently deleted loci on chromosome 9 may harbor several tumor suppressor genes in human renal cell carcinoma
B Grady1, R Goharderakhshan, J Chang
1Department of Urology, Veterans Affairs Medical Center and University of California-San Francisco, San Francisco, CA, USA.
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.
Insights
This study found frequent loss of heterozygosity on chromosome 9 in renal cell carcinoma, particularly in the 9p21 region. These deletions suggest the involvement of tumor suppressor genes in kidney cancer development.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Loss of genetic material on chromosome 9 is implicated in various cancers.
- Understanding chromosomal alterations in renal cell carcinoma (RCC) is crucial for identifying potential tumor suppressor genes.
Purpose of the Study:
- To determine the frequency of deletions at different loci on chromosome 9 in renal cell carcinoma.
- To analyze microdissected samples of normal renal epithelium and carcinoma from the same patients.
Main Methods:
- DNA was isolated from 60 microdissected renal specimens (normal and tumor cells).
- Polymerase chain reaction (PCR) was used to amplify DNA.
- Loss of heterozygosity (LOH) on chromosome 9 was analyzed using 16 microsatellite markers.
Main Results:
- A high incidence of LOH on chromosome 9 was observed in 73% of RCC cases (at ≥1 locus).
- The 9p21 region showed significant deletions (57% of cases), with specific loci D9S1749 (42%) and D9S171 (38%) frequently affected.
- Higher deletion rates correlated with advanced grades of RCC, and reduced p16 protein expression was noted, suggesting its role in carcinogenesis.
Conclusions:
- High LOH incidence on chromosome 9, particularly 9p21 and 9p22-23, is demonstrated in RCC.
- These findings suggest the presence of several putative tumor suppressor genes in these deleted regions.
- Further research is warranted to identify other tumor suppressor genes in the 9p21 and 9p22-23 regions.
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