Defective DNA Repair in Renal Cell Carcinoma
RM Cox, H Zhang, C Xie, N Gokden, C-Y Fan. University of Arkansas for Medical Sciences, Little Rock, AR; John L. McClellan Memorial Veterans Hospital, Little Rock, AR
Background: One of the mechanisms involved in carcinogenesis is somatic mutation of tumor suppressor genes. Cellular metabolites, such as free radicals and N-nitroso compounds, can generate mutagenic DNA base lesions 8-oxoguanine and 06-methyl-guanine respectively. A mismatch between guanine and thymine (G:T mismatch) will occur in DNA if 8-oxoguanine and 06-methyl-guanine are not promptly removed by their respective repair enzymes, 8-oxoquanine DNA glycosylase 1 (hOGG1) and 06-methyl-guanine DNA methyltransferase (MGMT). These mismatches can be corrected by a mismatch repair enzyme, hMLH1. Persistence of DNA mismatches due to insufficient hMLH1 mismatch repair can lead to permanent somatic mutations. The kidney is very prone to DNA damages of various forms because it disposes, and is exposed to, most toxic metabolites produced in the body. In this study, we aim at characterizing the gene expression levels of 3 important DNA repair genes, hOGG1, MGMT and hMLH1 in clear cell renal cell carcinoma as compared to matched normal renal parenchyma.
Design: Total RNA was extracted from 14 fresh RCC tissue samples and their matched benign renal parenchyma. Gene expression levels for hOGG1, MGMT and hMLH1 genes were analyzed by real-time RT-PCR quantitation with ABI Fast 7500 Real-time PCR System, using Taqman -actin as an internal controls for normalization.
Results: The mRNA expression levels were significantly lower in RCC than those seen in adjacent normal parenchyma in 12 of 14 cases (85.7%) for hOGG1 gene, 11 of 14 cases (78.5%) for the MGMT gene and 11 of 14 cases (78.5%) for the hMLH1 gene. Overall, the mRNA expression levels in RCC is about 28% for hOGG1 gene, 53% for MGMT gene and 42% for hMLH1 gene of those seen in normal renal tissues. The mean relative mRNA levels for hOGG1, MGMT and hMLH1 in all 14 cases were 0.78, 1.0 and 1.4 respectively as compared to a mean of 2.72, 1.9 and 3.4 for normal renal parenchyma. The differences in mRNA expression between RCC and adjacent normal tissues for hOGG1, MGMT and hMLH1 genes are statistically very significant (p <0.01).
Conclusions: Significant defects in DNA repair occurs commonly in CC-RCC as seen in 85.7% cases for hOGG1 gene and in 78.5% cases for MGMT and hMLH1 genes. These results indicate that insufficient DNA repair may play crucial roles in the development and/or progression of renal cell carcinoma.
Category: Genitourinary (including renal tumors)
Wednesday, March 11, 2009 1:00 PM
Poster Session VI # 122, Wednesday Afternoon