GENETIC INSTABILITY IN RENAL-CELL CARCINOMA

Objective: To investigate the incidence of loss of heterozygosity (LOH ) and microsatellite instability (MI) in human renal cell carcinoma (R CC), and to determine a possible activation of H-ras oncogene in these tumours via implication of its polymorphic regions within the first i ntron and 3' ends. Methods: In the present study, we investigated the incidence of MI and LOH in 22 RCCs, using a bank of 8 microsatellite m arkers located on chromosomes 2 (IL1A), 3 (D3S1234), 8 (MYC), 14 (D14S 51) and 17 (THRA1, D17S250, D17S579). We also studied the microsatelli te DNA of the H-ms oncogene within the first intron (HRM) and the mini satellite DNA of the variable tandem repeat (VTR), which is located 1, 000 bp downstream of the H-ras gene and possesses enhancer activity, f or genetic instability. Alterations of the 28-bp repetition core were studied employing restriction fragment length polymorphism analysis. R esults: MI and LOH were observed in 8 (4 MI and 4 LOH) out of 22 (18%) specimens at 3p21.1-p14.2 and 17q21, indicating the presence of putat ive tumour suppressor genes (TSGs) at these loci. Alterations of the 2 8-bp repetition core of H-ras VTR were found in 2 out of 22 cases (9%) , while point mutations of the same repetition core were detected in o nly 1 case (5%). Additionally, 1 case (5%), showed LOH. Conclusions: O ur results indicate that genetic instability is a detectable phenomeno n in human RCC and it might be associated with the development of the disease. LOH at 3p21.1-p14.2 and 17q21 suggests that important TSGs ma y be located on these chromosomal regions involved in the tumorigenesi s or progression of RCC. Considering the fact that the DNA sequence of this VTR region contains a target area for transcription and other re gulation factors of H-ras gene expression, these findings could be of importance as regards the involvement of this gene in the process of c arcinogenesis in RCC.