ALLELIC LOSS AT THE PREDISPOSING GENE LOCUS IN SPONTANEOUS AND CHEMICALLY-INDUCED RENAL-CELL CARCINOMAS IN THE EKER RAT

Hereditary renal carcinoma (RC) in the rat, originally reported by Eke r in 1954, is an example of a Mendelian dominant predisposition to a s pecific cancer in an experimental animal. We previously reported that ionizing radiation induces additional tumors in a linear dose-response relationship, suggesting that in heterozygotes two events (one inheri ted, one somatic) are necessary to produce tumors. Recently, the predi sposing gene has been mapped to rat chromosome 10. This study was desi gned to examine loss of heterozygosity (LOH) at chromosome 10 in the R Cs developed from hybrid F1 rats carrying Eker mutation. In spontaneou s RCs, 6 of 10 (60%) showed loss of the wild-type allele covering over 30 cM, consistent with two-hit hypothesis. Individual tumors have dif ferent patterns of LOH even from the same kidney, showing independent clonal origins of RCs. In contrast, none of N-ethyl-N-nitrosourea-indu ced RCs had allelic loss (0 of 9 = 0%, P < 0.01). Thus, the nature of the second event differs between spontaneous and chemically induced tu mors in the Eker rat. These results suggest that chemically induced tu mors in experimental animals involve intragenic mutations and so do no t cause LOH of syntenic markers. Interestingly, 1 of 5 spontaneous pit uitary tumors that developed in the Eker rat showed LOH for chromosome 10 markers.