PROLIFERATIVE HETEROGENEITY OF HUMAN RENAL-CELL CARCINOMAS AND PREVALENCE OF RAS GENE POINT MUTATIONS

The variable prevalence and a possible stage-dependent increase of ras gene point mutations in human tumors might correspond to clonal growt h advantages of ras-activated cells. Tumor areas with activated ras ge nes might thus differ in proliferative activity from those lacking ras gene activation. This hypothesis is studied in a series of human rena l cell carcinomas that had been used previously for an analysis of pro liferative compartments after postoperative vascular [H-3]/[C-14]thymi dine perfusion [Rabes et al. (1979) Cancer 44: 799-813]. The growth fr action of different subcompartments of these tumors was studied by imm unohistochemistry with mibl antibody, recognizing a fixation- and embe dding-resistant epitope of Ki-67 protein. Thirty subpopulations of 14 human renal cell carcinomas that exhibited a broad spectrum of prolife rative activity were chosen for an analysis of the prevalence of K-ras point mutations in exon 1 by a mutation-enriching primer-mediated res triction-fragment-length-polymorphism analysis and/or direct sequencin g of polymerase-chain-reaction-amplified material. The combined autora diographic and immunohistochemical analysis confirmed the intra- and i ntertumoral proliferative heterogeneity. Compared to [H-3]/[C-14]thymi dine labeling indices, mibl labeling indices are higher. The ratio of mibl to [H-3]/[C-14]thymidine labeling indices varies from 1.9 to 4.1 for the individual tumor subcompartments. However, neither in K-ras co dons 12/13 nor in adjacent codons did we detect any mutations in the v arious tumor compartments. The results suggest that neither mode of pr oliferation nor type of differentiation is related to K-ras exon 1 poi nt mutations in human renal cell carcinomas.