AN ALTERNATIVE ROUTE FOR MULTISTEP TUMORIGENESIS IN A NOVEL CASE OF HEREDITARY RENAL-CELL CANCER AND A T(2-3)(Q35-Q21) CHROMOSOME-TRANSLOCATION

Through allele-segregation and loss-of-heterozygosity analyses, we dem onstrated loss of the translocation-derivative chromosome 3 in five in dependent renal cell tumors of the clear-cell type, obtained from thre e members of a family in which a constitutional t(2;3)(q35;q21) was en countered. In addition, analysis of the von Hippel-Lindau gene, VHL, r evealed distinct insertion, deletion, and substitution mutations in fo ur of the five tumors tested. On the basis of these results, we conclu de that, in this familial case, an alternative route for renal cell ca rcinoma development is implied. In contrast to the first hit in the ge nerally accepted two-hit tumor-suppressor model proposed by Knudson, t he familial translocation in this case may act as a primary oncogenic event leading to (nondisjunctional) loss of the der(3) chromosome harb oring the VHL tumor-suppressor gene. The risk of developing renal cell cancer may be correlated directly with the extent of somatic (kidney) mosaicism resulting from this loss.