The genetic locus NRC-1 within chromosome 3p12 mediates tumor suppression in renal cell carcinoma independently of histological type, tumor microenvironment, and VHL mutation

Human chromosome 3p cytogenetic abnormalities and loss of heterozygosity ha ve been observed at high frequency in the nonpapillary form of sporadic ren al cell carcinoma (RCC), The von Hippel-Lindau (VHL) gene has been identifi ed as a tumor suppressor gene for RCC at 3p25, and functional studies as we ll as molecular genetic and cytogenetic analyses have suggested as many as two or three additional regions of 3p that could harbor tumor suppressor ge nes for sporadic RCC, We have previously functionally defined a novel genet ic locus nonpapillary renal carcinoma-1 (NRC-1) within chromosome 3p12, dis tinct from the VHL gene, that mediates tumor suppression and rapid cell dea th of RCC cells in vivo, We now report the suppression of tumorigenicity of RCC cells in vivo after the transfer of a defined centric 3p fragment into different histological types of RCC, Results document the functional invol vement of NRC-1 in not only different cell types of RCC (i.e., clear cell, mixed granular cell/clear cell, and sarcomatoid types) but also in papillar y RCC, a less frequent histological type of RCC for which chromosome 3p LOH and genetic aberrations have only rarely been observed. We also report tha t the tumor suppression observed in functional genetic screens was independ ent of the microenvironment of the tumor, further supporting a role for NRC -I as a more general mediator of in vivo growth control. Furthermore, this report demonstrates the first functional evidence for a VHL-independent pat hway to tumorigenesis in the kidney via the genetic locus NRC-1.