Sexually dimorphic effects of mutations in ccRCC driver genes in renal proximal tubule cells

Clear cell renal cell carcinoma (ccRCC) arises more frequently in men than in women, but it remains unclear why this is the case. Mouse models that mimic the truncal mutation of the two most commonly affected tumor suppressor genes in human ccRCC revealed that the transcriptional effects of Vhl or Vhl/Pbrm1 mutation in male and female proximal tubule cells only partially overlap. Cellular responses to mutations in these genes were also sex-specific. Vhl and Vhl/Pbrm1 mutation in females, but only Vhl/Pbrm1 mutation in males, induced the accumulation of PLIN2-coated lipid droplets. The accumulation of optically-clear lipid droplets, reflecting the hallmark clear-cell histological feature of ccRCC, only arose in Vhl/Pbrm1 mutant male mice. Consistent with lipotoxic tubular damage, markers of tubular repair and ongoing epithelial cell proliferation correlated with the lipid accumulation phenotypes. Vhl/Pbrm1 mutation caused stronger clonal expansion than Vhl mutation in males, but not in females. These findings suggest that there are likely to be sexual dimorphisms at the very earliest stages of ccRCC evolution that result from the interplay of intrinsic and mutation-induced transcriptional differences between male and female proximal tubule cells.