Comparative Analysis of the APOL1 Variants in the Genetic Landscape of Renal Carcinoma Cells

Although the relative risk of renal cell carcinoma associated with chronic kidney injury is particularly high among sub‐Saharan African ancestry populations, it is unclear yet whether the APOL1 gene risk variants (RV) for kidney disease additionally elevate this risk. APOL1 G1 and G2 RV contribute to increased risk for kidney disease in black populations, although the disease mechanism has still not been fully deciphered. While high expression levels of all three APOL1 allelic variants, G0 (the wild type allele), G1, and G2 are injurious to normal human cells, renal carcinoma cells (RCC) naturally tolerate inherent high expression levels of APOL1. We utilized CRISPR/Cas9 gene editing to generate isogenic RCC clones expressing APOL1 G1 or G2 risk variants on a similar genetic background, thus enabling a reliable comparison between the phenotypes elicited in RCC by each of the APOL1 variants. Here, we demonstrate that knocking in the G1 or G2 APOL1 alleles, or complete elimination of APOL1 expression, has major effects on proliferation capacity, mitochon-drial morphology, cell metabolism, autophagy levels, and the tumorigenic potential of RCC cells. The most striking effect of the APOL1 RV effect was demonstrated in vivo by the complete abolish-ment of tumor growth in immunodeficient mice. Our findings suggest that, in contrast to the WT APOL1 variant, APOL1 RV are toxic for RCC cells and may act to suppress cancer cell growth. We conclude that the inherent expression of non‐risk APOL1 G0 is required for RCC tumorigenicity. RCC cancer cells can hardly tolerate increased APOL1 risk variants expression levels as opposed to APOL1 G0.