Genotype and expression analyses of FTO and ALKBH5 in renal cell carcinoma cohort from MENA region

RNA-modifying proteins significantly contribute to cancer progression. Fat mass and obesity-associated protein (FTO) and alkB homolog 5 RNA demethylase (ALKBH5) are RNA-demethylating proteins with opposing roles in renal cell carcinoma (RCC) across different populations. This study evaluates the genotype and expression of FTO and ALKBH5 in RCC patients from the Middle East and Northern Africa (MENA) region. Formalin-fixed paraffin-embedded samples from kidney biopsies of RCC patients and controls were analyzed through targeted DNA sequencing, whole transcriptome profiling, and immunohistochemistry. Our findings indicated that the rs11075995T variant in FTO is linked to an increased risk of ccRCC. ALKBH5 and FTO protein expression were significantly downregulated in clear cell RCC (ccRCC) and chromophobe RCC (chRCC) but not in papillary RCC (pRCC) patients. In ccRCC, transcriptomic data revealed significant downregulation of FTO (log2FC = -5.2, q <0.001) and ALKBH5 (log2FC = -4.7, q <0.001) compared to controls. A significant negative correlation was found in ccRCC between FTO expression and T allele frequency in rs11075995, suggesting an impact on FTO expression. To our knowledge, this is the first study to examine FTO and ALKBH5 mutations and expression in RCC patients from the MENA region. Overall design: Formalin-fixed paraffin-embedded samples from kidney biopsies of RCC patients and controls were analyzed through targeted DNA sequencing to sequence common variant in FTO and ALKBH5 genes. 11 controls, 22 ccRCC, 6 chRCC, and 7 pRCC samples Abbreviations: (RCC: Renal cell carcinoma, ccRCC: clear cell RCC, chRCC: chromphobe RCC, pRCC: papillary RCC)