Background/Objectives: RNA-modifying proteins play a crucial role in the progression of cancer. The fat mass and obesity-associated protein (FTO) and alkB homolog 5 RNA demethylase (ALKBH5) are RNA-demethylating proteins that have contrasting effects in renal cell carcinoma (RCC) among different populations. This research investigates the genotype and expression levels of FTO and ALKBH5 in RCC patients from the Middle East and Northern Africa (MENA) region.Methods: Formalin-fixed paraffin-embedded samples from the kidney biopsies of RCC patients and controls were examined using targeted DNA sequencing, whole transcriptome profiling, and immunohistochemistry.Results: Our findings show that the rs11075995T variant in FTO is associated with a heightened risk of clear-cell RCC (ccRCC). ALKBH5 and FTO protein expression were significantly lower in ccRCC and chromophobe RCC (chRCC) patients but not in papillary RCC (pRCC) patients. In ccRCC, transcriptomic data revealed a 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 that FTO expression is affected.Conclusions: This is the first demonstration of the association of the dysregulated expression of FTO and ALKBH5 in ccRCC and chRCC patients from the MENA region. FTO variant rs11075995T increased the risk of ccRCC and was negatively associated with FTO protein expression.
背景/目的：RNA修饰蛋白在癌症进展中起着关键作用。脂肪量与肥胖相关蛋白（FTO）和AlkB同源物5 RNA去甲基化酶（ALKBH5）作为RNA去甲基化蛋白，在不同人群的肾细胞癌（RCC）中表现出相反的作用。本研究旨在探讨中东和北非（MENA）地区RCC患者中FTO和ALKBH5的基因型及表达水平。 方法：采用靶向DNA测序、全转录组分析和免疫组织化学技术，对RCC患者及对照组的肾活检福尔马林固定石蜡包埋样本进行检测。 结果：研究发现，FTO基因中的rs11075995T变异与透明细胞肾细胞癌（ccRCC）的风险增加相关。在ccRCC和嫌色细胞肾细胞癌（chRCC）患者中，ALKBH5和FTO蛋白表达显著降低，但在乳头状肾细胞癌（pRCC）患者中未观察到这一现象。转录组数据显示，与对照组相比，ccRCC中FTO（log2FC = −5.2，q < 0.001）和ALKBH5（log2FC = −4.7，q < 0.001）的表达显著下调。在ccRCC中，FTO表达与rs11075995位点的T等位基因频率呈显著负相关，表明FTO表达受到影响。 结论：本研究首次揭示了MENA地区ccRCC和chRCC患者中FTO和ALKBH5表达失调的关联。FTO变异rs11075995T增加了ccRCC的风险，并与FTO蛋白表达呈负相关。
Analysis of Genotype and Expression of FTO and ALKBH5 in a MENA-Region Renal Cell Carcinoma Cohort
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