Abstract
(1) Background: Methylation of N6-adenosine (m6A) is the most abundant messenger RNA (mRNA) modification in eukaryotes. We assessed the expression profiles of m6A regulatory proteins in renal cell carcinoma (RCC) and their clinical relevance, namely, as potential biomarkers. (2) Methods: In silico analysis of The Cancer Genome Atlas (TCGA) dataset was use for evaluating the expression of the m6A regulatory proteins among RCC subtypes and select the most promising candidates for further validation. ALKBH5 and FTO transcript and protein expression were evaluated in a series of primary RCC (n = 120) and 40 oncocytomas selected at IPO Porto. (3) Results: In silico analysis of TCGA dataset disclosed altered expression of the major m6A demethylases among RCC subtypes, particularly FTO and ALKBH5. Furthermore, decreased FTO mRNA levels associated with poor prognosis in ccRCC and pRCC. In IPO Porto’s cohort, FTO and ALKBH5 transcript levels discriminated ccRCC from oncocytomas. Furthermore, FTO and ALKBH5 immunoexpression differed among RCC subtypes, with higher expression levels found in ccRCC comparatively to the other RCC subtypes and oncocytomas. (4) Conclusion: We conclude that altered expression of m6A RNA demethylases is common in RCC and seems to be subtype specific. Specifically, FTO and ALKBH5 might constitute new candidate biomarkers for RCC patient management, aiding in differential diagnosis of renal masses and prognostication.
Highlights
Renal cell carcinoma (RCC) is the one of the most prevalent urological cancers in both genders, with 431,288 new cases and 179,368 deaths according to GLOBOCAN 2020 [1].RCC is stratified into different subtypes, including clear cell renal cell carcinoma(75–85%), papillary RCC (10–15%), chromophobe RCC (5–10%) and other less common entities, including collecting duct RCC and medullary RCC [2,3]
Analysis of the genomic regions encoding Methylation of N6-adenosine (m6A) players disclosed no (FTO) or less than 1% (METTL3, METLL14, Wilms’ tumor 1-associated protein (WTAP) and alkB homologue 5 (ALKBH5)) genomic alterations in RCC, except for VIRMA, which disclosed an amplification frequency of 1.4% (Figure 1A)
We explored messenger RNA (mRNA) expression of the several players among different 5tumor of 14 subtypes and found that erasers, fat mass and obesity-associated protein (FTO) and ALKBH5, were expressed at higher levels, compared to writers
Summary
Renal cell carcinoma (RCC) is the one of the most prevalent urological cancers in both genders, with 431,288 new cases and 179,368 deaths according to GLOBOCAN 2020 [1].RCC is stratified into different subtypes, including clear cell renal cell carcinoma (ccRCC)(75–85%), papillary RCC (pRCC) (10–15%), chromophobe RCC (chRCC) (5–10%) and other less common entities, including collecting duct RCC and medullary RCC [2,3]. Renal cell carcinoma (RCC) is the one of the most prevalent urological cancers in both genders, with 431,288 new cases and 179,368 deaths according to GLOBOCAN 2020 [1]. RCC is stratified into different subtypes, including clear cell renal cell carcinoma (ccRCC). Renal oncocytomas are rather common benign tumors, which simulate RCC, constituting an important differential diagnosis [4]. 20–30% of RCC cases are diagnosed as disseminated disease, and about. Survival rate at 5 years in stage IV disease is only 12%, making RCC one of the deadliest urogenital neoplasms. Improvements in molecular understanding of RCC and identification of new biomarkers predictive of survival will refine treatment strategies and will be critical to the improvement of subtype-specific targeted therapies [5,6,7]
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