Abstract
Simple SummaryThe accumulated evidence on the role of epigenetic markers of prognosis in clear cell renal cell carcinoma (ccRCC) is reviewed, as well as state of the art on epigenetic treatments for this malignancy. Several epigenetic markers are likely candidates for clinical use, but still have not passed the test of prospective validation. Development of epigenetic therapies, either alone or in combination with tyrosine-kinase inhibitors of immune-checkpoint inhibitors, are still in their infancy.Clear cell renal cell carcinoma (ccRCC) is curable when diagnosed at an early stage, but when disease is non-confined it is the urologic cancer with worst prognosis. Antiangiogenic treatment and immune checkpoint inhibition therapy constitute a very promising combined therapy for advanced and metastatic disease. Many exploratory studies have identified epigenetic markers based on DNA methylation, histone modification, and ncRNA expression that epigenetically regulate gene expression in ccRCC. Additionally, epigenetic modifiers genes have been proposed as promising biomarkers for ccRCC. We review and discuss the current understanding of how epigenetic changes determine the main molecular pathways of ccRCC initiation and progression, and also its clinical implications. Despite the extensive research performed, candidate epigenetic biomarkers are not used in clinical practice for several reasons. However, the accumulated body of evidence of developing epigenetically-based biomarkers will likely allow the identification of ccRCC at a higher risk of progression. That will facilitate the establishment of firmer therapeutic decisions in a changing landscape and also monitor active surveillance in the aging population. What is more, a better knowledge of the activities of chromatin modifiers may serve to develop new therapeutic opportunities. Interesting clinical trials on epigenetic treatments for ccRCC associated with well established antiangiogenic treatments and immune checkpoint inhibitors are revisited.
Highlights
Simple Summary: The accumulated evidence on the role of epigenetic markers of prognosis in clear cell renal cell carcinoma is reviewed, as well as state of the art on epigenetic treatments for this malignancy
It is well known that some genes including APC, BNC1, CDH1, ECAD, GSTP1, KTN19, IGFBP1, IGFBP3, MGMT, PTGS2, p14ARF, p16/CDKN2a, p16INK4a, RASSF1A, RARB2, SRFP, TIMP3, UCHL1, and Von Hippel Lindau (VHL) are silenced in Renal cell carcinoma (RCC) by DNA methylation and this could be useful for the diagnosis of RCC in tumor tissue, serum, or urine samples, both in the familiar and sporadic forms [12,59,60,61,62,63,64,65,66]
RASSF1A and SPINT2 are more frequently methylated in Papillary RCC (pRCC) [63,69,70] while COL1A1 and IGFBP1 hypermethylation is more common in Clear cell renal cell carcinoma (ccRCC) [62,63]
Summary
Renal cell carcinoma (RCC) is the seventh most common form of human neoplasm, with an incidence of 10 new cases per 100,000 inhabitants in Western Europe and United. Other rarer tumors enter in the differential diagnosis of solid renal masses [5] Both ccRCC and pRCC arise from the proximal tubule while chromophobe RCC (chRCC) has an origin in the distal part of the nephron. Heterogeneity of RCC stands at the molecular, genomic, histopathological, and clinical levels [6,7] It explains how appropriate tumor sampling is needed for a correct identification, and implies great difficulty for the development of accurate diagnostic and prognostic markers. Small renal masses are often detected by imaging studies performed for other reasons and tend to be treated by nephron-sparing surgery, ablation or active surveillance when diagnosed in an elder population is increasingly used In this clinical situation, imaging monitoring to evaluate clinical progression is mandatory in the absence of reliable molecular tumor marker of disease progression. The introduction of biomarkers into clinical practice will allow personalized patient care for renal cancer [29,30]
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