<p>The Impact Of <em>Succinate Dehydrogenase</em> Gene (SDH) Mutations In Renal Cell Carcinoma (RCC): A Systematic Review</p>

Abstract

IntroductionRenal cell cancer (RCC) syndrome is linked to Krebs cycle compartments and their coding genes' alterations like succinate dehydrogenase genes (SDHx). Here we present a systematic review of the SDH genes’ mutations and their impact on both RCC diagnosis and prognosis.MethodsThis systematic review includes any study in which tissue samples of RCC are considered in correlation with the SDHx mutations, microsatellite instability (MSI), and protein expression. For this purpose, a systematic search of MEDLINE (PubMed), Scopus, Embase, and Web of Science databases was conducted and finally 5384 articles were recruited. All studies' content was checked to find the related ones which were 145 articles, which with data extraction were limited to nineteen.ResultsThe final selected nineteen studies investigating the SDHx role in RCC tumor genesis were included, among which fifteen were mutation analysis, three were just SDHx protein expression, and two were MSI and mutation analysis studies. A total of 432 RCC patients were reported by SDH mutations, and 64 patients with MSI and SDH expression change were reported in 514 surgically resected renal epithelial tumors. The most common mutation was the single nucleotide variant rs772551056 (c.137G>A) of SDHB. For SDHC, c.380A>G presented in 48 RCC patients, and for SDHA a novel germline mutation c.2T>C: p.M1T in an occasional case of gastrointestinal stromal tumor intricate with RCC.ConclusionRCC as an aggressive type of kidney cancer needs some biomarkers to be diagnosed exactly. It was shown recently that the succinate dehydrogenase gene variations can provide this diagnostic and prognostic biomarker. For this purpose, SDHB rs772551056 associated with its protein expression alterations can be taken into account. It is possible that a novel mutation of SDHA (c.2T>C: p.M1T) can provide evidence of GIST associated with RCC as well.

Multifaceted Roles of Mitochondrial Components and Metabolites in Metabolic Diseases and Cancer

“…Deleterious mutations in any of the four subunits of complex II decrease SDH activity and result in abnormal accumulation of succinate, as observed in complex II-mutated cells in vitro and in the extracellular fluids (plasma, urine, saliva, and feces) of complex II-deficient patients. Complex II mutations, principally affecting SDHB and SDHD subunits, have been associated with various cancers including hereditary paraganglioma and pheochromocytoma (i.e., neuroendocrine tumors of the paraganglionic tissue), gastrointestinal stromal tumors [ 60 ], and renal cell carcinoma [ 61 ]. Therefore, SDH has now been defined as a tumor suppressor and succinate as an oncometabolite [ 62 , 63 ].…”

From Metabolism to Genetics and Vice Versa: The Rising Role of Oncometabolites in Cancer Development and Therapy

“…The LoF of SDH occurs by the loss of heterozygosity (LOH) due to the second allele deletion that arrests the succinate- fumarate conversion [ 37 ]. Cellular metabolomics investigations pointed out the specific accumulation of the succinate [ 38 , 39 , 40 , 41 , 42 ] in tumours that carry the LOH for the SDH x mutated genes including renal cell carcinoma, gastrointestinal stromal tumour, pituitary adenomas pancreatic neuroendocrine tumours [ 43 , 44 , 45 , 46 , 47 , 48 ] and PGLs [ 49 ]. The SDH immunohistochemistry (IHC) staining using specific SDHB antibodies has been proposed as test for the screening of SDH x mutations since the loss of SDHB subunit is correlated with any SDHx mutations [ 50 ].…”

Genetic Alterations in Renal Cancers: Identification of The Mechanisms Underlying Cancer Initiation and Progression and of Therapeutic Targets

“…Ajamir et al have performed a systematic review of all the main studies reporting SDH-mutant renal cell carcinoma [ 46 ]. The most commonly mutated gene was SDHB (with 137G>A being the most frequent mutation) and less frequently SDHC (380A>G being the most frequent mutation) and SDHA [ 46 ].…”

“…Ajamir et al have performed a systematic review of all the main studies reporting SDH-mutant renal cell carcinoma [ 46 ]. The most commonly mutated gene was SDHB (with 137G>A being the most frequent mutation) and less frequently SDHC (380A>G being the most frequent mutation) and SDHA [ 46 ]. Rare cases of SDH-deficient renal cell cancers are related to alterations of the SDHA gene: Yakirevich et al reported a case of SDH-deficiency RCC, characterized by homozygous deletion of the SDHA gene (9 of the SDHA gene exons were deleted): at immunohistochemical level, the expression of both SDHA and SDHB was lost [ 47 ].…”