Working Paper Article Version 1 This version is not peer-reviewed

Succinate Dehydrogenase A (SDHA) Gene Mutation in Renal Cell Carcinoma: A New Subset of Hereditary Renal Cancer

Version 1 : Received: 13 April 2019 / Approved: 16 April 2019 / Online: 16 April 2019 (13:06:41 CEST)

How to cite: Kamai, T.; Abe, H.; Murakami, S.; Kuroda, H.; Jamiyan, T.; Arai, K.; Yoshida, K. Succinate Dehydrogenase A (SDHA) Gene Mutation in Renal Cell Carcinoma: A New Subset of Hereditary Renal Cancer. Preprints 2019, 2019040190 Kamai, T.; Abe, H.; Murakami, S.; Kuroda, H.; Jamiyan, T.; Arai, K.; Yoshida, K. Succinate Dehydrogenase A (SDHA) Gene Mutation in Renal Cell Carcinoma: A New Subset of Hereditary Renal Cancer. Preprints 2019, 2019040190

Abstract

Background: Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) is mainly associated with SDHB gene mutation and sometimes with SDHC or SDHD mutation. However, only three case of SDHA-deficient RCC have been reported, and the relation of SDHA mutation to RCC has not been clarified. Methods: We investigated SDHA/B/C/D gene mutations in 72 human RCCs by targeted next-generation sequencing, and also assessed SDHA and nuclear factor erythroid 2–related factor 2 (Nrf2) protein expression in 30 tumors. Results: NGS revealed SDHA gene mutations associated with amino acid sequence variations in 12 tumors, while no tumors had SDHB/C/D mutations. The SDHA gene mutations were identical in somatic and germline DNA of all 12 patients. Tumors with SDHA mutations showed a decrease of SDHA protein (p = 0.0177) and an increase of Nrf2 protein (p = 0.0120), with an inverse correlation between SDHA and Nrf2 protein expression (p = 0.0321). Tumor cells with SDHA mutations characteristically had eosinophilic cytoplasm and showed various patterns of proliferation. Conclusions: Our observations suggested that germline SDHA gene mutations might be linked to hereditary RCC associated with mitochondrial dysfunction.

Subject Areas

succinate dehydrogenase (SDH); fumarate hydratase (FH); renal cell carcinoma

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