Persistent Severe Hyperlactatemia and Metabolic Derangement in Lethal <i>SDHB</i>-Mutated Metastatic Kidney Cancer: Clinical Challenges and Examples of Extreme Warburg Effect.

Abstract

To describe the unique clinical features, determine the genomics, and investigate the metabolic derangement of an extremely rare form of a hereditary lethal kidney cancer syndrome. Three patients with lethal kidney cancer (age 19, 20, and 37 years) exhibiting persistent (1 to 3 months) extremely high levels of blood lactate (> 5 mM) despite normal oxygen perfusion, highly avid tumors on [¹⁸F]fluorodeoxyglucose positron emission tomography (PET), and pleomorphic histopathologic features were identified and treated in a single institute. Integrated studies including whole-genome sequencing (WGS), targeted sequencing, immunohistochemistry, cell-based assays, and ¹⁸F-glutamine PET imaging were performed to investigate this rare kidney cancer syndrome. All three patients with kidney cancer were initially given various diagnoses as a result of diverse tumor histopathology and atypical clinical presentations. The correct diagnoses of these <i>SDHB</i>-mutated renal cell carcinomas were first made based on cancer genomics. Genomic studies of the blood and tumors of these patients identified three different kinds of germline loss-of-function mutations in the <i>SDHB</i> gene and the common loss of heterozygosity in the remaining <i>SDHB</i> allele thorough somatic chromosome 1p deletion. In one patient, WGS revealed that a germline mutation of <i>SDHB</i> coupled with loss of heterozygosity was the sole genetic event. Cancer evolution analysis of <i>SDHB</i> tumors based on WGS demonstrated that <i>SDHB</i> in kidney epithelium fulfills the Knudson two-hit criteria as a major tumor suppressor gene. <i>SDHB</i> ^-/- tumor cells displayed increase in glucose uptake and lactate production, alteration in mitochondrial architecture, and defect in oxidative respiration. ¹⁸F-Glutamine PET imaging studies demonstrated increased glutamine metabolism. SDHB-deficient metastatic renal cell carcinoma is a rare, aggressive form of kidney cancer that manifests with clinical evidence of a severe Warburg effect, and genomic studies demonstrated two genetic hits at <i>SDHB</i> genes during kidney tumorigenesis.