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

UNLABELLED

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.

PATIENTS AND METHODS

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 [F]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 F-glutamine PET imaging were performed to investigate this rare kidney cancer syndrome.

RESULTS

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 -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 gene and the common loss of heterozygosity in the remaining allele thorough somatic chromosome 1p deletion. In one patient, WGS revealed that a germline mutation of coupled with loss of heterozygosity was the sole genetic event. Cancer evolution analysis of tumors based on WGS demonstrated that in kidney epithelium fulfills the Knudson two-hit criteria as a major tumor suppressor gene. tumor cells displayed increase in glucose uptake and lactate production, alteration in mitochondrial architecture, and defect in oxidative respiration. F-Glutamine PET imaging studies demonstrated increased glutamine metabolism.

CONCLUSION

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 genes during kidney tumorigenesis.