Persistent severe hyperlactatemia and metabolic derangement in lethal SDHB-mutated metastatic kidney cancer: Clinical challenges and examples of extreme warburg effect

Chung Han Lee, Gunes Gundem, William Lee, Ying Bei Chen, Justin R. Cross, Yiyu Dong, Almedina Redzematovic, Roy Mano, Elizabeth Y. Wei, Emily H. Cheng, Ramaprasad Srinivasan, Dayna Oschwald, A. Ari Hakimi, Mark P. Dunphy, W. Marston Linehan, Elli Papaemmanuil, James J. Hsieh

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Purpose 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 [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. 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 SDHB-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 lossof- function mutations in theSDHBgene andthecommonloss of heterozygosity in the remaining SDHB allele thorough somatic chromosome 1p deletion. In one patient, WGS revealed that a germline mutation of SDHB coupled with loss of heterozygosity was the sole genetic event. Cancer evolution analysis of SDHB tumors based on WGS demonstrated that SDHB in kidney epithelium fulfills the Knudson two-hit criteria as a major tumor suppressor gene. SDHB-/- 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. 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 SDHB genes during kidney tumorigenesis.

Original languageEnglish
Pages (from-to)1-14
Number of pages14
JournalJCO Precision Oncology
Volume2017
Issue number1
DOIs
StatePublished - 2017

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