Germline Mutations in the Mitochondrial 2-Oxoglutarate/Malate Carrier SLC25A11 Gene Confer a Predisposition to Metastatic Paragangliomas

• Published in: Cancer research (Chicago, Ill.) Vol. 78; no. 8; pp. 1914 - 1922
• Main Authors: Buffet, Alexandre, Morin, Aurélie, Castro-Vega, Luis-Jaime, Habarou, Florence, Lussey-Lepoutre, Charlotte, Letouzé, Eric, Lefebvre, Hervé, Guilhem, Isabelle, Haissaguerre, Magalie, Raingeard, Isabelle, Padilla-Girola, Mathilde, Tran, Thi, Tchara, Lucien, Bertherat, Jérôme, Amar, Laurence, Ottolenghi, Chris, Burnichon, Nelly, Gimenez-Roqueplo, Anne-Paule, Favier, Judith
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research, Inc 15.04.2018; American Association for Cancer Research
• Subjects: Adrenal Gland Neoplasms - genetics; Adrenal Gland Neoplasms - pathology; Animals; Cancer; Cellular Biology; Cohort Studies; CRISPR; CRISPR-Cas Systems; Endocrinology and metabolism; Genetic analysis; Genetic Predisposition to Disease; Germ-Line Mutation; Heterozygosity; Human health and pathology; Humans; Ketoglutaric acid; Life Sciences; Loss of Heterozygosity; Membrane Transport Proteins - genetics; Metastases; Metastasis; Mice; Mice, Knockout; Mitochondria; Mutation; Neoplasm Metastasis; Neuroendocrine tumors; Paraganglioma; Paraganglioma - genetics; Paraganglioma - secondary; Phenotype; Pheochromocytoma; Pheochromocytoma - genetics; Pheochromocytoma - secondary; Tissues and Organs; Tumors
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-17-2463

Comprehensive genetic analyses have identified germline SDHB and FH gene mutations as predominant causes of metastatic paraganglioma and pheochromocytoma. However, some suspicious cases remain unexplained. In this study, we performed whole-exome sequencing of a paraganglioma exhibiting an SDHx-like molecular profile in the absence of SDHx or FH mutations and identified a germline mutation in the SLC25A11 gene, which encodes the mitochondrial 2-oxoglutarate/malate carrier. Germline SLC25A11 mutations were identified in six other patients, five of whom had metastatic disease. These mutations were associated with loss of heterozygosity, suggesting that SLC25A11 acts as a tumor-suppressor gene. Pseudohypoxic and hypermethylator phenotypes comparable with those described in SDHx- and FH-related tumors were observed both in tumors with mutated SLC25A11 and in Slc25a11Δ/Δ immortalized mouse chromaffin knockout cells generated by CRISPR-Cas9 technology. These data show that SLC25A11 is a novel paraganglioma susceptibility gene for which loss of function correlates with metastatic presentation. Significance: A gene encoding a mitochondrial carrier is implicated in a hereditary cancer predisposition syndrome, expanding the role of mitochondrial dysfunction in paraganglioma. Cancer Res; 78(8); 1914–22. ©2018 AACR.