Endocrine Abstracts (2018) 56 OC7.4 | DOI: 10.1530/endoabs.56.OC7.4

Germline mutations in the mitochondrial 2-oxoglutarate/malate carrier (SLC25A11) gene confer predisposition to metastatic paragangliomas

Alexandre Buffet1,2, Aurelie Morin1,2, Luis-Jaime Castro-Vega1,2, Florence Habarou3,2, Charlotte Lussey-Lepoutre1,2, Eric Letouzé4, Hervé Lefebvre5, Isabelle Guilhem6, Magalie Haissaguerre7, Isabelle Raingeard8, Mathilde Padilla-Girola1, Thi Tran1, Lucien Tchara3, Jérôme Bertherat9,2, Laurence Amar10,1,2, Chris Ottolenghi3,2, Nelly Burnichon1,2,11, Anne-Paule Gimenez-Roqueplo1,2,11 & Judith Favier1,2


1INSERM, UMR970, Paris-Centre de Recherche Cardiovasculaire, Paris, France; 2Université Paris Descartes, PRES Sorbonne Paris Cité, Faculté de Médecine, Paris, France; 3Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Service de Biochimie Métabolique, Paris, France; 4Programme Cartes d’Identité des Tumeurs, Ligue Nationale Contre Le Cancer, Paris, France; 5Service d’Endocrinologie, Diabète et Maladies Métaboliques, INSERM U982, Centre Hospitalier Universitaire de Rouen, Rouen, France; 6Service d’Endocrinologie-Diabétologie-Nutrition, CHU de Rennes, Hôpital Sud, Rennes, France; 7Service d’Endocrinologie, Hôpital Haut-Lévêque, CHU de Bordeaux, Pessac, France; 8Service d’Endocrinologie, CHU Montpellier, Hôpital Lapeyronie, Montpellier, France; 9Service d’Endocrinologie ‘Centre de référence maladies rares de la surrénale’, Hôpital Cochin, Assistance Publique, Hôpitaux de Paris, Paris, France; 10Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service d’hypertension artérielle et médecine vasculaire, Paris, France; 11Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Paris, France.


Integrative genomics studies of paragangliomas (PGL) have shown that PGL susceptibility genes are the main drivers of tumorigenesis. Comprehensive genetic analyses have identified germline SDHB and, to a lesser extent, FH gene mutations, as predominant causes of metastatic PGL. However, some suspicious cases remain unexplained. 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. This gene encodes the mitochondrial 2-oxoglutarate/malate carrier. Germline SLC25A11 mutations were identified in six other patients, five of whom had a metastatic disease. These mutations were associated with loss of heterozygosity and loss of SLC25A11 protein expression, suggesting that SLC25A11 acts as a tumour suppressor gene. Pseudo-hypoxic and hypermethylator phenotypes comparable to that described in SDHx- and FH-related tumours were observed both in tumours 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 PPGL susceptibility gene, for which loss of function correlates with metastatic presentation. Its identification expands the role of mitochondrial dysfunction in paraganglioma tumorigenesis and reveals a new pathway linking metabolic defects and cancer.

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