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

Cancer Res. 2018 Apr 15;78(8):1914-1922. doi: 10.1158/0008-5472.CAN-17-2463.

Alexandre Buffet ¹ ², Aurélie Morin ¹ ², Luis-Jaime Castro-Vega ¹ ², Florence Habarou ² ³, Charlotte Lussey-Lepoutre ¹ ², Eric Letouzé ² ⁴ ⁵ ⁶ ⁷, Hervé Lefebvre ⁸, Isabelle Guilhem ⁹, Magalie Haissaguerre ¹⁰, Isabelle Raingeard ¹¹, Mathilde Padilla-Girola ¹, Thi Tran ¹ ², Lucien Tchara ³, Jérôme Bertherat ² ¹² ¹³, Laurence Amar ¹ ² ¹³ ¹⁴, Chris Ottolenghi ² ³, Nelly Burnichon ¹ ² ¹⁵, Anne-Paule Gimenez-Roqueplo ¹⁶ ² ¹³ ¹⁵, Judith Favier ¹⁶ ²

Affiliations

1 INSERM, UMR970, Paris-Centre de Recherche Cardiovasculaire, Paris, France; Equipe labellisée Ligue contre le Cancer.
2 Université Paris Descartes, PRES Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
3 Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Service de Biochimie Métabolique, Paris, France.
4 Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre Le Cancer, Paris, France.
5 INSERM, UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d'Hématologie, Paris, France.
6 Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine, Bobigny, France.
7 Université Paris Diderot, Paris, France.
8 Service d'Endocrinologie, Diabète et Maladies Métaboliques, INSERM U982, Centre Hospitalier Universitaire de Rouen, Rouen Cedex, France.
9 Service d'Endocrinologie-Diabétologie-Nutrition, CHU de Rennes, Hôpital Sud, Rennes, France.
10 Service d'Endocrinologie, Hôpital Haut-Lévêque, CHU de Bordeaux, Pessac, France.
11 Service d'Endocrinologie, CHU Montpellier, Hôpital Lapeyronie, Montpellier Cedex 5, France.
12 Service d'Endocrinologie "Centre de référence maladies rares de la surrénale", Hôpital Cochin, Assistance Publique, Hôpitaux de Paris, Paris, France.
13 Centre Expert National COMETE-Cancer de la surrénale, Paris, France.
14 Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service d'hypertension artérielle et médecine vasculaire, Paris, France.
15 Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Paris, France.
16 INSERM, UMR970, Paris-Centre de Recherche Cardiovasculaire, Paris, France; Equipe labellisée Ligue contre le Cancer. judith.favier@inserm.fr anne-paule.gimenez-roqueplo@inserm.fr.

PMID: 29431636 DOI: 10.1158/0008-5472.CAN-17-2463

Abstract

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 Slc25a11^Δ/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.

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