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

Alexandre Buffet (1, 2) , Aurélie Morin (2, 1) , 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, 9) , Isabelle Guilhem (10) , Magalie Haissaguerre (11) , Isabelle Raingeard (12) , Mathilde Padilla-Girola (1) , Thi Tran (1, 2) , Lucien Tchara (3) , Jérôme Bertherat (2) , Laurence Amar (13, 1, 2, 3) , Chris Ottolenghi (3, 2) , Nelly Burnichon (1, 2, 3) , Anne-Paule Gimenez-Roqueplo (1, 2, 3) , Judith Favier (1, 2)

1 PARCC (UMR_S 970/ U970) - Paris-Centre de Recherche Cardiovasculaire
2 UFR Médecine UPCité - UFR Médecine [Santé] - Université Paris Cité
3 AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP)
4 Ligue Nationale Contre le Cancer - Paris
5 INSERM - Institut National de la Santé et de la Recherche Médicale
6 USPC - Université Sorbonne Paris Cité
7 UPD7 - Université Paris Diderot - Paris 7
8 DC2N - Différenciation et communication neuronale et neuroendocrine
9 CHU Rouen
10 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
11 CHU Bordeaux
12 CHU - Hôpital Lapeyronie [Montpellier]
13 DE - Développement et évolution

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.

Domaines: Endocrinologie et métabolisme; Biologie cellulaire; Physiologie [q-bio.TO]

Alexandre Buffet, Aurélie Morin, Luis-Jaime Castro-Vega, Florence Habarou, Charlotte Lussey-Lepoutre, et al.. Germline Mutations in the Mitochondrial 2-Oxoglutarate/Malate Carrier SLC25A11 Gene Confer a Predisposition to Metastatic Paragangliomas. Cancer Research, 2018, 78 (8), pp.1914-1922. ⟨10.1158/0008-5472.CAN-17-2463⟩. ⟨hal-02419997⟩