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

Abstract : 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-xoglutarate/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 Slc25a11D/D 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. DOI: 10.1530/endoabs.56.OC7.4
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https://hal-normandie-univ.archives-ouvertes.fr/hal-02470394
Contributor : Hervé Lefebvre <>
Submitted on : Friday, February 7, 2020 - 11:35:11 AM
Last modification on : Wednesday, August 19, 2020 - 11:18:00 AM

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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 predisposition to metastatic paragangliomas. 20th European Congress of Endocrinology, May 2018, Barcelone, Spain. pp.OC7.4, ⟨10.1530/endoabs.56.OC7.4⟩. ⟨hal-02470394⟩

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