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