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.
19 - 22 May 2018
European Society of Endocrinology