Paragangliomas 6

A number sign (#) is used with this entry because of evidence that paragangliomas-6 (PGL6) is caused by heterozygous germline mutation in the SLC25A11 gene (604165) on chromosome 17p13.

Description

Paragangliomas-6 (PGL6) is an adult-onset tumor predisposition syndrome in which affected individuals develop neuroendocrine neoplasms, known as paragangliomas. Many tumors arise in the abdomen, although some may arise in other regions, including the head and neck. Some of the tumors may secrete biologically active normetanephrines, resulting in secondary hypertension. Tumors may be benign or malignant, and some may metastasize (summary by Buffet et al., 2018).

For a general phenotypic description and a discussion of genetic heterogeneity of familial paragangliomas, see PGL1 (168000).

Clinical Features

Buffet et al. (2018) reported 7 unrelated patients with onset of paragangliomas (PGL) between 32 and 87 years of age. All but 1 patient had abdominal PGLs; 1 patient had a head-and-neck PGL (in the carotid body). Five of the 7 patients had tumors that secreted normetanephrines and catecholamines, and all of these patients also had metastatic disease. Those with secreting tumors tended to have arterial hypertension and other associated features, such as palpitations, headaches, or sweating. One patient had a significant paternal family history of various types of cancers, but details and tissues from these patients were not available. None of the other 6 patients had a family history of PGL.

Molecular Genetics

In a patient with PGL6, Buffet et al. (2018) identified a germline heterozygous missense mutation in the SLC25A11 gene (P239T; 604165.0001). The mutation, which was found by whole-genome sequencing, was confirmed by Sanger sequencing. Tumor tissue derived from the patient showed homozygosity for the mutation. Subsequent direct Sanger sequencing of the SLC25A11 gene in 639 patients with paragangliomas, in whom mutations in other known PGL-associated genes had been excluded, identified 6 patients with germline heterozygous SLC25A11 mutations (e.g., 604165.0002-604165.0005). Mutation types included missense, splice site, frameshift, and a silent change; none were found in the dbSNP or ExAC databases. The missense mutations affected highly conserved residues in the signature protein sequence or alpha matrix helix. Five of the 7 patients had metastatic disease. Available tumor tissue derived from the patients showed loss of heterozygosity (LOH) for SLC25A11. Immunohistochemical studies of the tumor tissue showed absence of the SLC25A11 protein and hypermethylation of DNA and histones compared to controls. Knockdown of the Slc25a11 gene in immortalized mouse chromaffin cells resulted in a hypermethylated and pseudohypoxic phenotype, and the cells showed increased adhesion and migration compared to controls, suggesting the acquisition of metastatic properties. These defects could be rescued by wildtype Slc25a11. The cells also showed lower levels of 2-oxoglutarate compared to controls, and treatment with 2-oxoglutarate reversed the migratory phenotype. Succinate levels were normal in these cells and in patient tumor cells, but aspartate and glutamate were increased. Buffet et al. (2018) noted that somatic mutations or copy-number alterations affecting the SLC25A11 gene have been identified in various types of cancer, suggesting that SLC25A11 can act as a tumor-suppressor gene.