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- Title
The SDHD :p.H102R Variant Is Frequent in Russian Patients with Head and Neck Paragangliomas and Associated with Loss of 11p15.5 Region and Hypermethylation of H19-DMR.
- Authors
Snezhkina, Anastasiya; Fedorova, Maria; Kobelyatskaya, Anastasiya; Markova, Daria; Lantsova, Margarita; Ikonnikova, Anna; Emelyanova, Marina; Kalinin, Dmitry; Pudova, Elena; Melnikova, Nataliya; Dmitriev, Alexey; Krasnov, George; Pavlov, Vladislav; Kudryavtseva, Anna
- Abstract
Head and neck paragangliomas (HNPGLs) are rare neuroendocrine neoplasms derived from the parasympathetic paraganglia of the head and neck. At least 30% of HNPGLs are linked to germline mutations, predominantly in SDHx genes. In this study, we analyzed an extended cohort of Russian patients with HNPGLs using whole-exome sequencing and found a highly frequent missense variant p.H102R in the SDHD gene. We determined this variant in 34% of the SDHD mutation carriers. This variant was associated with somatic loss of the gene wild-type allele. Data from the B allele frequency method and microsatellite and microdeletion analysis indicated evident LOH at the 11p15.5 region and potential loss of the whole of chromosome 11. We found hypermethylation of H19-DMR in all tumors, whereas differential methylation of KvDMR was mostly retained. These findings do not support the paternal transmission of SDHD:p.H102R but are in agreement with the Hensen model. Using targeted sequencing, we also studied the variant frequency in a control cohort; we found SDHD:p.H102R in 1.9% of cases, allowing us to classify this variant as pathogenic. The immunohistochemistry of SDHB showed that the SDHD:p.H102R mutation, even in combination with wild-type allele loss, does not always lead to SDH deficiency. The obtained results demonstrate the frequent variant associated with HNPGLs in a Russian population and support its pathogenicity. Our findings help with understanding the mechanism of tumorigenesis and are also important for the development of cost-effective genetic screening programs.
- Subjects
GENETIC testing; NEUROENDOCRINE tumors; MISSENSE mutation; PLANT chromosomes; NECK; HEAD
- Publication
International Journal of Molecular Sciences, 2023, Vol 24, Issue 1, p628
- ISSN
1661-6596
- Publication type
Academic Journal
- DOI
10.3390/ijms24010628