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

• Published in: International journal of molecular sciences Vol. 24; no. 1; p. 628
• Main 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
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 30.12.2022; MDPI AG
• Subjects: Alleles; Genetic Testing; Germ-Line Mutation; H19-DMR; Head and Neck Neoplasms - genetics; head and neck paraganglioma; Humans; KvDMR; LOH; mutation frequency; Paraganglioma - genetics; SDHD; Succinate Dehydrogenase - genetics; mutation frequency; head and neck paraganglioma; LOH; KvDMR; H19-DMR; SDHD; 11p15
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24010628

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 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 gene. We determined this variant in 34% of the 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 :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 :p.H102R in 1.9% of cases, allowing us to classify this variant as pathogenic. The immunohistochemistry of SDHB showed that the :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.