Effects of Sdhd-H50R Missense Mutation on Thyroid Tumorigenesis
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Date
2019-05
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The Ohio State University
Abstract
Thyroid cancer is among the most common cancers and is the most frequent type of endocrine malignancy. Increased risk of thyroid cancer has been associated with Cowden syndrome (CS), an inherited endocrine tumor disorder. CS has been associated with germline mutations in PTEN tumor suppressor gene, identified in about 85% of CS-associated and 10% of sporadic thyroid cancers. Germline variations in Krebs cycle enzyme complex succinate dehydrogenase (SDH) genes were first observed in patients with pheochromocytoma/paraganglioma and recently discovered in patients with CS. Moreover, CS patients with variants in succinate dehydrogenase subunit D (SDHD) gene either alone/in combination with PTEN mutation have increased thyroid and breast cancers risk compared to patients with PTEN-only mutations. Studies examining SDHD germline variations have identified the His50Arg (H50R) variation as associated more frequently with sporadic thyroid tumor cases in patients. Therefore, modeling this tumor progression in vivo is essential to better understand how such mutations in the human patient population lead to thyroid cancer. Previous studies of mouse models with thyroid-specific Sdhd deletion displayed larger thyroid volumes, decreased follicle size, and increased cell proliferation. Novel mouse models with thyroid-specific Sdhd deletion and/or global Sdhd H50R mutation were generated using CRISPR-Cas9 genome editing technology, yielding a heterozygous Sdhd H50R mutant founder mouse to generate experimental Sdhd H50R mouse models: SdhdH50R/Wt, SdhdH50R/H50R, and Tpo-SdhdH50R/- (heterozygous Sdhd H50R mutation with thyroid-specific deletion of wildtype allele). While SdhdH50R/H50R mice were viable and born in normal Mendelian ratios, early demise was observed in certain SdhdH50R/H50R mice, potentially indicating a mortality associated phenotype in mutant models. Survival analysis displayed lower trends of viability between SdhdH50R/H50R and SdhdH50R/Wt in comparison to the SdhdWt/Wt models at 12 months. To assess whether the demise could be related to physiological wasting, weights were recorded for the models, which revealed that the SdhdH50R/H50R had lower body weights compared to wildtypes. Ultrasound imaging of the thyroid glands revealed relatively little difference between wildtype and SdhdH50R/H50R thyroid glands. Pathology of the SdhdH50R/Wt founder mouse revealed that there were no tumors present within the thyroid glands. However, closer analysis of thyroid tissue revealed dysplasia of follicles and greater cellular proliferation compared to SdhdWt/Wt. In addition, histology of the adrenal glands in mutant models have displayed cellular alterations that were also indicative of cellular dysplasia, implying alterations in other endocrine glands. These effects may suggest putative initiation of tumor development and potential progression to cancer, lending support that the Sdhd H50R mutation may cause thyroid tumorigenesis due to a gain-of-function and/or dominant-negative effect instead of the postulated loss-of-function method.