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Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
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PDPR Gene Variants Predisposing to Papillary Thyroid Cancer
Pamela Brock1, Myriam Sevigny2, Sandya Liyanarachchi3,4
1Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
Thyroid : Official Journal of the American Thyroid Association
|December 8, 2023
Summary
Novel genetic variants in the pyruvate dehydrogenase phosphatase regulatory (PDPR) gene suggest it plays a role in papillary thyroid cancer (PTC) susceptibility. Loss of PDPR function may contribute to thyroid cancer development.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- Papillary thyroid cancer (PTC) is the most common thyroid cancer subtype.
- Some PTC cases exhibit an autosomal dominant inheritance pattern, suggesting a genetic predisposition.
- Identifying novel susceptibility genes is crucial for understanding PTC development.
Purpose of the Study:
- To identify novel genes and mechanisms underlying papillary thyroid cancer susceptibility.
- To investigate the role of pyruvate dehydrogenase phosphatase regulatory (PDPR) variants in familial and sporadic PTC.
- To elucidate the functional consequences of PDPR loss in thyroid cells.
Main Methods:
- Whole-genome sequencing in an autosomal dominant PTC family.
- Screening of PDPR variants in sporadic PTC and familial adenomatous polyposis-associated PTC cases.
- CRISPR-Cas9 gene editing to create PDPR-deficient cell lines.
- Analysis of cellular metabolism and gene expression.
Main Results:
- Truncating PDPR splice donor variants were identified in affected members of a familial PTC cohort and in a sporadic PTC case.
- PDPR-deficient thyroid cells exhibited altered glucose metabolism and increased pyruvate dehydrogenase phosphorylation.
- PDPR gene expression was significantly lower in thyroid cancer tissues compared to normal tissues.
Conclusions:
- Germline and somatic variants in PDPR are associated with an increased risk of papillary thyroid cancer.
- PDPR plays a critical role in regulating glucose metabolism in thyroid cells.
- Loss of PDPR function is implicated in thyroid cancer tumorigenesis.
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