한빛사논문
Se-Young Jo1,2,8, Namki Hong3,8, Seunghyun Lee3,4, Jong Ju Jeong5, Jeongsoo Won1,2, Jiho Park1, Gi Jeong Kim6, Sang Kyum Kim6, Sangwoo Kim1,2,7 and Yumie Rhee3
1Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Korea.
2Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
3Department of Internal Medicine, Severance Hospital, Endocrine Research Institute, Yonsei University College of Medicine, Seoul, South Korea.
4Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea.
5Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
6Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.
7Postech Biotech Center, Pohang University of Science and Technology (POSTECH), Pohang, Korea.
8These authors contributed equally: Se-Young Jo, Namki Hong.
Corresponding authors : Correspondence to Sangwoo Kim or Yumie Rhee.
Abstract
Genomic and transcriptomic profiling has enhanced the diagnostic and treatment options for many cancers. However, the molecular characteristics of parathyroid cancer remain largely unexplored, thereby limiting the development of new therapeutic interventions. Herein, we conducted genomic and transcriptomic sequencing of 50 parathyroid tissues (12 carcinomas, 28 adenomas, and 10 normal tissues) to investigate the intrinsic and comparative molecular features of parathyroid carcinoma. We confirmed multiple two-hit mutation patterns in cell division cycle 73 (CDC73) that converged to biallelic inactivation, calling into question the presence of a second hit in other genes. In addition, allele-specific repression of CDC73 in copies with germline-truncating variants suggested selective pressure prior to tumorigenesis. Transcriptomic analysis identified upregulation of the expression of E2F targets, KRAS and TNF-alpha signaling, and epithelial-mesenchymal transition pathways in carcinomas compared to adenomas and normal tissues. A molecular classification model based on carcinoma-specific genes clearly separated carcinomas from adenomas and normal tissues, the clinical utility of which was demonstrated in two patients with uncertain malignant potential. A deeper analysis of gene expression and functional prediction suggested that Wilms tumor 1 (WT1) is a potential biomarker for CDC73-mutant parathyroid carcinoma, which was further validated through immunohistochemistry. Overall, our study revealed the genomic and transcriptomic profiles of parathyroid carcinoma and may help direct future precision diagnostic and therapeutic improvements.
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