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Updated: Mar 5, 2026
Comparative Lesions Analysis Through a Targeted Sequencing Approach
Published on: November 5, 2019
Genomic profiling reveals mutational landscape in parathyroid carcinomas
Chetanya Pandya1, Andrew V Uzilov1, Justin Bellizzi2
1Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Abstract:
Parathyroid carcinoma (PC) is an extremely rare malignancy lacking effective therapeutic intervention. We generated and analyzed whole-exome sequencing data from 17 patients to identify somatic and germline genetic alterations. A panel of selected genes was sequenced in a 7-tumor expansion cohort. We show that 47% (8 of 17) of the tumors harbor somatic mutations in the CDC73 tumor suppressor, with germline inactivating variants in 4 of the 8 patients. The PI3K/AKT/mTOR pathway was altered in 21% of the 24 cases, revealing a major oncogenic pathway in PC. We observed CCND1 amplification in 29% of the 17 patients, and a previously unreported recurrent mutation in putative kinase ADCK1. We identified the first sporadic PCs with somatic mutations in the Wnt canonical pathway, complementing previously described epigenetic mechanisms mediating Wnt activation. This is the largest genomic sequencing study of PC, and represents major progress toward a full molecular characterization of this rare malignancy to inform improved and individualized treatments.
Insights
Genetic analysis of parathyroid carcinoma (PC) reveals frequent CDC73 mutations and PI3K/AKT/mTOR pathway alterations. This study advances molecular understanding of this rare cancer, paving the way for targeted therapies.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Parathyroid carcinoma (PC) is a rare endocrine malignancy with limited treatment options.
- Understanding the genetic landscape of PC is crucial for developing effective therapies.
Purpose of the Study:
- To identify somatic and germline genetic alterations in parathyroid carcinoma.
- To characterize the molecular pathways involved in PC development.
Main Methods:
- Whole-exome sequencing of 17 PC tumors.
- Targeted gene sequencing in an additional 7 PC tumors.
- Analysis of somatic and germline mutations, copy number alterations, and pathway involvement.
Main Results:
- Somatic mutations in the CDC73 tumor suppressor gene were found in 47% of tumors, with germline variants in 4 patients.
- The PI3K/AKT/mTOR pathway was altered in 21% of cases.
- CCND1 amplification (29%) and recurrent ADCK1 mutations were observed, alongside novel Wnt pathway mutations in sporadic PCs.
Conclusions:
- This study provides the most comprehensive genomic characterization of PC to date.
- Identified key driver genes (CDC73) and oncogenic pathways (PI3K/AKT/mTOR, Wnt) offer potential therapeutic targets.
- Findings pave the way for improved, individualized treatment strategies for parathyroid carcinoma.
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