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Purpose <p>A lack of targeted therapies make parathyroid carcinoma, a diagnostically challenging malignancy, difficult to treat. The rarity of this tumor type necessitates international collaboration to collect a sizable sample set for study. Prior studies have revealed the importance of driver mutations in the <i>CDC73</i> gene and identified several putative drivers/aberrant pathways including PI3K/mTOR activation and <i>CCND1</i> (cyclin D1) amplification. In this study, we sought to better understand the prevalence of putative oncogenic drivers in parathyroid carcinoma.</p> Methods <p>We subjected an expanded cohort of 71 sporadic parathyroid carcinomas, fulfilling stringent WHO criteria, to next-generation DNA sequencing on a custom 16-gene targeted panel.</p> Results <p>One or more variant was detected in 44 tumors (62%) and 27 (38%) had no detectable variant. Consistent with earlier studies, we detected loss-of-function <i>CDC73</i> mutations in 44% (31/70) of evaluable patients, including germline pathogenic variants in 9 patients (36 patients evaluable for somatic status as matched normal available). Notably, mutations in the PI3K/AKT/mTOR pathway were seen in 12.9% (9/70) of evaluable patients, providing further evidence of this as a key therapeutically actionable pathway in parathyroid carcinoma. Correlating genomic and clinical features revealed that patients harboring <i>CDC73</i> mutations are more likely suffer from life threatening recurrent/metastatic parathyroid carcinoma (<i>P</i> = 0.024) than those without <i>CDC73</i> variants.</p> Conclusions <p>This genomic characterization of a large parathyroid carcinoma cohort improves understanding of the genomic underpinnings of this rare malignancy, provides novel evidence for genotype-phenotype correlation with recurrent/metastatic disease, and may help to provide a rational basis for individualized treatments.</p>

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Mutational patterns in a large cohort of parathyroid carcinomas

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月25日

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  • Chetanya Pandya,
  • Andrew V. Uzilov,
  • Jessica Costa-Guda,
  • Justin Bellizzi,
  • Patricia Taik,
  • Aye S. Moe,
  • Maya Strahl,
  • Karin van der Tuin,
  • Mark Stevenson,
  • Branca M. Cavaco,
  • Filomena Cetani,
  • Claudio Marcocci,
  • Auli Karhu,
  • Johanna Arola,
  • Camilla Schalin-Jäntti,
  • Hans Morreau,
  • Rajesh V. Thakker,
  • Eric E. Schadt,
  • Robert Sebra,
  • Shuyu D. Li,
  • Rong Chen,
  • Andrew Arnold

摘要

Purpose

A lack of targeted therapies make parathyroid carcinoma, a diagnostically challenging malignancy, difficult to treat. The rarity of this tumor type necessitates international collaboration to collect a sizable sample set for study. Prior studies have revealed the importance of driver mutations in the CDC73 gene and identified several putative drivers/aberrant pathways including PI3K/mTOR activation and CCND1 (cyclin D1) amplification. In this study, we sought to better understand the prevalence of putative oncogenic drivers in parathyroid carcinoma.

Methods

We subjected an expanded cohort of 71 sporadic parathyroid carcinomas, fulfilling stringent WHO criteria, to next-generation DNA sequencing on a custom 16-gene targeted panel.

Results

One or more variant was detected in 44 tumors (62%) and 27 (38%) had no detectable variant. Consistent with earlier studies, we detected loss-of-function CDC73 mutations in 44% (31/70) of evaluable patients, including germline pathogenic variants in 9 patients (36 patients evaluable for somatic status as matched normal available). Notably, mutations in the PI3K/AKT/mTOR pathway were seen in 12.9% (9/70) of evaluable patients, providing further evidence of this as a key therapeutically actionable pathway in parathyroid carcinoma. Correlating genomic and clinical features revealed that patients harboring CDC73 mutations are more likely suffer from life threatening recurrent/metastatic parathyroid carcinoma (P = 0.024) than those without CDC73 variants.

Conclusions

This genomic characterization of a large parathyroid carcinoma cohort improves understanding of the genomic underpinnings of this rare malignancy, provides novel evidence for genotype-phenotype correlation with recurrent/metastatic disease, and may help to provide a rational basis for individualized treatments.