Germline- and Somatic-Inactivating FLCN Variants in Parathyroid Cancer and Atypical Parathyroid Tumors

Area of Science:

• Endocrinology
• Oncology
• Genetics

Background:

• Parathyroid cancer (PC) is a rare endocrine neoplasm with high mortality.
• Current treatments for PC have high recurrence rates and limited systemic therapy options.
• Severe hypercalcemia is a common cause of mortality in PC patients.

Purpose of the Study:

• To identify novel genes implicated in the development of parathyroid cancer.
• To investigate the role of FLCN variants in sporadic PC and atypical parathyroid tumors (APTs).

Main Methods:

• Germline DNA analysis of 17 PC and 3 APT patients without known pathogenic variants in CDC73 or MEN1.
• Tumor tissue sequencing from 14 PC and 2 APT patients.
• Analysis of FLCN variants in 74 sporadic parathyroid adenomas.

Main Results:

• Germline FLCN variants were identified in 3 unrelated PC patients.
• Two identified FLCN variants are known Birt-Hogg-Dubé (BHD) syndrome mutations; one missense variant's pathogenicity is under investigation.
• Patients with germline FLCN variants exhibited BHD-associated features like renal and lung cysts.
• Somatic FLCN variants were found in 2 of 16 PC/APT tumors, and loss of heterozygosity was observed in 2 of 3 patients with germline FLCN variants.

Conclusions:

• The identification of FLCN variants in PC suggests a potential genetic link.
• FLCN variants may serve as a foundation for developing novel therapeutic strategies for parathyroid cancer.
• Further research into FLCN's role could improve treatment outcomes for PC.