Germline and somatic inactivating FLCN variants in parathyroid cancer and atypical parathyroid tumors

Parathyroid cancer (PC) is a rare endocrine neoplasm with high mortality. While surgery is the treatment for patients with the disease, recurrence rates are high, and patients usually succumb to severe hypercalcemia. There is no effective systemic therapy for the disease. We analyzed the germline DNA of 17 patients with "sporadic" PC and 3 with atypical parathyroid tumors (APT) who did not have germline CDC73 or MEN1 pathogenic variants. Sequencing of available tumor tissue from 14 patients with PC and 2 with APT was also performed (including two patients with no available germline DNA). In addition, sporadic parathyroid adenomas from 74 patients were analyzed for FLCN variants. We identified germline FLCN variants in three unrelated patients with PC. The two frameshift variants have been described in patients with Birt-Hogg-Dubé (BHD) syndrome while the pathogenicity of the missense variant c.124G > C (p.G42R) has not been definitively established. Functional analysis of the missense variant showed a potential impact on post-translational modification. All three patients with germline FLCN variants were noted to have renal cysts and two had lung cysts, features associated with BHD syndrome. Somatic FLCN variants were identified in tumors from 2 (one APT) of 16 patients with PC/APT and in none of the 74 sporadic parathyroid adenomas. No second hits in FLCN were noted on sequencing however, LOH at the locus was demonstrated in 2 of 3 patients with identified germline FLCN variant. The finding of FLCN variants associated with PC may provide the foundation for the development of therapy for this malignancy. Published by Oxford University Press on behalf of the Endocrine Society 2023.

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