The following is a summary of “Germline- and Somatic-Inactivating FLCN Variants in Parathyroid Cancer and Atypical Parathyroid Tumors ,” published in the October 2023 issue of Endocrinology by Jha, et al.
Parathyroid cancer (PC) is a rare and potentially fatal endocrine neoplasm characterized by high mortality rates. Despite surgical intervention being the primary treatment, recurrence is common, often leading to severe hypercalcemia. Currently, there is a lack of effective systemic therapy for this disease. For a study, researchers sought to investigate novel genes implicated in developing parathyroid cancer.
The germline DNA of 17 patients with “sporadic” PC and 3 with atypical parathyroid tumors (APTs), lacking germline CDC73 or MEN1 pathogenic variants, was analyzed. Additionally, sequencing of available tumor tissue from 14 PC patients and 2 APT patients was performed. Germline DNA was unavailable for two PC patients. Furthermore, FLCN variants were analyzed in sporadic parathyroid adenomas from 74 patients.
Germline FLCN variants were identified in three unrelated PC patients. Two frameshift variants were previously associated with Birt-Hogg-Dubé (BHD) syndrome, while the missense variant c.124G > C (p.G42R) had an undetermined pathogenicity. Functional analysis of the missense variant suggested a potential impact on posttranslational modification. All three patients with germline FLCN variants exhibited renal cysts, and two had lung cysts consistent with features of BHD syndrome. Somatic FLCN variants were found in tumors from two patients (including one with APT) out of 16 with PC/APT and none of the 74 sporadic parathyroid adenomas. While no second hits in FLCN were observed on sequencing, loss of heterozygosity at the locus was demonstrated in two out of three patients with the identified germline FLCN variant.
The discovery of FLCN variants associated with PC may lead to the development of targeted therapies for malignancy.
Source: academic.oup.com/jcem/article-abstract/108/10/2686/7080719?redirectedFrom=fulltext
