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

Overview

Journal J Clin Endocrinol Metab

Publisher Oxford University Press

Specialty Endocrinology

Date 2023 Mar 20

PMID 36935552

Authors

Smita Jha

James Welch

Rana Tora

Justin Lack

Andrew Warner

Jaydira Del Rivero

Samira M Sadowski

Naris Nilubol

Laura S Schmidt

W Marston Linehan

Lee S Weinstein

William F Simonds

Sunita K Agarwal

Affiliations

Soon will be listed here.

Abstract

Context: 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.

Objective: To investigate for novel genes causing parathyroid cancer.

Methods: We analyzed the germline DNA of 17 patients with "sporadic" PC and 3 with atypical parathyroid tumors (APTs) 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 2 patients with no available germline DNA). In addition, sporadic parathyroid adenomas from 74 patients were analyzed for FLCN variants.

Results: We identified germline FLCN variants in 3 unrelated patients with PC. The 2 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 effect on posttranslational modification. All 3 patients with germline FLCN variants were noted to have renal cysts and 2 had lung cysts, features associated with BHD syndrome. Somatic FLCN variants were identified in tumors from 2 (1 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, loss of heterozygosity at the locus was demonstrated in 2 of 3 patients with the identified germline FLCN variant.

Conclusion: The finding of FLCN variants associated with PC may provide the foundation for the development of therapy for this malignancy.

Citing Articles

Variants in Parathyroid Carcinoma and Atypical Parathyroid Tumors.

Burke C, Bellizzi J, Costa-Guda J, Arnold A J Endocr Soc. 2025; 9(2):bvaf009.

PMID: 39885950 PMC: 11781200. DOI: 10.1210/jendso/bvaf009.

A Comparative Genomic Analysis of Parathyroid Adenomas and Carcinomas Harboring Heterozygous Germline CDC73 Mutations.

Li Y, Simonds W, Chen H J Clin Endocrinol Metab. 2024; 110(2):429-440.

PMID: 39044678 PMC: 11747674. DOI: 10.1210/clinem/dgae506.

A novel variant in the FLCN gene in a Chinese family with Birt-Hogg-Dubé syndrome.

Miao H, Zhou Y, Ge S, Gu Y, Qu L, Zhou W Mol Genet Genomic Med. 2024; 12(7):e2488.

PMID: 38963008 PMC: 11222970. DOI: 10.1002/mgg3.2488.

New Perspective on the Genetic Dissection Underlying the Development of Parathyroid Cancer.

Falchetti A J Clin Endocrinol Metab. 2023; 108(12):e1751-e1752.

PMID: 37149780 PMC: 10655506. DOI: 10.1210/clinem/dgad253.

References

Baba M, Hong S, Sharma N, Warren M, Nickerson M, Iwamatsu A . Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proc Natl Acad Sci U S A. 2006; 103(42):15552-7. PMC: 1592464. DOI: 10.1073/pnas.0603781103. View

Hu Y, Zhang X, Wang O, Cui M, Li X, Wang M . Integrated Whole-Exome and Transcriptome Sequencing of Sporadic Parathyroid Adenoma. Front Endocrinol (Lausanne). 2021; 12:631680. PMC: 8163014. DOI: 10.3389/fendo.2021.631680. View

Cromer M, Starker L, Choi M, Udelsman R, Nelson-Williams C, Lifton R . Identification of somatic mutations in parathyroid tumors using whole-exome sequencing. J Clin Endocrinol Metab. 2012; 97(9):E1774-81. PMC: 5393442. DOI: 10.1210/jc.2012-1743. View

McLaren W, Gil L, Hunt S, Riat H, Ritchie G, Thormann A . The Ensembl Variant Effect Predictor. Genome Biol. 2016; 17(1):122. PMC: 4893825. DOI: 10.1186/s13059-016-0974-4. View

Vocke C, Yang Y, Pavlovich C, Schmidt L, Nickerson M, Torres-Cabala C . High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dubé-associated renal tumors. J Natl Cancer Inst. 2005; 97(12):931-5. DOI: 10.1093/jnci/dji154. View

Sattler E, Steinlein O . Delayed diagnosis of Birt-Hogg-Dubé syndrome due to marked intrafamilial clinical variability: a case report. BMC Med Genet. 2018; 19(1):45. PMC: 5857113. DOI: 10.1186/s12881-018-0558-0. View

Perrier N, Arnold A, Costa-Guda J, Busaidy N, Nguyen H, Chuang H . HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: New and future perspectives for parathyroid carcinoma. Endocr Relat Cancer. 2020; 27(8):T53-T63. DOI: 10.1530/ERC-20-0018. View

Clausen L, Stein A, Gronbaek-Thygesen M, Nygaard L, Soltoft C, Nielsen S . Folliculin variants linked to Birt-Hogg-Dubé syndrome are targeted for proteasomal degradation. PLoS Genet. 2020; 16(11):e1009187. PMC: 7660926. DOI: 10.1371/journal.pgen.1009187. View

Mikesell K, Kulaylat A, Donaldson K, Saunders B, Crist H . A rare soft tissue tumor masquerading as a parathyroid adenoma in a patient with birt-hogg-dubé syndrome and multiple cervical endocrinopathies. Case Rep Pathol. 2015; 2014:753694. PMC: 4290639. DOI: 10.1155/2014/753694. View

10.

Toro J, Wei M, Glenn G, Weinreich M, Toure O, Vocke C . BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports. J Med Genet. 2008; 45(6):321-31. PMC: 2564862. DOI: 10.1136/jmg.2007.054304. View

11.

Chung J, Beers B, Ford M, Flowers F . Multiple lipomas, angiolipomas, and parathyroid adenomas in a patient with Birt-Hogg-Dube syndrome. Int J Dermatol. 1996; 35(5):365-7. DOI: 10.1111/j.1365-4362.1996.tb03642.x. View

12.

Mahtani K, Park D, Abbott J, Panneer Selvam P, Atwal P . Importance of Family History in the Era of Exome Analysis: A Report of a Family with Multiple Concurrent Genetic Diseases. Hum Hered. 2021; 86(1-4):28-33. DOI: 10.1159/000519356. View

13.

Wei Z, Sun B, Wang Z, He J, Fu W, Fan Y . Whole-Exome Sequencing Identifies Novel Recurrent Somatic Mutations in Sporadic Parathyroid Adenomas. Endocrinology. 2018; 159(8):3061-3068. DOI: 10.1210/en.2018-00246. View

14.

Kang H, Pettinga D, Schubert A, Ladenson P, Ball D, Chung J . Genomic Profiling of Parathyroid Carcinoma Reveals Genomic Alterations Suggesting Benefit from Therapy. Oncologist. 2018; 24(6):791-797. PMC: 6656481. DOI: 10.1634/theoncologist.2018-0334. View

15.

Newey P, Nesbit M, Rimmer A, Attar M, Head R, Christie P . Whole-exome sequencing studies of nonhereditary (sporadic) parathyroid adenomas. J Clin Endocrinol Metab. 2012; 97(10):E1995-2005. PMC: 4446457. DOI: 10.1210/jc.2012-2303. View

16.

Kutahyalioglu M, Nguyen H, Kwatampora L, Clarke C, Silva A, Ibrahim E . Genetic profiling as a clinical tool in advanced parathyroid carcinoma. J Cancer Res Clin Oncol. 2019; 145(8):1977-1986. DOI: 10.1007/s00432-019-02945-9. View

17.

Vinit J, Friedel J, Bielefeld P, Muller G, Goudet P, Besancenot J . [Birt-Hogg-Dubé syndrome and multiple recurrent tumors]. Rev Med Interne. 2010; 32(3):e40-2. DOI: 10.1016/j.revmed.2010.01.016. View

18.

Hasumi H, Baba M, Hong S, Hasumi Y, Huang Y, Yao M . Identification and characterization of a novel folliculin-interacting protein FNIP2. Gene. 2008; 415(1-2):60-7. PMC: 2727720. DOI: 10.1016/j.gene.2008.02.022. View

19.

Fingeret A . Contemporary Evaluation and Management of Parathyroid Carcinoma. JCO Oncol Pract. 2020; 17(1):17-21. DOI: 10.1200/JOP.19.00540. View

20.

Nickerson M, Warren M, Toro J, Matrosova V, Glenn G, Turner M . Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome. Cancer Cell. 2002; 2(2):157-64. DOI: 10.1016/s1535-6108(02)00104-6. View