Fumarate Hydratase is a Novel Gene for Familial Non-Medullary Thyroid Cancer

Author:

Alzahrani Ali S12ORCID,Alswailem Meshael2,Alghamdi Balgees2,Al-Hindi Hindi3

Affiliation:

1. Department of Medicine, King Faisal Specialist Hospital & Research Centre , Riyadh 11211 , Saudi Arabia

2. Department of Molecular Oncology, King Faisal Specialist Hospital & Research Centre , Riyadh 11211 , Saudi Arabia

3. Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital & Research Centre , Riyadh 11211 , Saudi Arabia

Abstract

Abstract Context The majority of cases of epithelial cell-derived thyroid cancer are sporadic. Familial non-medullary thyroid cancer (FNMTC) occurs in about 5% to 9% of cases, either as a part of known syndromes such as Cowden syndrome or in the form of familial clustering of 2 or more affected family members. Hereditary leiomyoma and renal cell cancer (HLRCC) syndrome is a rare familial cancer syndrome. The underlying etiology is heterozygous germline mutations of the fumarate hydratase (FH) gene. In addition to extensive uterine and skin leiomyomas and RCC, other tumors may arise in this syndrome. However, thyroid cancer has never been described as part of HLRCC. Here, we describe a woman who presented with an aggressive poorly differentiated thyroid cancer (PDTC) and was found to have HLRCC syndrome because of a novel heterozygous germline FH mutation. Results A 43-year-old woman presented with a large lower neck mass that was found to be PDTC. During her evaluation, she was found to have extensive uterine leiomyomatosis and bilateral adrenal nodules. Whole exome and subsequent Sanger sequencing of leucocyte DNA revealed a novel monoallelic nonsense FH mutation (c.760C>T, p.Q254*). Sequencing of the thyroid tumor tissue showed a biallelic loss at the same mutation site (loss of heterozygosity) and immunohistochemistry of the PDTC showed loss of FH staining in the tumor tissue, indicating the pathogenic role of this mutation in the development of PDTC in this patient. Conclusion Thyroid cancer is a novel feature of the FH-related HLRCC syndrome. This syndrome can be added to the rare genetic causes of syndromic FNMTC.

Publisher

The Endocrine Society

Subject

Biochemistry (medical),Clinical Biochemistry,Endocrinology,Biochemistry,Endocrinology, Diabetes and Metabolism

Reference27 articles.

1. Biologic and clinical perspectives on thyroid cancer;Fagin;N Engl J Med.,2016

2. Familial non-medullary thyroid cancer: unraveling the genetic maze;Peiling Yang;Endocr Relat Cancer.,2016

3. Genetics of familial non-medullary thyroid carcinoma (FNMTC);Diquigiovanni;Cancers (Basel),2021

4. Cutaneous leiomyomata with uterine leiomyomata;Reed;Acta Derm Venereol.,1973

5. Inherited susceptibility to uterine leiomyomas and renal cell cancer;Launonen;Proc Natl Acad Sci USA.,2001

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