Identification of a novel germline FOXE1 variant in patients with familial thyroid cancer

The familial forms of non-medullary thyroid carcinoma (FNMTC) represent 5% of thyroid neoplasms. To date, three FNMTC susceptibility genes have been identified (NKX2-1, DICER1 and SRGAP1). This study represents the first evidence of involvement of a germline FOXE1 rare variant in FNMTC etiology. This gene, which encodes the FOXE1 transcription factor involved in the morphogenesis and differentiation of the thyroid, may represent a novel susceptibility gene for this familial thyroid disease.

Authors and Affiliations:

Joana Sousa Pereira ^1,4, Joana Gomes da Silva^1,4, Rute Alexandra Tomaz^1,4, António Evaristo Pinto^3, Maria João Bugalho^1,2, Valeriano Leite^{1,2, 4,} Branca Maria Cavaco^1,4

¹ –Unidade de Investigação em Patobiologia Molecular (UIPM) 

² - Serviço de Endocrinologia

³ - Serviço de Anatomia Patológica, Instituto Português de Oncologia de Lisboa Francisco Gentil, 1099-023 Lisboa, Portugal.

⁴ - CEDOC, Chronic Diseases Research Center, NOVA Medical School / Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Campo dos Mártires da Pátria, 1169-056 Lisboa, Portugal.

Abstract:

The familial forms of non-medullary thyroid carcinoma (FNMTC) represent approximately 5 % of thyroid neoplasms. Nine FNMTC susceptibility loci have been mapped; however, only the DICER1 and SRGAP1 susceptibility genes have been identified. The transcription factors NKX2-1, FOXE1, PAX8, and HHEX are involved in the morphogenesis and differentiation of the thyroid. Recent studies have identified NKX2-1 germline mutations in FNMTC families. However, the role of high-penetrant FOXE1 variants in FNMTC etiology remains unclear. The aim of this study was to investigate the role of FOXE1 germline mutations in the pathogenesis of FNMTC. We searched for molecular changes in the FOXE1 gene in the probands from 60 Portuguese families with FNMTC. In this series, we identified nine polymorphisms and one variant (c.743C>G, p.A248G) which was not previously described. This variant, which involved an amino acid residue conserved in evolution, segregated with disease in one family, and was also detected in an apparently unrelated case of sporadic NMTC. Functional studies were performed using rat normal thyroid cells (PCCL3) clones and human papillary thyroid carcinoma cell line (TPC-1) pools, expressing the wild type and mutant (p.A248G) forms of FOXE1. In these experiments, we observed that the p.A248G variant promoted cell proliferation and migration, suggesting that it may be involved in thyroid tumorigenesis. Additionally, somatic p.V600E BRAF mutations were also detected in the thyroid tumors of two members of the family carrying the p.A248G variant. This study represents the first evidence of involvement of a germline FOXE1 rare variant in FNMTC etiology and suggests that mutations in MAPK pathway-related genes may contribute to tumor development in these familial cases.

Journal: Endocrine

Link: http://www.springer.com/-/7/ced0622627594a4da2519d428bd380b6