TY - JOUR
T1 - Identification of a novel germline FOXE1 variant in patients with familial non-medullary thyroid carcinoma (FNMTC)
AU - Pereira, Joana S.
AU - da Silva, Joana Gomes
AU - Tomaz, Rute Alexandra
AU - Pinto, António Evaristo
AU - Bugalho, Maria João
AU - Leite, Valeriano
AU - Cavaco, Branca Maria
N1 - Funding Information:
The authors are thankful for the collaboration of the Endocrinology Department (Limbert E., Santos R. and Reis D.), the Head and Neck Surgery Department, and the Pathology Department, from the Instituto Português de Oncologia (IPO) Lisboa, and Research Centre (Teixeira M.) and Endocrinology Service (Torres I., Santos A.P.) from IPO Porto. The authors are also grateful to the patients and their families for their cooperation in this study. Rute A. Tomaz was a recipient of a B.Sc. fellowship from Associação de Endocrinologia Oncológica, and Centro de Estudos de Doenças Crónicas, Lisboa, Portugal. This work was funded by Núcleo Regional Sul da Liga Portuguesa Contra o Cancro - Terry Fox, Lisboa, Portugal.
Publisher Copyright:
© 2014, Springer Science+Business Media New York.
PY - 2015/5/1
Y1 - 2015/5/1
N2 - 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.
AB - 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.
KW - Clone
KW - Familial non-medullary thyroid carcinoma (FNMTC)
KW - FOXE1
KW - Pool
KW - Thyroid
KW - Variant
UR - http://www.scopus.com/inward/record.url?scp=84938342196&partnerID=8YFLogxK
U2 - 10.1007/s12020-014-0470-0
DO - 10.1007/s12020-014-0470-0
M3 - Article
C2 - 25381600
AN - SCOPUS:84938342196
SN - 1355-008X
VL - 49
SP - 204
EP - 214
JO - Endocrine
JF - Endocrine
IS - 1
ER -