Germline ESR2 mutation predisposes to medullary thyroid carcinoma and causes up-regulation of RET expression

Familial medullary thyroid cancer (MTC) and its precursor, C cell hyperplasia (CCH), is associated with germline RET mutations causing multiple endocrine neoplasia type 2. However, some rare families with apparent MTC/CCH predisposition do not have a detectable RET mutation. To identify novel MTC/CC...

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Bibliographic Details
Published in:Human molecular genetics 2016-05, Vol.25 (9), p.1836-1845
Main Authors: Smith, Joel, Read, Martin L, Hoffman, Jon, Brown, Rachel, Bradshaw, Beth, Campbell, Christopher, Cole, Trevor, Navas, Johanna Dieguez, Eatock, Fiona, Gundara, Justin S, Lian, Eric, Mcmullan, Dom, Morgan, Neil V, Mulligan, Lois, Morrison, Patrick J, Robledo, Mercedes, Simpson, Michael A, Smith, Vicki E, Stewart, Sue, Trembath, Richard C, Sidhu, Stan, Togneri, Fiona S, Wake, Naomi C, Wallis, Yvonne, Watkinson, John C, Maher, Eamonn R, McCabe, Christopher J, Woodward, Emma R
Format: Article
Language:English
Subjects:
Adult
Carcinoma, Medullary - congenital
Carcinoma, Medullary - genetics
Carcinoma, Medullary - metabolism
Carcinoma, Medullary - pathology
Cell Proliferation
Disease Susceptibility
Estrogen Receptor beta - genetics
Gene Expression Regulation, Neoplastic
Genotype
Germ-Line Mutation - genetics
Humans
Male
Multiple Endocrine Neoplasia Type 2a - genetics
Multiple Endocrine Neoplasia Type 2a - metabolism
Multiple Endocrine Neoplasia Type 2a - pathology
Pedigree
Proto-Oncogene Proteins c-ret - genetics
Proto-Oncogene Proteins c-ret - metabolism
Thyroid Neoplasms - genetics
Thyroid Neoplasms - metabolism
Thyroid Neoplasms - pathology
Tumor Cells, Cultured
Up-Regulation
Young Adult
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Summary:Familial medullary thyroid cancer (MTC) and its precursor, C cell hyperplasia (CCH), is associated with germline RET mutations causing multiple endocrine neoplasia type 2. However, some rare families with apparent MTC/CCH predisposition do not have a detectable RET mutation. To identify novel MTC/CCH predisposition genes we undertook exome resequencing studies in a family with apparent predisposition to MTC/CCH and no identifiable RET mutation. We identified a novel ESR2 frameshift mutation, c.948delT, which segregated with histological diagnosis following thyroid surgery in family members and demonstrated loss of ESR2-encoded ERβ expression in the MTC tumour. ERα and ERβ form heterodimers binding DNA at specific oestrogen-responsive elements (EREs) to regulate gene transcription. ERβ represses ERα-mediated activation of the ERE and the RET promoter contains three EREs. In vitro, we showed that ESR2 c.948delT results in unopposed ERα mediated increased cellular proliferation, activation of the ERE and increased RET expression. In vivo, immunostaining of CCH and MTC using an anti-RET antibody demonstrated increased RET expression. Together these findings identify germline ESR2 mutation as a novel cause of familial MTC/CCH and provide important insights into a novel mechanism causing increased RET expression in tumourigenesis.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddw057