title: Germline ESR2 mutation predisposes to medullary thyroid carcinoma and causes up-regulation of RET expression.
abstract: 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.
authors.affiliation: Centre for Rare Diseases and Personalised Medicine.
authors.forename: Joel
authors.initials: J
authors.lastname: Smith
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Read
authors.affiliation: West Midlands Regional Genetics Service.
authors.forename: Jon
authors.initials: J
authors.lastname: Hoffman
authors.affiliation: Queen Elizabeth Hospital, Queen Elizabeth Medical Centre, Birmingham B15 2TH, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Brown
authors.affiliation: West Midlands Regional Genetics Laboratory, Birmingham Women's Hospital, Birmingham B15 2TG, UK.
authors.forename: Beth
authors.initials: B
authors.lastname: Bradshaw
authors.affiliation: West Midlands Regional Genetics Laboratory, Birmingham Women's Hospital, Birmingham B15 2TG, UK, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre (MAHSC), Manchester M13 9WL, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Campbell
authors.affiliation: West Midlands Regional Genetics Service.
authors.forename: Trevor
authors.initials: T
authors.lastname: Cole
authors.affiliation: Human Biomaterials Resource Centre, College of Medical and Dental Sciences, University of Birmingham, Vincent Drive, Edgbaston B15 2TT, UK.
authors.forename: Johanna Dieguez
authors.initials: JD
authors.lastname: Navas
authors.affiliation: Department of Endocrine Surgery, Belfast Health and Social Care Trust, Royal Victoria Hospital, Belfast, Northern Ireland, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Eatock
authors.affiliation: Cancer Genetics, Level 9, Kolling Building and Endocrine Surgical Unit, Royal North Shore Hospital, University of Sydney, Pacific Highway, St Leonards, NSW 2065, Australia.
authors.forename: Justin S
authors.initials: JS
authors.lastname: Gundara
authors.affiliation: Division of Cancer Biology and Genetics, Cancer Research Institute, Queen's University, Kingston, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Lian
authors.affiliation: West Midlands Regional Genetics Laboratory, Birmingham Women's Hospital, Birmingham B15 2TG, UK.
authors.forename: Dom
authors.initials: D
authors.lastname: Mcmullan
authors.affiliation: Centre for Rare Diseases and Personalised Medicine.
authors.forename: Neil V
authors.initials: NV
authors.lastname: Morgan
authors.affiliation: Division of Cancer Biology and Genetics, Cancer Research Institute, Queen's University, Kingston, Canada.
authors.forename: Lois
authors.initials: L
authors.lastname: Mulligan
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University of Belfast, 97 Lisburn Road, Belfast BT9 7AE, UK.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Morrison
authors.affiliation: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain, Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Robledo
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, London, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Simpson
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Vicki E
authors.initials: VE
authors.lastname: Smith
authors.affiliation: West Midlands Regional Genetics Service.
authors.forename: Sue
authors.initials: S
authors.lastname: Stewart
authors.affiliation: Queen Mary University of London, Barts and The London School of Medicine and Dentistry, London, UK.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Trembath
authors.affiliation: Cancer Genetics, Level 9, Kolling Building and Endocrine Surgical Unit, Royal North Shore Hospital, University of Sydney, Pacific Highway, St Leonards, NSW 2065, Australia.
authors.forename: Stan
authors.initials: S
authors.lastname: Sidhu
authors.affiliation: West Midlands Regional Genetics Laboratory, Birmingham Women's Hospital, Birmingham B15 2TG, UK.
authors.forename: Fiona S
authors.initials: FS
authors.lastname: Togneri
authors.affiliation: Centre for Rare Diseases and Personalised Medicine.
authors.forename: Naomi C
authors.initials: NC
authors.lastname: Wake
authors.affiliation: West Midlands Regional Genetics Laboratory, Birmingham Women's Hospital, Birmingham B15 2TG, UK.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Wallis
authors.affiliation: Queen Elizabeth Hospital, Queen Elizabeth Medical Centre, Birmingham B15 2TH, UK.
authors.forename: John C
authors.initials: JC
authors.lastname: Watkinson
authors.affiliation: Centre for Rare Diseases and Personalised Medicine, Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK and.
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: McCabe
authors.affiliation: Centre for Rare Diseases and Personalised Medicine, West Midlands Regional Genetics Service, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre (MAHSC), Manchester M13 9WL, UK emma.woodward@cmft.nhs.uk.
authors.forename: Emma R
authors.initials: ER
authors.lastname: Woodward
mesh_terms: D000328:Adult; D018276:Carcinoma, Medullary / Q000151:congenital* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D004198:Disease Susceptibility; D047629:Estrogen Receptor beta / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008297:Male; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D010375:Pedigree; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D055815:Young Adult
chemical_list: C000600034:ESR2 protein, human; D047629:Estrogen Receptor beta; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human