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

Research output: Contribution to journalArticle


  • Jon Hoffman
  • Rachel Brown
  • Beth Bradshaw
  • Christopher Campbell
  • Trevor Cole
  • Johanna Dieguez Navas
  • Fiona Eatock
  • Justin Gundara
  • Eric Lian
  • Dominic McMullan
  • Fiona MacDonald
  • Lois Mulligan
  • Patrick J. Morrison
  • Mercedes Robledo
  • Michael Simpson
  • Sue Stewart
  • Richard Trembath
  • Stan Sidhu
  • Fiona Togneri
  • Lindsey Vialard
  • Yvonne Wallis
  • John Watkinson
  • Eamonn Maher
  • Christopher McCabe
  • Emma Woodward

External organisations

  • Queen Elizabeth Hosp
  • West Midlands Regional Genetics Laboratory
  • Royal Victoria Hospital, Belfast Health and Social Care Trust
  • Cancer Genetics, Level 9, Royal North Shore Hospital, Australia
  • Division Cancer Biology and Genetics, Cancer Research Institute, Queen's University, Canada
  • Department of Medical Genetics, Belfast City Hospital, Belfast, BT9 7AB
  • Spanish National Cancer Research Centre (CNIO), Madrid, Spain
  • Division of Genetics and Molecular Medicine, Department of Medical and Molecular Genetics, Kings College London, London, UK
  • West Midlands Regional Genetics Service, Birmingham Women's Hospital, Birmingham B15 2TG, UK.
  • Queen Mary University of London, Barts and the London School of Medicine and Dentistry, Institute of Dentistry, London E1 4NS, UK
  • Queen Elizabeth Hosp
  • University of Cambridge
  • Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester, M13 9WL


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 estrogen response elements (ERE) to regulate gene transcription. ERβ represses ERα mediated activation of the ERE and the RET promoter contains three ERE. 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.


Original languageEnglish
Pages (from-to)1836-1845
JournalHuman Molecular Genetics
Issue number9
Early online date3 Mar 2016
Publication statusPublished - 1 May 2016


  • ESR2, RET, Medullary thyroid cancer