PLoS ONE (Jan 2013)

Ultra-rare mutation in long-range enhancer predisposes to thyroid carcinoma with high penetrance.

  • Huiling He,
  • Wei Li,
  • Dayong Wu,
  • Rebecca Nagy,
  • Sandya Liyanarachchi,
  • Keiko Akagi,
  • Jaroslaw Jendrzejewski,
  • Hong Jiao,
  • Kevin Hoag,
  • Bernard Wen,
  • Mukund Srinivas,
  • Gavisha Waidyaratne,
  • Rui Wang,
  • Anna Wojcicka,
  • Ilene R Lattimer,
  • Elzbieta Stachlewska,
  • Malgorzata Czetwertynska,
  • Joanna Dlugosinska,
  • Wojciech Gierlikowski,
  • Rafal Ploski,
  • Marek Krawczyk,
  • Krystian Jazdzewski,
  • Juha Kere,
  • David E Symer,
  • Victor Jin,
  • Qianben Wang,
  • Albert de la Chapelle

DOI
https://doi.org/10.1371/journal.pone.0061920
Journal volume & issue
Vol. 8, no. 5
p. e61920

Abstract

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Thyroid cancer shows high heritability but causative genes remain largely unknown. According to a common hypothesis the genetic predisposition to thyroid cancer is highly heterogeneous; being in part due to many different rare alleles. Here we used linkage analysis and targeted deep sequencing to detect a novel single-nucleotide mutation in chromosome 4q32 (4q32A>C) in a large pedigree displaying non-medullary thyroid carcinoma (NMTC). This mutation is generally ultra-rare; it was not found in 38 NMTC families, in 2676 sporadic NMTC cases or 2470 controls. The mutation is located in a long-range enhancer element whose ability to bind the transcription factors POU2F and YY1 is significantly impaired, with decreased activity in the presence of the C- allele compared with the wild type A-allele. An enhancer RNA (eRNA) is transcribed in thyroid tissue from this region and is greatly downregulated in NMTC tumors. We suggest that this is an example of an ultra-rare mutation predisposing to thyroid cancer with high penetrance.