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 PloskiMarek Krawczyk, Krystian Jazdzewski, Juha Kere, David E. Symer, Victor Jin, Qianben Wang, Albert de la Chapelle

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


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.

Original languageEnglish (US)
Article numbere61920
JournalPloS one
Issue number5
StatePublished - May 14 2013
Externally publishedYes

ASJC Scopus subject areas

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