title: Ultra-rare mutation in long-range enhancer predisposes to thyroid carcinoma with high penetrance.
abstract: 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.
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Wexner Medical Center and Comprehensive Cancer Center, the Ohio State University, Columbus, Ohio, USA. huiling.he@osumc.edu
authors.forename: Huiling
authors.initials: H
authors.lastname: He
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Dayong
authors.initials: D
authors.lastname: Wu
authors.forename: Rebecca
authors.initials: R
authors.lastname: Nagy
authors.forename: Sandya
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authors.lastname: Liyanarachchi
authors.forename: Keiko
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authors.lastname: Akagi
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Jendrzejewski
authors.forename: Hong
authors.initials: H
authors.lastname: Jiao
authors.forename: Kevin
authors.initials: K
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authors.forename: Bernard
authors.initials: B
authors.lastname: Wen
authors.forename: Mukund
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authors.lastname: Srinivas
authors.forename: Gavisha
authors.initials: G
authors.lastname: Waidyaratne
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Anna
authors.initials: A
authors.lastname: Wojcicka
authors.forename: Ilene R
authors.initials: IR
authors.lastname: Lattimer
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Stachlewska
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Czetwertynska
authors.forename: Joanna
authors.initials: J
authors.lastname: Dlugosinska
authors.forename: Wojciech
authors.initials: W
authors.lastname: Gierlikowski
authors.forename: Rafal
authors.initials: R
authors.lastname: Ploski
authors.forename: Marek
authors.initials: M
authors.lastname: Krawczyk
authors.forename: Krystian
authors.initials: K
authors.lastname: Jazdzewski
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.forename: David E
authors.initials: DE
authors.lastname: Symer
authors.forename: Victor
authors.initials: V
authors.lastname: Jin
authors.forename: Qianben
authors.initials: Q
authors.lastname: Wang
authors.forename: Albert
authors.initials: A
authors.lastname: de la Chapelle
mesh_terms: D016022:Case-Control Studies; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D004252:DNA Mutational Analysis; D030541:Databases, Genetic; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D008040:Genetic Linkage; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D023281:Genomics; D006801:Humans; D009154:Mutation; D019683:Penetrance; D013964:Thyroid Neoplasms / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics