Ultra-Rare Mutation in Long-Range Enhancer Predisposes to Thyroid Carcinoma with High Penetrance

• DOI: 10.1371/journal.pone.0061920
• Publication Date: 2013-05-14T17:05:32Z
• Authors: Huiling He; Wei Li; Dayong Wu; Rebecca Nagy; Sandya Liyanarachchi; Keiko Akagi; Jaroslaw Jendrzej...; Hong Jiao; Kevin Hoag; Bernard Wen; Mukund Srinivas; Gavisha Waidyaratne; Rui Wang; Anna Wojcicka; Ilene R. Lattimer; Elzbieta Stachlewska; Malgorzata Czetwe...; Joanna Dlugosinska; Wojciech Gierliko...; Rafal Ploski; Marek Krawczyk; Krystian Jazdzewski; Juha Kere; David E. Symer; Victor Jin; Qianben Wang; Albert de la Chap...
• Keywords: 0301 basic medicine; Transcription, Genetic; Genetic Linkage; Science; ANAPLASTIC TRANSFORMATION; DNA Mutational Analysis; CANCER-RISK; Penetrance; COLORECTAL-CANCER; FIRST-DEGREE RELATIVES; 03 medical and health sciences; Databases, Genetic; Humans; Genetic Predisposition to Disease; Thyroid Neoplasms; SUSCEPTIBILITY LOCUS; GENE-EXPRESSION; LINKAGE ANALYSIS; Q; R; COMMON VARIANTS; Genomics; HUMAN-DISEASE; PROSTATE-CANCER; 3. Good health; Biomedicine; Enhancer Elements, Genetic; Genetic Loci; Case-Control Studies; Mutation; Medicine; Chromosomes, Human, Pair 4; Research Article

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.