TY - JOUR
T1 - Ultra-Rare Mutation in Long-Range Enhancer Predisposes to Thyroid Carcinoma with High Penetrance
AU - He, Huiling
AU - Li, Wei
AU - Wu, Dayong
AU - Nagy, Rebecca
AU - Liyanarachchi, Sandya
AU - Akagi, Keiko
AU - Jendrzejewski, Jaroslaw
AU - Jiao, Hong
AU - Hoag, Kevin
AU - Wen, Bernard
AU - Srinivas, Mukund
AU - Waidyaratne, Gavisha
AU - Wang, Rui
AU - Wojcicka, Anna
AU - Lattimer, Ilene R.
AU - Stachlewska, Elzbieta
AU - Czetwertynska, Malgorzata
AU - Dlugosinska, Joanna
AU - Gierlikowski, Wojciech
AU - Ploski, Rafal
AU - Krawczyk, Marek
AU - Jazdzewski, Krystian
AU - Kere, Juha
AU - Symer, David E.
AU - Jin, Victor
AU - Wang, Qianben
AU - de la Chapelle, Albert
N1 - Funding Information:
We thank members of the de la Chapelle Laboratory for discussions and technical assistance. We are grateful to Drs. Saul Suster, Paul Wakely, and Veronica Vieland for help. The OSUCCC Nucleic Acid Shared Resource performed SNP and microsatellite marker genotyping and Sanger sequencing. The Biomedical Genomics Core of The Research Institute at Nationwide Children's Hospital, Columbus, Ohio performed targeted deep sequencing. Tissue samples were provided by the Cooperative Human Tissue Network at the Ohio State University which is funded by the National Cancer Institute.
PY - 2013/5/14
Y1 - 2013/5/14
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0061920
DO - 10.1371/journal.pone.0061920
M3 - Article
C2 - 23690926
AN - SCOPUS:84877788249
SN - 1932-6203
VL - 8
JO - PloS one
JF - PloS one
IS - 5
M1 - e61920
ER -