Multiple functional variants in long-range enhancer elements contribute to the risk of SNP rs965513 in thyroid cancer. Proc Natl Acad Sci U S A 2015 May 12;112(19):6128-33
Date
04/29/2015Pubmed ID
25918370Pubmed Central ID
PMC4434723DOI
10.1073/pnas.1506255112Scopus ID
2-s2.0-84929206967 (requires institutional sign-in at Scopus site) 69 CitationsAbstract
The [A] allele of SNP rs965513 in 9q22 has been consistently shown to be highly associated with increased papillary thyroid cancer (PTC) risk with an odds ratio of ∼1.8 as determined by genome-wide association studies, yet the molecular mechanisms remain poorly understood. Previously, we noted that the expression of two genes in the region, forkhead box E1 (FOXE1) and PTC susceptibility candidate 2 (PTCSC2), is regulated by rs965513 in unaffected thyroid tissue, but the underlying mechanisms were not elucidated. Here, we fine-mapped the 9q22 region in PTC and controls and detected an ∼33-kb linkage disequilibrium block (containing the lead SNP rs965513) that significantly associates with PTC risk. Chromatin characteristics and regulatory element signatures in this block disclosed at least three regulatory elements functioning as enhancers. These enhancers harbor at least four SNPs (rs7864322, rs12352658, rs7847449, and rs10759944) that serve as functional variants. The variant genotypes are associated with differential enhancer activities and/or transcription factor binding activities. Using the chromosome conformation capture methodology, long-range looping interactions of these elements with the promoter region shared by FOXE1 and PTCSC2 in a human papillary thyroid carcinoma cell line (KTC-1) and unaffected thyroid tissue were found. Our results suggest that multiple variants coinherited with the lead SNP and located in long-range enhancers are involved in the transcriptional regulation of FOXE1 and PTCSC2 expression. These results explain the mechanism by which the risk allele of rs965513 predisposes to thyroid cancer.
Author List
He H, Li W, Liyanarachchi S, Srinivas M, Wang Y, Akagi K, Wang Y, Wu D, Wang Q, Jin V, Symer DE, Shen R, Phay J, Nagy R, de la Chapelle AAuthor
Victor X. Jin PhD Professor in the Institute for Health and Equity department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AllelesCarcinoma
Carcinoma, Papillary
Cell Line, Tumor
Chromatin
Chromatin Immunoprecipitation
Enhancer Elements, Genetic
Forkhead Transcription Factors
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Haplotypes
Histones
Humans
Odds Ratio
Penetrance
Polymorphism, Single Nucleotide
Thyroid Neoplasms
