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The role of SMAD3 in the genetic predisposition to papillary thyroid carcinoma.

The role of SMAD3 in the genetic predisposition to papillary thyroid carcinoma.
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Wang Y, He H, Liyanarachchi S, Genutis LK, Li W, Yu L, Phay JE, Shen R, Brock P, de la Chapelle A,


Wang Y, He H, Liyanarachchi S, Genutis LK, Li W, Yu L, Phay JE, Shen R, Brock P, de la Chapelle A, (click to view)

Wang Y, He H, Liyanarachchi S, Genutis LK, Li W, Yu L, Phay JE, Shen R, Brock P, de la Chapelle A,

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Genetics in medicine : official journal of the American College of Medical Genetics 2018 01 04() doi 10.1038/gim.2017.224

Abstract

PurposeTo identify and characterize the functional variants, regulatory gene networks, and potential binding targets of SMAD3 in the 15q22 thyroid cancer risk locus.MethodsWe performed linkage disequilibrium (LD) and haplotype analyses to fine map the 15q22 locus. Luciferase reporter assays were applied to evaluate the regulatory effects of the candidate variants. Knockdown by small interfering RNA, microarray analysis, chromatin immunoprecipitation (ChIP) and quantitative real-time polymerase chain reaction assays were performed to reveal the regulatory gene network and identify its binding targets.ResultsWe report a 25.6-kb haplotype within SMAD3 containing numerous single-nucleotide polymorphisms (SNPs) in high LD. SNPs rs17293632 and rs4562997 were identified as functional variants of SMAD3 by luciferase assays within the LD region. These variants regulate SMAD3 transcription in an allele-specific manner through enhancer elements in introns of SMAD3. Knockdown of SMAD3 in thyroid cancer cell lines revealed its regulatory gene network including two upregulated genes, SPRY4 and SPRY4-IT1. Sequence analysis and ChIP assays validated the actual binding of SMAD3 protein to multiple SMAD binding element sites in the region upstream of SPRY4.ConclusionOur data provide a functional annotation of the 15q22 thyroid cancer risk locus.GENETICS in MEDICINE advance online publication, 4 January 2018; doi:10.1038/gim.2017.224.

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