The Role of NRG1 in the Predisposition to Papillary Thyroid Carcinoma

• Published in: The journal of clinical endocrinology and metabolism Vol. 103; no. 4; pp. 1369 - 1379
• Main Authors: He, Huiling, Li, Wei, Liyanarachchi, Sandya, Wang, Yanqiang, Yu, Lianbo, Genutis, Luke K, Maharry, Sophia, Phay, John E, Shen, Rulong, Brock, Pamela, de la Chapelle, Albert
• Format: Journal Article
• Language: English
• Published: Washington, DC Endocrine Society 01.04.2018; Copyright Oxford University Press; Oxford University Press
• Subjects: Adult; Alleles; Assaying; Carcinoma, Papillary - genetics; Carcinoma, Papillary - metabolism; Chromatin; Chromosome 8; Clinical s; Deoxyribonucleic acid; DNA; Downstream; Female; Gene expression; Gene Expression Regulation, Neoplastic - physiology; Gene Knockdown Techniques; Gene polymorphism; Gene regulation; Genes; Genetic Predisposition to Disease; Genome-wide association studies; Genomes; Genotype; Genotypes; Haplotypes; Health risks; Humans; Immunoprecipitation; Isoforms; Life assessment; Male; Middle Aged; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Neuregulin-1 - biosynthesis; Neuregulin-1 - genetics; Papillary thyroid carcinoma; Polymerase chain reaction; Polymorphism, Single Nucleotide; Protein Isoforms - biosynthesis; Protein Isoforms - genetics; Quantitative Trait Loci; Reverse transcription; RNA, Small Interfering - genetics; Single-nucleotide polymorphism; siRNA; Thyroid cancer; Thyroid Cancer, Papillary; Thyroid carcinoma; Thyroid Gland - metabolism; Thyroid Neoplasms - genetics; Thyroid Neoplasms - metabolism; Transcription, Genetic
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2017-01798

Abstract Context Previous genome-wide association studies have shown that single-nucleotide polymorphism (SNP) rs2439302 in chromosome 8p12 is significantly associated with papillary thyroid carcinoma (PTC) risk and dysregulated NRG1 expression. The underlying mechanisms remain to be discovered. Objective To evaluate the expression of NRG1 isoforms, candidate functional variants, and potential genes downstream of NRG1 in thyroid tissue. Methods Quantitative reverse transcription polymerase chain reaction was applied for gene expression analysis. SNaPshot assay, haplotype, and computer analyses were performed to evaluate candidate functional variants. Other functional assays [chromatin immunoprecipitation (ChIP) assay, luciferase assay, small interfering RNA knockdown, and RNA sequencing] were performed. Results Three NRG1 isoforms (NM_004495, NM_013958, and NM_001160008) tested were highly expressed in thyroid tissue. The expression levels of the three isoforms were significantly correlated with the genotypes of rs2439302. A DNA block of ~32 kb containing the risk G allele of rs2439302 was revealed, harboring multiple candidate functional variants. ChIP assay for active chromatin markers indicated at least nine regions in the DNA block showing strong H3Kme1 and H3K27Ac signals in thyroid tissue. Luciferase reporter assays revealed differential allelic activities associated with seven SNPs. Knocking down NRG1 in primary thyroid cells revealed downstream or interacting genes related to NRG1. Conclusions Our data suggest a role for transcriptional regulation of NRG1 in the predisposition to PTC. The thyroid cancer risk [G] allele of rs2439302 belongs to a haplotype whose SNPs regulate NRG1 expression followed by transcriptional regulation of NRG1-targeting or -interacting genes.