Abstract
Papillary thyroid carcinoma (PTC) is the most common histotype of thyroid carcinoma. The heritability of PTC is high compared to other cancers, but its underlying causes are unknown. A recent genome-wide association study revealed the association of a variant at the 5q22 locus, rs73227498, with PTC predisposition. We report that rs17134155, a variant in high linkage disequilibrium with rs73227498, is located in an enhancer region downstream of coding transcripts of EPB41L4A. Rs17134155 showed significant enhancer activity in luciferase assays, and haplotypes containing the protective allele of this variant conferred a significantly lower risk of PTC. While the index SNP, rs73227498, acted as a significant cis-eQTL for expression of EPB41L4A, rs17134155 was a significant cis-sQTL for the alternative splicing of a non-coding transcript of EPB41L4A, called EPB41L4A-203. We also performed knockdown of EPB41L4A followed by microarray analysis. Some of the top differentially-expressed genes were represented among regulators of the WNT/β-catenin signaling pathway. Our results indicate that an enhancer region at 5q22 regulates the expression and splicing of EPB41L4A transcripts. We also provide evidence that EPB41L4A expression is involved in regulating growth and differentiation pathways, suggesting that decreased expression of EPB41L4A is a mechanism in the predisposition to PTC.
Highlights
Papillary thyroid carcinoma (PTC) is the most common histotype of thyroid carcinoma
In the present study we characterized a locus at 5q22 that was reported in a recent genome-wide association studies (GWASs) of PTC
We performed linkage disequilibrium (LD) analysis and identified 51 variants that were in high LD with the index single-nucleotide polymorphism (SNP), rs73227498
Summary
Papillary thyroid carcinoma (PTC) is the most common histotype of thyroid carcinoma. The heritability of PTC is high compared to other cancers, but its underlying causes are unknown. We report that rs17134155, a variant in high linkage disequilibrium with rs73227498, is located in an enhancer region downstream of coding transcripts of EPB41L4A. While most NMTCs are sporadic, a number of case reports and studies have shown the aggregation of non-syndromic thyroid carcinoma in families[1,8,9,10,11,12,13,14]. We reported the association of a variant at 5q22, rs73227498, with P TC22 This variant is a non-coding variant in close proximity to the gene body for erythrocyte membrane protein band 4.1 like 4A (EPB41L4A). EPB41L4A is a member of the band FERM (Four-point-one, Ezrin, Radixin, Moesin) superfamily of proteins Members of this superfamily comprise a group of membrane-associated proteins whose major biological. In addition to coding isoforms of EPB41L4A, there are several long noncoding RNA (lncRNA) transcripts, including EPB41L4A-AS1 and EPB41L4A-AS2, both of which have several documented functions in regulating the proliferation and metabolism of cancer cells[27,28,29,30]
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