Quantitative Assessment of Common Genetic Variants on FOXE1 and Differentiated Thyroid Cancer Risk

Abstract

Forkhead box E1 encodes the transcription factor FOXE1 (or TTF-2), which together with Homeobox protein NKX2-1, PAX8 and HHEX, are pivotal proteins required for thyroid gland formation, differentiation and function. Recently, genome-wide association studies have identified FOXE1 as a thyroid cancer (TC) susceptibility gene in populations of European descent. After that, a number of studies reported that the rs965513, rs1867277, and rs71369530 polymorphism in FOXE1 has been implicated in TC risk. However, the causal variants remain unknown. To derive a more precise estimation of the relationship, a meta-analysis of 9,828 TC cases and 109,995 controls from 14 case–control studies was performed. Overall, significant results were observed for rs965513 (OR = 1.71, 95% CI: 1.59–1.85, P<10−5), rs1867277 (OR = 1.64, 95% CI: 1.51–1.78, P<10−5) and rs71369530 (OR = 2.01, 95% CI: 1.66–2.44, P<10−5) polymorphism. In the subgroup analysis by ethnicity, we found that rs965513 polymorphism confer high risk for Caucasians with per-allele OR of 1.80 (95% CI: 1.69–1.92, P<10−5) compared to East Asians of 1.35 (95% CI: 1.09–1.67, P = 0.006). There was strong evidence of heterogeneity, which largely disappeared after stratification by ethnicity. In the subgroup analysis by sample size, and study design, significantly increased risks were found for the polymorphism. In conclusion, this meta-analysis demonstrated that common variations of FOXE1 are a risk factor associated with increased TC susceptibility.

MYH9 binds to lncRNA gene PTCSC2 and regulates FOXE1 in the 9q22 thyroid cancer risk locus

“…In efforts to explain the genomic background to PTC, genome-wide association studies (GWASs) have disclosed an SNP marker, rs965513, in 9q22.33 strongly associated with PTC in European populations [odds ratio (OR) = 1.75; P = 1.7 × 10 −27 ] (2, 3). The association has been observed in other populations as well (4)(5)(6)(7)(8). Additionally, rs965513 has been reported to be associated with levels of thyroid-related hormones, hypothyroidism, goiter, and other abnormal thyroid functions (2,3,9).…”

Multiple functional variants in long-range enhancer elements contribute to the risk of SNP rs965513 in thyroid cancer

“…8 (4). The association between rs965513 and thyroid cancer risk has been independently confirmed in different populations (5)(6)(7)(8)(9)(10)(11). The association was also observed in familial PTC and in patients with radiation-induced PTC (12)(13)(14)(15).…”

“…SNP rs965513 resides ∼60 kb upstream of forkhead box E1 (FOXE1) (also known as thyroid transcription factor 2), a critical transcription factor (TF) in thyroid development, differentiation, and function (16)(17)(18)(19). It has been repeatedly proposed that FOXE1 is involved in the tumorigenesis of PTC (11,19,20). A DNA variant (rs1867277) in the promoter region of FOXE1 was reported as a functional variant involved in transcriptional regulation of FOXE1 (19).…”

Papillary Thyroid Carcinoma: Association Between Germline DNA Variant Markers and Clinical Parameters

“…Rs965513 is part of a haplotype block that regulates FOXE1 and PTCSC2 expression through long-range enhancer elements (13). A role for FOXE1 in PTC development has been proposed in several studies (14)(15)(16)(17).…”