rs944289 — FOXE1

A Hidden Switch for Thyroid Cancer — rs944289 and the PTCSC3 Tumor Suppressor

Tucked into the intergenic region of chromosome 14q13.3, rs944289 was one of the first common variants identified as a thyroid cancer susceptibility locus. Discovered in a landmark Icelandic GWAS¹¹ landmark Icelandic GWAS
Gudmundsson et al. Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations. Nature Genetics 2009 alongside rs965513 on chromosome 9, this variant does not sit within a protein-coding gene. Instead, it controls a molecular switch: the expression of PTCSC3²² PTCSC3
Papillary Thyroid Carcinoma Susceptibility Candidate 3, a long noncoding RNA with tumor suppressor properties that is expressed exclusively in thyroid tissue, a long noncoding RNA gene with tumor suppressor activity that is expressed exclusively in the thyroid gland.

The Mechanism

The rs944289 variant sits within a binding site for C/EBP transcription factors³³ binding site for C/EBP transcription factors
CCAAT/enhancer binding proteins alpha and beta, which activate the PTCSC3 promoter. The protective C allele preserves this binding site, allowing C/EBPalpha and C/EBPbeta to activate the PTCSC3 promoter. The risk T allele disrupts this binding site, reducing transcription factor affinity and lowering PTCSC3 expression.

PTCSC3 functions as a tumor suppressor⁴⁴ PTCSC3 functions as a tumor suppressor
Restoration of PTCSC3 expression in PTC cell lines inhibited cell growth and affected genes involved in DNA replication, cellular movement, and cell death in thyroid tissue. When PTCSC3 is experimentally restored in papillary thyroid carcinoma cell lines, it inhibits cell growth and alters the expression of genes involved in DNA replication, recombination, cellular movement, tumor morphology, and cell death. In thyroid tumor tissue from 46 PTC patients, PTCSC3 was strongly downregulated compared to normal thyroid, and TT homozygotes showed the most severe suppression (P=0.004 vs CT heterozygotes).

The PTCSC3 gene is located 3.2 kb downstream of rs944289 and is strictly thyroid-specific in expression⁵⁵ strictly thyroid-specific in expression
Unlike most lncRNAs with broader tissue expression, PTCSC3 transcripts are detected only in thyroid tissue, explaining why this variant specifically affects thyroid cancer risk rather than cancer risk broadly.

The Evidence

The discovery GWAS by Gudmundsson et al.⁶⁶ discovery GWAS by Gudmundsson et al.
Gudmundsson et al. Nature Genetics 2009, 192 Icelandic cases, 37,196 controls with European replication found rs944289 associated with thyroid cancer at an odds ratio of 1.37 per T allele (P=2.0x10^-9). Critically, individuals homozygous for both rs944289-TT and rs965513-AA had a 5.7-fold greater risk of thyroid cancer compared to non-carriers at either locus, with approximately 3.7% of Europeans carrying this double-homozygous genotype.

A meta-analysis of 15 studies⁷⁷ meta-analysis of 15 studies
Chen & Zhang. BMC Medical Genetics 2018 confirmed the association with differentiated thyroid cancer (OR 1.08, 95% CI 1.035-1.131). A separate meta-analysis of 8 case-control studies with 51,120 subjects⁸⁸ separate meta-analysis of 8 case-control studies with 51,120 subjects
Associations between rs965513/rs944289 and papillary thyroid carcinoma risk. Endocrine 2014 found a per-allele OR of 1.29 (95% CI 1.23-1.37) for papillary thyroid carcinoma, with stronger effects in Caucasian populations.

A Japanese population study⁹⁹ Japanese population study
Rogounovitch et al. Thyroid 2015, 535 PTC cases, 959 follicular adenoma cases, 2,766 controls confirmed the association extends to both malignant thyroid tumors (PTC: OR 1.23, P=0.003) and benign thyroid tumors (follicular adenoma: OR 1.18, P=0.002), suggesting the variant acts on early thyroid tumorigenesis rather than malignant transformation specifically.

The T allele frequency varies substantially across populations: approximately 59% in Europeans, 50% in South Asians, 45% in East Asians, 39% in Latinos, and only 21% in Africans. This population stratification partly mirrors global thyroid cancer incidence patterns, though environmental factors like iodine intake and radiation exposure also contribute.

Practical Implications

The rs944289 T allele confers a modest but well-replicated increase in thyroid cancer risk. Because papillary thyroid cancer is relatively uncommon (annual incidence approximately 14 per 100,000), even a 1.37-fold relative risk increase translates to a small absolute risk change for most carriers. However, for individuals with additional risk factors — family history of thyroid cancer, prior radiation exposure, or known thyroid nodules — this genotype provides context for surveillance decisions.

The variant also associates with benign thyroid tumors (follicular adenoma), meaning TT carriers may be more likely to develop thyroid nodules that require evaluation even when they turn out to be non-malignant. Adequate selenium and iodine status support thyroid health and may help mitigate risk.

Interactions

The rs944289 locus on 14q13.3 interacts multiplicatively with the rs965513 locus on 9q22.33 for thyroid cancer risk. The Gudmundsson 2009 study demonstrated that carriers homozygous at both loci face a 5.7-fold increased risk. Both loci operate through distinct regulatory mechanisms — rs944289 through PTCSC3 suppression and rs965513 through PTCSC2/FOXE1 downregulation — but converge on thyroid cell differentiation and tumor suppression pathways. This makes the combination of both risk genotypes substantially more concerning than either alone.