rs965513

rs965513 is located at 9q22.23 approximately 57 kb from the FOXE1 locus. The rs965513 SNP is associated with papillary and follicular thyroid cancer. The major allele is G and the minor is A. The risk allele is A. Each A at rs965513 increased the odds of thyroid cancer by 1.75 times. ==Clinical Picture== In a given year, roughly 5 in 100,000 males and 14 in 100,000 females will develop differentiated thyroid carcinoma (DTC). It is the most common endocrine cancer and rates are steadily rising, though this is likely due to increased detection. Significant risk factors for developing DTC include radiation exposure during childhood whether during treatment of childhood cancers or from environmental exposure, family history, occupational exposures, and possibly hepatitis-C related chronic hepatitis. Thyroid cancer presents commonly as a palpable mass detected by exam or imaging studies. Occasionally, DTC presents with symptoms of hypo- or hyperthyroidism. At the time of detection, 80% of patients have nodal involvement; between 2-10% of patients have metastasis beyond the neck, usually to the lungs or bones. A positive prognosis is favored by a young age of diagnosis, smaller tumor size, absence of soft tissue invasion and absence of distal metastasis. In general, the prognosis for DTC is good, and most individuals with DTC do not die of the disease. Management of DTC nearly always involves thyroidectomy and when there is evidence of some nodal involvement, neck dissection of the central lymph nodes. Surgery is often followed with radioiodine therapy in patients with distant metastases, large primary tumors, lymph node metastases or other predictive factors for a high risk of recurrence. Long term management includes thyroid stimulating hormone suppression therapy, monitoring of serum thyroglobulin and serial neck ultrasounds. Further investigation may take place as necessary. ==SNP Association== In a case-control GWAS, Gudmundsson et al. (2009) identified two SNPs&#8212;rs965513 and rs944289&#8212;associated with DTC. The study population (recruited from the Icelandic Cancer Registry) consisted of 192 cases who were histopathologically diagnosed with DTC and genotyped and an additional 186 DTC cases whose genomes were imputed from the genotypes of relatives. There were 37,196 controls (recruited from participants in separate research at the institution). The study looked at 304,083 SNPs. For the rs965513 SNP, the frequency of the risk allele [A] in cases is 0.490 compared to 0.352 in controls. The allelic odds ratio is 1.77 (95% CI, 1.57-2.00) with a p-value of 6.8 x 10-20. Following the initial study, results were tested in a replication study with two populations: first, 342 cases and 384 controls from Columbus, Ohio; and second, 90 cases and 1,343 controls from Spain. The results from the initial study for rs965513 were replicated in both replication study groups. Gudmundsson et al. computed the genotype specific frequencies and ORs. They estimated that 11% of individuals are homozygous AA at the rs965513 site and that this is associated with a 3.1-fold increased risk compared to non-carriers for developing DTC. Takahashi et al. (2010) followed to assess the association of rs965513 with radiation associated papillary thyroid cancer (PTC) in a population of Belarusian patients with PTC and radiation exposure and age matched radiation exposed controls. They conducted a series of GWA studies, validation studies and meta-analyses and concluded that rs965513 is associated with radiation associated PTC (meta-analysis of all study groups, cases:660, controls:1268; mhp=4.8 x 10-12, OR=1.65 (1.43-1.91)). Matuse et al. (2011) looked at the association of rs965513 with PTC using TaqMan SNP assays in a Japanese population with no radiation exposure. The study included 479 cases and 2764 controls. They again found a significant association OR=1.69 (1.29-2.21 at p=1.27 x 10-4). Wang et al. (2013) similarly assessed the association between rs965513 and PTC in a Chinese Han population with 846 cases and 1006 controls. A selection of SNPs were genotyped and the association between rs965513 and PTC was found to be OR=1.53 with a false discovery rate corrected p=1.827 x 10-4. A more recent study by Zhuang et al. (2014) conducted a meta-analysis study with a total of 8,491 cases and 103,218 controls. This study pooled data from 13 case-control or family based studies. Consistent with the results of Gudmundsson et al., Zhuang et al. report an allelic OR of 1.74 (95% CI, 1,62-1.86) with p<10-5. Zhuang et al. stratified their analysis by ethnicity to assess the potential for population stratification. In Asian populations, the OR associated with [A] allele is only 1.42 (95% CI, 1.12-1.81, p=0.004) compared with an OR of 1.79 (95% CI, 1.69-1.91, p<10-5) in Caucasian population. Further studies need to be done to assess the risk associated with the rs965513 SNP in different ethnic populations. ==Proposed Mechanism== rs965513 is located in a linkage-disequilibrium block containing the XPA, FOXE1, C9orf156 and HEMGN genes. XPA is involved in excision repair, for example following adduct formation via the chemotherapeutic cisplatin. HEMGN is associated with erythroid development and regulation of proliferation and differentiation of hematopoietic cells. The function of C9orf156 is not clearly defined. Though it is possible that a mutation in XPA that impairs excision repair could potentially predispose an individual to developing DTC following DNA damage, FOXE1 seems the most likely to be associated with the development of thyroid cancer given its known role in thyroid development. FOXE1 (TTF-2, FKHL15) is a thyroid specific forkhead transcription factor critical to thyroid gland differentiation and morphogenesis during development, and maintenance of differentiated state during adulthood. FOXE1 interacts with nucleosomes through its DNA binding domain and alters the chromatin structure to expose sites for other transcription factors. Mutations in the FOXE1 gene or changes in the expression pattern may lead to a loss of the stable differentiated state. Expression of FOXE1 has been shown to be abnormal in DTC . Gudmundsson et al.(2009) investigate the association between rs965513[A] and thyroid function by looking at values of thyroid stimulating hormone (TSH), T3 and T4. Each rs965513 [A] was associated with a 5.9% decrease in TSH (p=2.9 x 10-4), a 1.2% increase in T3 (p=3 x 10-3), and a 1.2% decrease in T4 (p=6.1 x 10-5). These result indicate that the rs965513[A] affects thyroid function. Given the proximity of rs965513 to FOXE1, FOXE1&#8217;s known role in thyroid development and function, rs965513 association with the disturbance of normal thyroid and DTC, it seems likely that some rs965513 tags some sort of disruption of normal FOXE1 function. When combined with another risk factor like radiation exposure, a dysfunctional FOXE1 may facilitate progression in to the malignant state. Notably Landa et al. (2009) identified rs1867277 as a causal SNP in the FOXE1 5&#8217;UTR region. RS1867277 is associated with increased recruitment of the USF1/USF2 transcription factors leading to increased transcription of FOXE1. However, Matsuse et al. (2011) determined that evidence for linkage-disequilibrium between rs1867277 and rs965513 is poor (D&#8217;=0.23) and concluded that the two SNPs likely have different functional significance. Published 2015: "Multiple functional variants in long-range enhancer elements contribute to the risk of SNP rs965513 in thyroid cancer." "The [A] allele of SNP rs965513 in 9q22 has been consistently shown to be highly associated with increased papillary thyroid cancer (PTC) risk with an odds ratio of ∼1.8 as determined by genome-wide association studies, yet the molecular mechanisms remain poorly understood." ... "Our results suggest that multiple variants coinherited with the lead SNP and located in long-range enhancers are involved in the transcriptional regulation of FOXE1 and PTCSC2 expression. These results explain the mechanism by which the risk allele of rs965513 predisposes to thyroid cancer." (Abstract) ==Additional References== A genoset, Gs137, has also been created in SNPedia to represent the increased risk reported for carriers of both variants. See also: 23andMe blog