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From SNPedia

Geno Mag Summary
(A;A) 2 3.1x increased thyroid cancer risk
(A;G) 2 1.77x increased thyroid cancer risk
(G;G) 0.1 normal
ReferenceGRCh38 38.1/141
is asnp
is mentioned by
dbSNP (classic)rs965513
1000 genomesrs965513
GWAS Ctlgrs965513
Max Magnitude2
? (A;A) (A;G) (G;G) 28

GWAS snp
PMID [PMID 23894154]
Trait Thyroid cancer
Title Genome-wide association study on differentiated thyroid cancer.
Risk Allele A
P-val 3E-10
Odds Ratio 1.78 [NR]

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[edit]

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[edit]

In a case-control GWAS, Gudmundsson et al. (2009) [PMID 19198613OA-icon.png] identified two SNPs—rs965513 and rs944289—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) [PMID 20350937] 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) [PMID 21730105] 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) [PMID 24744143] 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[edit]

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 [PMID 11762722].

Gudmundsson et al.(2009) [PMID 19198613OA-icon.png] 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’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) [PMID 19730683OA-icon.png] identified rs1867277 as a causal SNP in the FOXE1 5’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) [PMID 21730105] determined that evidence for linkage-disequilibrium between rs1867277 and rs965513 is poor (D’=0.23) and concluded that the two SNPs likely have different functional significance.

[PMID 25918370OA-icon.png] 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[edit]

A genoset, Gs137, has also been created in SNPedia to represent the increased risk reported for carriers of both variants.

See also: 23andMe blog

[PMID 20350937] The FOXE1 locus is a major genetic determinant for radiation-related thyroid carcinoma in Chernobyl

[PMID 21730105] The FOXE1 and NKX2-1 loci are associated with susceptibility to papillary thyroid carcinoma in the Japanese population

[PMID 22282540OA-icon.png] Thyroid cancer susceptibility polymorphisms: confirmation of loci on chromosomes 9q22 and 14q13, validation of a recessive 8q24 locus and failure to replicate a locus on 5q24

[PMID 22586128OA-icon.png] The polymorphism rs944289 predisposes to papillary thyroid carcinoma through a large intergenic noncoding RNA gene of tumor suppressor type

[PMID 22267200OA-icon.png] Discovery of common variants associated with low TSH levels and thyroid cancer risk.

[PMID 19730683OA-icon.png] The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors.

[PMID 20628519OA-icon.png] Genetic Predisposition to Familial Nonmedullary Thyroid Cancer: An Update of Molecular Findings and State-of-the-Art Studies.

[PMID 22493691OA-icon.png] Novel associations for hypothyroidism include known autoimmune risk loci.

[PMID 23659773OA-icon.png] Cumulative Risk Impact of Five Genetic Variants Associated With Papillary Thyroid Carcinoma

[PMID 23847140] Confirmation of papillary thyroid cancer susceptibility loci identified by genome-wide association studies of chromosomes 14q13, 9q22, 2q35 and 8p12 in a Chinese population

[PMID 24325646OA-icon.png] FOXE1 association with differentiated thyroid cancer and its progression

[PMID 24591304OA-icon.png] Significant SNPs have limited prediction ability for thyroid cancer

[PMID 22882326] FOXE1 polymorphisms are associated with familial and sporadic nonmedullary thyroid cancer susceptibility.

[PMID 23327367OA-icon.png] Patterns of FOXE1 expression in papillary thyroid carcinoma by immunohistochemistry.

[PMID 23344678OA-icon.png] Genetic associations with neonatal thyroid-stimulating hormone levels.

[PMID 25849217OA-icon.png] Common Variants at 9q22.33, 14q13.3, and ATM Loci, and Risk of Differentiated Thyroid Cancer in the French Polynesian Population

[PMID 25879635OA-icon.png] Common variants at the 9q22.33, 14q13.3 and ATM loci, and risk of differentiated thyroid cancer in the Cuban population

[PMID 25746573] Clinical significance of papillary thyroid cancer risk loci identified by genome-wide association studies

[PMID 26490305] Association Between GWAS-derived rs966423 Genetic Variant and Overall Mortality in Patients with Differentiated Thyroid Cancer

[PMID 26843521] A comprehensive meta-analysis of case-control association studies to evaluate polymorphisms associated with the risk of differentiated thyroid carcinoma.

[PMID 27610545] Foxe1 Polymorphism Interacts with Dietary Iodine Intake in Differentiated Thyroid Cancer Risk in the Cuban Population.

[PMID 27824288] Genotype analyses in the Japanese and Belarusian populations reveal independent effects of rs965513 and rs1867277 but do not support the role of FOXE1 polyalanine tract length in conferring risk for papillary thyroid carcinoma.

[PMID 28660995] Age at diagnosis and gender modify the risk of 9q22 and 14q13 polymorphisms for papillary thyroid carcinoma.

[PMID 31681970] Clinical implications of GWAS variants associated with differentiated thyroid cancer.

[PMID 32104174OA-icon.png] Association of rs944289, rs965513, and rs1443434 in TITF1/TITF2 with Risks of Papillary Thyroid Carcinoma and with Nodular Goiter in Northern Chinese Han Populations.