• Cumulative risk
• Differentiated thyroid cancer
• Functional annotations
• Genetic variants/SNPs
• GWAS

Differentiated thyroid cancer (DTC) is an endocrine tumor arising from the follicular cells of the thyroid gland. Although it is relatively rare, it is the most common endocrine tumor, showing a relatively high incidence in Italy. There are few known DTC risk factors except for a previous benign thyroid disease, exposure to ionizing radiation and female gender. In addition, a significantly higher risk in first-degree relatives of DTC patients compared to the general population suggests that genetic variations may contribute to the risk of the disease. Genome-wide association studies (GWASs) on DTC identified robust associations with single nucleotide polymorphisms (SNPs) at 9q22.33 (FOXE1), 14q13.3 (NKX2-1) and 2q35 (DIRC3).
In order to identify additional DTC susceptibility loci, we conducted a novel GWAS on the Italian populations followed by the validation of the most significant SNPs in additional European cohorts.
A strong relationship of DTC predisposition was found with SNPs on 2q35 (DIRC3), 14q24.3 (BATF) and 2q11.22-q12 (DHX35) across different populations. Moreover, risk loci at 3q25.32 (RARRES1), 7q21 (IMMP2L), 9q34.3 (SNAPC4), 5q14 (ARSB), 13q12.12 (SPATA13), 11p15.3 (GALNTL4) and 20p11 (FOXA2) were associated with DTC only among Italians. The assessment of the cumulative risk of the eleven SNPs identified showed that DTC risk increases with an increasing number of risk alleles (p-trend=3.13×10-47), consistently with a polygenic model of DTC predisposition. However, only a small fraction (about 4% of the disease liability scale) of DTC is explained by these SNPs.
As the identified SNPs are located within non-coding genomic regions, computational approaches were employed to test whether they map within transcriptional regulatory regions and whether they may influence the nearest gene expression (cis-eQTL). According to the ENCODE Project data all the GWAS-identified loci (except 13q12.12) may have a regulatory function because they are located in particular genomic features, as histones modifications markers, DNase hypersensitive sites or transcription factor binding sites in several human cell lines. Moreover, we found that rs10781500 (7q21) and rs1203952 (20p11) are eQTL SNPs in thyroid tissues and rs7800391 (7q21), rs7267944 (2q11.22-q12) and rs7935113 (11p15.3) are eQTL SNPs in lymphoblastoid cells.
In conclusion, novel DTC risk alleles were identified and in silico analyses provided new insights into possible functional influence for these loci. The success of this project will lead to a better characterization of heritable risk of DTC and give precious insights into the etiological mechanisms of the disease.