IDENTIFICATION AND FUNCTIONAL CHARACTERIZATION OF GERMLINE GENETIC VARIANTS PREDISPOSING TO DIFFERENTIATED THYROID CANCER RISK

Abstract

Differentiated thyroid cancer (DTC) is the most common endocrine tumor, showing a high incidence in Italy. A significant higher risk of this cancer is described in first-degree relatives of DTC patients compared to the general population suggesting that germline genetic variants may contribute to its development. Previous genome-wide association studies (GWASs) on DTC have identified robust associations with single nucleotide polymorphisms (SNPs) at chromosomes 2q35, 9q22.33 and 14q13.3. In order to identify additional DTC susceptibility loci, a novel GWAS on the Italian population was conducted. The GWAS was followed by validation studies, where the most interesting SNPs were replicated in a larger Italian population and other European cohorts. Previously observed association for 2q35 and 9q22.33 was confirmed. Moreover, a strong relationship of DTC risk was found with SNPs on 14q24.3 and 20q11.22-q12 across all populations and SNPs on 3q25.32, 5q14, 7q21, 9q34.3, 11p15, 13q12.12 and 20p11 only among Italians. According to ENCODE Project data, many of these SNPs are located in transcription regulatory regions and eQTL analyses showed that five of the associated SNPs may affect the expression levels of their closest genes in different human tissues, including thyroid. In conclusion, novel DTC risk alleles were identified and new insights into their possible functional role were discovered.