ABSTRACT: Papillary thyroid cancer (PTC) is reported to be highly heritable in epidemiological studies. Genome-wide association studies (GWAS) have uncovered several variants associated with PTC predisposition. It remains unknown whether these variants might contribute to better clinical stratification of PTC patients.In order to assess the usefulness of germline genetic analyses in the management of PTC patients, the genotypes of five variants (rs965513, rs944289, rs116909374, rs2439302, and rs966423) were determined in 1216 PTC patients and 1416 controls. Additionally, the expression of seven genes located close to GWAS variants (PTCSC3, MBIP, NKX2-1, FOXE1, DIRC3, PTCSC2, and NRG1) were measured in 73 PTC paired tumor/normal tissues, respectively. Next, the association was analyzed between the genotypes of the germline variants and the levels of gene expression with clinical/pathological features such as age, sex, TNM staging, multifocality status, extrathyroidal expansion, and MACIS score.The risk allele of rs965513 was associated with larger tumor size (p?=?0.025) and extrathyroidal expansion (odd ratio [OR]?=?1.29, p?=?0.045). The variant rs2439302 showed association with lymph node metastasis (OR?=?1.24, p?=?0.016), and multifocality status of the tumor (OR?=?1.24, p?=?0.012). The expression of MBIP was associated with T stage (p?=?0.010). MBIP and PTCSC3 displayed lower expression in PTC tissue in males than in females (p?=?0.025 and p?=?0.036, respectively). NKX2-1 displayed lower expression in patients with N1 stage (p?=?0.040).The studied germline risk alleles predisposing to PTC were associated with a more aggressive course of the disease reflected by larger tumor diameter, higher multifocality rate, and more advanced N stage at the time of diagnosis. These results show that germline variants not only predispose to PTC but also might impact its clinical course. However, these associations were only moderate, and further large multi-ethnic studies are required to evaluate the usefulness of these germline variants in the clinical stratification of PTC patients.
