Association between GWAS-Derived rs966423 Genetic Variant and Overall Mortality in Patients with Differentiated Thyroid Cancer

Abstract

Purpose: Five germline genetic variants (rs116909374, rs965513, rs944289, rs966423, and rs2439302) have been associated in genome-wide association studies (GWAS) with increased risk of differentiated thyroid cancer (DTC), but their role in mortality of patients has not been established. Also, no preoperative marker of the clinical outcome of thyroid cancer had yet been identified. The aim of the study was to investigate the relationship between the variants and overall mortality in patients with DTC.Experimental Design: Retrospective study of 1,836 patients (1,643 women, 193 men) with median age at diagnosis of 49 years and overall median follow-up time of 8.7 years after initial treatment at a single comprehensive cancer center between 1990 and 2013.Results: Among 5 variants, rs966423 was associated with increased mortality, which was 6.4% (33 of 518) versus 3.7% (47 of 1,259) in TT carriers versus CC/CT carriers (P ¼ 0.017). The HR of TT versus TC/CC carriers was 1.6 [95% confidence interval (CI), 1.02-2.49; P ¼ 0.038] after adjustment for age at diagnosis and sex. Importantly, the association of rs966423 with mortality remained valid when clinicopathologic risk factors were included in the model (HR, 1.89; 95% CI, 1.14-3.13; P ¼ 0.014). Higher rs966423-associated patient mortality of TT versus CC/CT carriers was also observed in interaction with angioinvasion (adjusted HR, 3.48; 95% CI, 1.67-7.22; P < 0.001), lymph node metastasis (adjusted HR, 3.47; 95% CI, 1.16-10.4; P ¼ 0.018), extrathyroidal invasion (adjusted HR, 2.07; 95% CI, 1.15-3.73; P ¼ 0.013).Conclusions: The presence of the rs966423-TT genotype was associated with a significant increase in overall mortality of patients with DTC. Contrary to BRAF mutation and other somatic changes, the status of germline rs966423 is known before the treatment and might be used in the management of mortality risk by means of modification of therapy.

Papillary Thyroid Carcinoma: Association Between Germline DNA Variant Markers and Clinical Parameters

“…Curiously, it was the non-risk allele [T] that conferred higher mortality. Moreover, the risk was only significant when comparing [TT] homozygotes with carriers of the combined [TC] and [CC] genotypes (43). While these findings are difficult to interpret in comparison with those of the present study, it may be tentatively concluded that they are consistent with germline variants having an impact on clinical variables.…”

Genome-wide association and expression quantitative trait loci studies identify multiple susceptibility loci for thyroid cancer

“…showed that the variant rs966423 on DIRC3 was associated with an increased PTC risk, which was confirmed by our present study ((additive model of logistic regression) P =0.0067, Supplementary Table 11). In a recent report, rs966423 was associated with increased mortality in DTC34. In this study, two SNPs were associated with DTC that were different SNPs from the previous report.…”

Fine mapping of 14q13 reveals novel variants associated with different histological subtypes of papillary thyroid carcinoma

“…The risk allele of rs368187 was associated with M0 stage in cPTC (Table ). This seems to be conflicting but it has been shown that risk alleles of GWAS variants might be associated with favorable clinical outcome …”