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Novel genome-wide association study-based candidate loci for differentiated thyroid cancer risk
Gisella Figlioli1, Aleksandra Köhler, Bowang Chen
1Department of Biology (G.F., M.C., E.P., S.L., F.G.), University of Pisa, 56123 Pisa, Italy; Molecular Genetic Epidemiology (A.K., B.C., K.H., A.F.), German Cancer Research Center, 69120 Heidelberg, Germany; Department of Endocrinology and Metabolism (R.E., C.R., A.C.), University of Pisa, 56124 Pisa, Italy; Blood Centre (F.B.), Azienda Ospedaliero Universitaria A. Meyer, 50139 Firenze, Italy; Department of Genomics (P.H., S.H.), Life and Brain Center and Institute of Human Genetics (P.H., S.H.), University of Bonn, D-53127 Bonn, Germany; Division of Medical Genetics (P.H., S.H.), University Hospital Basel and Department of Biomedicine, University of Basel, CH-4058 Basel, Switzerland; Department of Nuclear Medicine and Endocrine Oncology (M.K., D.K., B.J.), Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, 44-101 Gliwice, Poland; Grup de Mutagènesi (S.P., R.M., A.V.), Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallés, Barcelona, Spain; Centro de Investigación Biomédica en Red y Epidemiologia y Salud Pública (S.P., R.M., A.V.), Instituto de Salud Carlos III, 28029 Madrid, Spain; and Center for Primary Health Care Research (K.H., A.F.), Clinical Research Center, Lund University, 205 02 Malmö, Sweden.
Context:
Genome-wide association studies (GWASs) on differentiated thyroid cancer (DTC) have identified robust associations with single nucleotide polymorphisms (SNPs) at 9q22.33 (FOXE1), 14q13.3 (NKX2-1), and 2q35 (DIRC3). Our recently published GWAS suggested additional susceptibility loci specific for the high-incidence Italian population.
Objective:
The purpose of this study was to identify novel Italian-specific DTC risk variants based on our GWAS and to test them further in low-incidence populations.
Design:
We investigated 45 SNPs selected from our GWAS first in an Italian population. SNPs that showed suggestive evidence of association were investigated in the Polish and Spanish cohorts.
Results:
The combined analysis of the GWAS and the Italian replication study (2260 case patients and 2218 control subjects) provided strong evidence of association with rs10136427 near BATF (odds ratio [OR] =1.40, P = 4.35 × 10(-7)) and rs7267944 near DHX35 (OR = 1.39, P = 2.13 × 10(-8)). A possible role in DTC susceptibility in the Italian populations was also found for rs13184587 (ARSB) (P = 8.54 × 10(-6)) and rs1220597 (SPATA13) (P = 3.25 × 10(-6)). Only the associations between rs10136427 and rs7267944 and DTC risk were replicated in the Polish and the Spanish populations with little evidence of population heterogeneity (GWAS and all replications combined, OR = 1.30, P = 9.30 × 10(-7) and OR = 1.32, P = 1.34 × 10(-8), respectively). In silico analyses provided new insights into the possible functional consequences of the SNPs that showed the strongest association with DTC.
Conclusions:
Our findings provide evidence for novel DTC susceptibility variants. Further studies are warranted to identify the specific genetic variants responsible for the observed associations and to functionally validate our in silico predictions.
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