title: Novel genetic variants in differentiated thyroid cancer and assessment of the cumulative risk.
abstract: A genome-wide association study (GWAS) performed on a high-incidence Italian population followed by replications on low-incidence cohorts suggested a strong association of differentiated thyroid cancer (DTC) with single nucleotide polymorphisms (SNPs) at 9q22.33, 2q35, 20q11.22-q12 and 14q24.3. Moreover, six additional susceptibility loci were associated with the disease only among Italians. The present study had two aims, first to identify loci involved in DTC risk and then to assess the cumulative effect of the SNPs identified so far in the Italian population. The combined analysis of the previous GWAS and the present Italian study provided evidence of association with rs7935113 (GALNTL4, OR = 1.36, 95%CI 1.20-1.53, p-value = 7.41 × 10(-7)) and rs1203952 (FOXA2, OR = 1.29, 95%CI 1.16-1.44, p-value = 4.42 × 10(-6)). Experimental ENCODE and eQTL data suggested that both SNPs may influence the closest genes expression through a differential recruitment of transcription factors. The assessment of the cumulative risk of eleven SNPs showed that DTC risk increases with an increasing number of risk alleles (p-trend = 3.13 × 10(-47)). Nonetheless, only a small fraction (about 4% on the disease liability scale) of DTC is explained by these SNPs. These data are consistent with a polygenic model of DTC predisposition and highlight the importance of association studies in the discovery of the disease hereditability.
authors.affiliation: 1] Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany [2] Department of Biology, University of Pisa, Pisa, Italy.
authors.forename: Gisella
authors.initials: G
authors.lastname: Figlioli
authors.affiliation: Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Bowang
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Elisei
authors.affiliation: Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Romei
authors.affiliation: 1] Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany [2] Department of Biology, University of Pisa, Pisa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Campo
authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Cipollini
authors.affiliation: Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Cristaudo
authors.affiliation: Blood Centre, Azienda Ospedaliero Universitaria A. Meyer, Firenze, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Bambi
authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Paolicchi
authors.affiliation: 1] Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany [2] Institute of Human Genetics, University of Bonn, Bonn, Germany [3] Division of Medical Genetics, University Hospital Basel; Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Per
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: 1] Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany [2] Institute of Human Genetics, University of Bonn, Bonn, Germany [3] Division of Medical Genetics, University Hospital Basel; Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Herms
authors.affiliation: Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland.
authors.forename: Michał
authors.initials: M
authors.lastname: Kalemba
authors.affiliation: Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Kula
authors.affiliation: 1] Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Cerdanyola del Vallés, Barcelona, Spain [2] CIBER Epidemiologia y Salud Pública, ISCIII, Madrid, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Pastor
authors.affiliation: 1] Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Cerdanyola del Vallés, Barcelona, Spain [2] CIBER Epidemiologia y Salud Pública, ISCIII, Madrid, Spain.
authors.forename: Ricard
authors.initials: R
authors.lastname: Marcos
authors.affiliation: 1] Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Cerdanyola del Vallés, Barcelona, Spain [2] CIBER Epidemiologia y Salud Pública, ISCIII, Madrid, Spain.
authors.forename: Antonia
authors.initials: A
authors.lastname: Velázquez
authors.affiliation: Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Jarząb
authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Landi
authors.affiliation: 1] Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany [2] Center for Primary Health Care Research, Clinical Research Center, Lund University, Malmö, Sweden.
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Gemignani
authors.affiliation: 1] Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany [2] Center for Primary Health Care Research, Clinical Research Center, Lund University, Malmö, Sweden.
authors.forename: Asta
authors.initials: A
authors.lastname: Försti
mesh_terms: D000483:Alleles; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D055106:Genome-Wide Association Study; D005838:Genotype; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics; D006801:Humans; D007558:Italy; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: C496502:FOXA2 protein, human; D051542:Hepatocyte Nuclear Factor 3-beta; D017350:N-Acetylgalactosaminyltransferases