title: Fine-mapping of two differentiated thyroid carcinoma susceptibility loci at 9q22.33 and 14q13.3 detects novel candidate functional SNPs in Europeans from metropolitan France and Melanesians from New Caledonia.
abstract: Incidence of differentiated thyroid carcinoma varies considerably between countries and ethnic groups, with particularly high incidence rates in Melanesians of New Caledonia. Differentiated thyroid cancer (DTC) has a familial relative risk higher than other cancers, highlighting the contribution of inherited factors to the disease. Recently, genome-wide association studies (GWAS) identified several DTC susceptibility loci. The most robust associations were reported at loci 9q22 (rs965513 and rs1867277) and 14q13 (rs944289 and rs116909734). In this study, we performed a fine-mapping study of the two gene regions among Europeans and Melanesians from Metropolitan France and New Caledonia. We examined 81 single nucleotide polymorphisms (SNPs) at 9q22 and 561 SNPs at 14q13 in Europeans (625 cases/776 controls) and in Melanesians (244 cases/189 controls). The association with the four SNPs previously identified in GWAS was replicated in Europeans while only rs944289 was replicated in Melanesians. Among Europeans, we found that the two SNPs previously reported at 9q22 were not independently associated to DTC and that rs965513 was the predominant signal; at 14q13, we showed that the haplotype rs944289[C]-rs116909374[C]-rs999460[T] was significantly associated with DTC risk and that the association with rs116909374 differed by smoking status (p-interaction = 0.03). Among Melanesians, a new independent signal was observed at 14q13 for rs1755774 which is strongly correlated to rs2787423; this latter is potentially a functional variant. Significant interactions with parity (p < 0.05) and body mass index were observed for rs1755774 and rs2787423. This study contributed to a better characterization of the DTC loci 9q22 and 14q13 in Europeans and in Melanesians and has identified novel variants to be prioritized for further functional studies.
authors.affiliation: CESP, INSERM, Université Paris-Sud, Université Paris-Saclay, Villejuif, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Tcheandjieu
authors.affiliation: Inserm, U900, Paris, France.|Institut Curie, Paris, France.|PSL Research University, Paris, France.|Mines ParisTech, Fontainebleau, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Lesueur
authors.affiliation: CESP, INSERM, Université Paris-Sud, Université Paris-Saclay, Villejuif, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Sanchez
authors.affiliation: Laboratory of Anatomy and Cytopathology, Noumea, New Caledonia, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Baron-Dubourdieu
authors.affiliation: Registre Général des tumeurs du Calvados, Centre François Baclesse, Caen, France.|U1086 Inserm-UCNB, Cancers and Prevention, Caen, France.
authors.forename: Anne-Valerie
authors.initials: AV
authors.lastname: Guizard
authors.affiliation: Université Paris Descartes, Inserm UMR 5775 EPIGENETEC, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Mulot
authors.affiliation: Université Paris Descartes, Inserm UMR 5775 EPIGENETEC, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig
authors.affiliation: Centre de Lutte Contre le Cancer Jean GODINOT, Reims, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Schvartz
authors.affiliation: CESP, INSERM, Université Paris-Sud, Université Paris-Saclay, Villejuif, France.
authors.forename: Therese
authors.initials: T
authors.lastname: Truong
authors.affiliation: CESP, INSERM, Université Paris-Sud, Université Paris-Saclay, Villejuif, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Guenel
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002883:Chromosomes, Human, Pair 14; D002899:Chromosomes, Human, Pair 9; D019295:Computational Biology / Q000379:methods; D005260:Female; D005602:France; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008542:Melanesia; D008875:Middle Aged; D009510:New Caledonia; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011159:Population Surveillance; D040641:Quantitative Trait Loci; D012307:Risk Factors; D013964:Thyroid Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*
keywords: cancer genetics; case-control study; fine-mapping study; thyroid cancer