Subject
thyroid cancer, cancer genetics, case-control study, fine-mapping study, single nucleotide polymorphism, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system

Domains
Santé, Biologie, Sciences du vivant

Description

International audience Differentiated thyroid carcinoma (DTC) incidence is characterized by wide ethnic and geographic variations, with high incidence rates observed in Oceanian populations. Genome-wide association studies (GWAS) identified mainly four DTC susceptibility loci at 9q22.33, 14q13.3, 2q35 and 8p12. Here we performed fine-mapping of the 2q35 and 8p12 loci in the population of the EPITHYR consortium that includes Europeans, Melanesians and Polynesians to identify likely causal variants for DTC risk. We conducted a colocalization analysis using eQTLs data to determine the SNPs with the highest probability of causality. At 2q35, we highlighted rs16857609 located in DIRC3. This SNP has a high probability of causality in the three populations, and a significant association in Europeans (OR = 1.4, p = 1.9 x 10-10). It is also associated with expression of DIRC3 and of the nearby gene IGFBP5 in thyroid tumour cells. At 8p12, we identified rs7844425 which was significantly associated with DTC in Europeans (OR = 1.32, p = 7.6 x 10-8) and rs2439304, which was highlighted by the colocalization analysis but only moderately associated with DTC in our dataset (OR = 1.2, p = 0.001). These SNPs are linked to the expression of NRG1 in thyroid tissue. Hence, our study identified novel variants at 2q35 and 8p12 to be prioritized for further functional studies.

Keywords

Language
English (en-GB)

Creators
Guibon, Julie, Sugier, Pierre-Emmanuel, Kulkarni, Om, Karimi, Mojgan, Bacq-Daian, Delphine, Besse, Céline, Boland, Anne, Adjadj, Elisabeth, Rachédi, Frédérique, Rubino, Carole, Xhaard, Constance, Mulot, Claire, Laurent- Puig, Pierre, Guizard, Anne-Valérie, Schvartz, Claire, Ortiz, Rosa, , Ren, Yan, Ostroumova, Evgenia, Deleuze, Jean-François, Boutron-Ruault, Marie-Christine, Kesminiene, Ausrele, de Vathaire, Florent, Guénel, Pascal, Lesueur, Fabienne, Truong, Thérèse

Contributors
Institut Gustave Roussy (IGR), Université Paris-Saclay, Centre de recherche en épidémiologie et santé des populations (CESP) ; Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe ; Mines Paris - PSL (École nationale supérieure des mines de Paris) ; Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Recherche en Génomique Humaine (CNRGH) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Hôpital de Taaone, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC) ; Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P) ; Centre d'investigation clinique [Nancy] (CIC) ; Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT) ; Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Epigenetec ; Centre de Ressources Biologiques (CRB), Université Sorbonne Paris Cité (USPC), Université Paris Descartes - Paris 5 (UPD5), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC) ; Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE) ; Université de Caen Normandie (UNICAEN) ; Normandie Université (NU)-Normandie Université (NU)-CHU Caen ; Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC) ; Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Jean Godinot [Reims] ; UNICANCER, Institute of Oncology and Radiobiology, International Agency for Cancer Research (IACR), This work was supported by the Institut National du Cancer (Inca grant 9533), the Fondation ARC pour la Recherche sur le Cancer (ARC grant PGA120150202302), the Centre National de Recherche en Génomique Humaine, CEA, Electricité de France (conseil scientifique de Radioprotection d’EDF, grant EP 2019-01), Fondation de France (Grant 2016-70074) and Plan Cancer (Project ThyrGenRad, Grant ENV201415). The E3N cohort received support from the MGEN, Gustave Roussy and Ligue contre le cancer for its set up and maintenance. The E3N cohort was also supported by a state grant from the Agence Nationale pour la Recherche (ANR, grant number ANR-10-COHO-0006) within the Investissement d’Avenir program; and from Ministère de l’enseignement supérieur, de la recherche et de l’innovation (MESRI, grant number 2102 918823). JG was the recipient of a PhD fellowship from Région Ile-de-France., ANR-10-COHO-0006,E4N,Etude Epidémiologique des Enfants de femmes de l'Education Nationale(2010)

Sources
ISSN: 1949-2553, Oncotarget, https://hal.univ-lorraine.fr/hal-03378212, Oncotarget, 2021, 12 (5), pp.493-506. ⟨10.18632/oncotarget.27888⟩

Relation
info:eu-repo/semantics/altIdentifier/doi/10.18632/oncotarget.27888
info:eu-repo/semantics/altIdentifier/pmid/33747362

Coverage
Melanesia

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