Author:
Kulkarni Om,Sugier Pierre-Emmanuel,Guibon Julie,Boland-Augé Anne,Lonjou Christine,Bacq-Daian Delphine,Olaso Robert,Rubino Carole,Souchard Vincent,Rachedi Frédérique,Lence-Anta Juan Jesus,Ortiz Rosa Maria,Xhaard Constance,Laurent-Puig Pierre,Mulot Claire,Guizard Anne-Valérie,Schvartz Claire,Boutron-Ruault Marie-Christine,Ostroumova Evgenia,Kesminiene Ausrele,Deleuze Jean-François,Guénel Pascal,De Vathaire Florent,Truong Thérèse,Lesueur Fabienne
Abstract
AbstractVariants identified in earlier genome-wide association studies (GWAS) on differentiated thyroid carcinoma (DTC) explain about 10% of the overall estimated genetic contribution and could not provide complete insights into biological mechanisms involved in DTC susceptibility. Integrating systems biology information from model organisms, genome-wide expression data from tumor and matched normal tissue and GWAS data could help identifying DTC-associated genes, and pathways or functional networks in which they are involved. We performed data mining of GWAS data of the EPITHYR consortium (1551 cases and 1957 controls) using various pathways and protein–protein interaction (PPI) annotation databases and gene expression data from The Cancer Genome Atlas. We identified eight DTC-associated genes at known loci 2q35 (DIRC3), 8p12 (NRG1), 9q22 (FOXE1, TRMO, HEMGN, ANP32B, NANS) and 14q13 (MBIP). Using the EW_dmGWAS approach we found that gene networks related to glycogenolysis, glycogen metabolism, insulin metabolism and signal transduction pathways associated with muscle contraction were overrepresented with association signals (false discovery rate adjusted p-value < 0.05). Additionally, suggestive association of 21 KEGG and 75 REACTOME pathways with DTC indicate a link between DTC susceptibility and functions related to metabolism of cholesterol, amino sugar and nucleotide sugar metabolism, steroid biosynthesis, and downregulation of ERBB2 signaling pathways. Together, our results provide novel insights into biological mechanisms contributing to DTC risk.
Funder
Fondation ARC our la Recherche sur le Cancer
Electricité de France
Institut National du Cancer
Région Ile-de-France
Centre National de Recherche en Génomique Humaine, CEA
Publisher
Springer Science and Business Media LLC