New somatic mutations andWNK1-B4GALNT3gene fusion in papillary thyroid carcinoma

// Valerio Costa 1,* , Roberta Esposito 1,* , Carmela Ziviello 1 , Romina Sepe 2 , Larissa Valdemarin Bim 2 , Nunzio Antonio Cacciola 2 , Myriam Decaussin-Petrucci 3 , Pierlorenzo Pallante 2 , Alfredo Fusco 2,4 and Alfredo Ciccodicola 1,5 1 Institute of Genetics and Biophysics “Adriano Buzzati-Traverso”, CNR, Naples, Italy 2 Istituto per l’Endocrinologia e l’Oncologia Sperimentale (IEOS), Consiglio Nazionale delle Ricerche (CNR), c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche (DMMBM), Università degli Studi di Napoli “Federico II”, Naples, Italy 3 Department of Pathology, Lyon Sud Hospital Center, Hospices Civils de Lyon, Pierre-Bénite, Lyon, France 4 Instituto Nacional de Câncer - INCA, Praça da Cruz Vermelha, Rio de Janeiro, RJ, Brazil 5 Department of Science and Technology, University “Parthenope” of Naples, Italy * These authors contributed equally to this article Correspondence to: Alfredo Fusco, email: // Alfredo Ciccodicola, email: // Keywords : thyroid, papillary carcinomas, RNA-Sequencing, gene fusions, mutations Received : February 24, 2015 Accepted : February 25, 2015 Published : March 14, 2015 Abstract Papillary thyroid carcinoma (PTC) is the most frequent thyroid malignant neoplasia. Oncogene activation occurs in more than 70% of the cases. Indeed, about 40% of PTCs harbor mutations in BRAF gene, whereas RET rearrangements (RET/PTC oncogenes) are present in about 20% of cases. Finally, RAS mutations and TRK rearrangements account for about 5% each of these malignancies. We used RNA-Sequencing to identify fusion transcripts and mutations in cancer driver genes in a cohort of 18 PTC patients. Furthermore, we used targeted DNA sequencing to validate identified mutations. We extended the screening to 50 PTC patients and 30 healthy individuals. Using this approach we identified new missense mutations in CBL , NOTCH1 , PIK3R4 and SMARCA4 genes . We found somatic mutations in DICER1, MET and VHL genes, previously found mutated in other tumors, but not described in PTC. We identified a new chimeric transcript generated by the fusion of WNK1 and B4GALNT3 genes, correlated with B4GALNT3 overexpression. Our data confirmed PTC genetic heterogeneity, revealing that gene expression correlates more with the mutation pattern than with tumor staging. Overall, this study provides new data about mutational landscape of this neoplasia, suggesting potential pharmacological adjuvant therapies against Notch signaling and chromatin remodeling enzymes.