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.
Highlights
Thyroid cancer is the most common endocrinerelated cancer, highly heterogeneous in clinical and genetic aspects
Our study describes the identification in papillary thyroid carcinoma (PTC) of a novel gene fusion, new somatic mutations in established cancer driver genes and known mutations not described yet in PTC
Taking advantage of next-generation RNA-Seq, we found that BRAF- and RAS-mutated tumors have distinct gene expression profiles, and that RET/PTC samples resemble tumors with BRAFV600E mutation, in line with the very recent results of TCGA [8]
Summary
Thyroid cancer is the most common endocrinerelated cancer, highly heterogeneous in clinical and genetic aspects. Mutations in BRAF and RAS genes (HRAS, KRAS and NRAS) and genomic rearrangements involving. RET gene (RET/PTC) account for about 70% of PTC cases [3]. In a small percentage of cases (~5%), TRK oncogenes rearrangements have been observed [4]. Despite the presence of tumor-initiating genetic alterations, cancer results from the progressive accumulation of mutations in genes that confer growth advantage over surrounding cells [5]. Innovative sequencing technologies (NextGeneration Sequencing, NGS, 6) have revolutionized cancer research [7], improving our ability to investigate tumor mutations’ landscape. PTC genetic characterization www.impactjournals.com/oncotarget will improve clinicians’ ability to establish diagnosis and to predict prognosis and individual response to treatments. During the writing of the manuscript, a largescale study exploring single nucleotide variants (SNVs), gene expression and epigenetic features in PTC has been published [8]
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