Molecular characterization of metastatic exon 11 mutant gastrointestinal stromal tumors (GIST) beyond KIT/PDGFRα genotype evaluated by next generation sequencing (NGS)
| Autor: | Maria Abbondanza Pantaleo, Margherita Nannini, Giorgio Ercolani, Cristian Lolli, Donatella Santini, Valentina Indio, Milena Urbini, Antonio Daniele Pinna, Michelangelo Fiorentino, Maristella Saponara, Annalisa Astolfi, Massimo Del Gaudio, Guido Biasco, Anna Mandrioli, Maria Giulia Pirini, Giovanni Brandi, Lidia Gatto |
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| Přispěvatelé: | Saponara, Maristella, Urbini, Milena, Astolfi, Annalisa, Indio, Valentina, Ercolani, Giorgio, Del Gaudio, Massimo, Santini, Donatella, Pirini, Maria Giulia, Fiorentino, Michelangelo, Nannini, Margherita, Lolli, Cristian, Mandrioli, Anna, Gatto, Lidia, Brandi, Giovanni, Biasco, Guido, Pinna, Antonio Daniele, Pantaleo, Maria Abbondanza |
| Rok vydání: | 2015 |
| Předmět: |
Male
PTEN Receptor Platelet-Derived Growth Factor alpha DNA Copy Number Variations Genotype Gastrointestinal Stromal Tumors CCND2 CDKN2C DMD GIST NGS Copy number analysis Gene mutation Translocation Genetic NO CDKN2A Humans Genetic Predisposition to Disease Hedgehog Proteins Neoplasm Metastasis Cells Cultured Aged Base Sequence biology GiST Reverse Transcriptase Polymerase Chain Reaction Gene Expression Profiling High-Throughput Nucleotide Sequencing Exons Middle Aged Transplantation Proto-Oncogene Proteins c-kit Oncology Chromosomes Human Pair 1 Tumor progression Mutation biology.protein Cancer research Female Chromosomes Human Pair 4 Research Paper Signal Transduction |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Maristella Saponara 1,* , Milena Urbini 2,* , Annalisa Astolfi 2 , Valentina Indio 2 , Giorgio Ercolani 3 , Massimo Del Gaudio 3 , Donatella Santini 4 , Maria Giulia Pirini 4 , Michelangelo Fiorentino 5 , Margherita Nannini 1 , Cristian Lolli 1 , Anna Mandrioli 1 , Lidia Gatto 1 , Giovanni Brandi 1 , Guido Biasco 1,2 , Antonio Daniele Pinna 3 and Maria Abbondanza Pantaleo 1,2 1 Department of Specialized, Experimental, and Diagnostic Medicine, Sant’Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy 2 Interdepartmental Centre of Cancer Research “G. Prodi”, University of Bologna, Bologna, Italy 3 Department of General and Emergency Surgery and Organ Transplantation, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy 4 Pathology Unit, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy 5 Laboratory of Molecular Oncologic and Transplantation Pathology, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy * These authors have contributed equally to the work Correspondence to: Maria Abbondanza Pantaleo, email: // Keywords : GIST, CCND2, NGS, PTEN, CDKN2C, DMD Received : May 04, 2015 Accepted : October 05, 2015 Published : November 02, 2015 Abstract About 85% of GISTs are associated with KIT and PDGFRα gene mutations, which predict response to tyrosine kinase inhibitors. Although the outcomes in patients affected by GIST have dramatically improved, tumor progression control still remains a challenge. The aim of this study is the genomic characterization of individual metastatic KIT-exon 11-mutant GIST to identify additional aberrations and simultaneous molecular events representing potential therapeutic targets. Seven patients with metastatic GIST were studied with whole transcriptome sequencing and copy number analysis. Somatic single nucleotide variations were called; however, no shared mutated genes were detected except KIT. Almost all patients showed loss of genomic regions containing tumor suppressor genes, sometimes coupled with single nucleotide mutation of the other allele. Additionally, six fusion transcripts were found and three patients showed amplifications involving known oncogenes. Evaluating the concordance between CN status and mRNA expression levels, we detected overexpression of CCND2 and EGFR and silencing of CDKN2A, CDKN2C, SMARCB1, PTEN and DMD. Altered expression of these genes could be responsible for aberrant activation of signaling pathways that support tumor growth. In this work, we assessed the effect of Hedgehog pathway inhibition in GIST882 cells, which causes decrement of cell viability associated with reduction of KIT expression. Additional genomic alterations not previously reported in GIST were found even if not shared by all samples. This contributes to a more detailed molecular understanding of this disease, useful for identification of new targets and novel therapeutics and representing a possible point of departure for a truly individualized clinical approach. |
| Databáze: | OpenAIRE |
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