Research Papers:

Molecular characterization of metastatic exon 11 mutant gastrointestinal stromal tumors (GIST) beyond KIT/PDGFRα genotype evaluated by next generation sequencing (NGS)

Maristella Saponara _, Milena Urbini, Annalisa Astolfi, Valentina Indio, Giorgio Ercolani, Massimo Del Gaudio, Donatella Santini, Maria Giulia Pirini, Michelangelo Fiorentino, Margherita Nannini, Cristian Lolli, Anna Mandrioli, Lidia Gatto, Giovanni Brandi, Guido Biasco, Antonio Daniele Pinna and Maria Abbondanza Pantaleo

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Oncotarget. 2015; 6:42243-42257. https://doi.org/10.18632/oncotarget.6278

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Maristella Saponara1,*, Milena Urbini2,*, Annalisa Astolfi2, Valentina Indio2, Giorgio Ercolani3, Massimo Del Gaudio3, Donatella Santini4, Maria Giulia Pirini4, Michelangelo Fiorentino5, Margherita Nannini1, Cristian Lolli1, Anna Mandrioli1, Lidia Gatto1, Giovanni Brandi1, Guido Biasco1,2, Antonio Daniele Pinna3 and Maria Abbondanza Pantaleo1,2

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:


Received: May 04, 2015 Accepted: October 05, 2015 Published: November 02, 2015


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.

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