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Open Access Research article

Chromosome copy number changes carry prognostic information independent of KIT/PDGFRA point mutations in gastrointestinal stromal tumors

Mara Silva1, Isabel Veiga1, Franclim R Ribeiro1, Joana Vieira1, Carla Pinto1, Manuela Pinheiro1, Bárbara Mesquita1, Catarina Santos1, Marta Soares2, José Dinis2, Lúcio Santos3, Paula Lopes4, Mariana Afonso4, Carlos Lopes4 and Manuel R Teixeira15*

Author Affiliations

1 Department of Genetics, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal

2 Department of Oncology, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal

3 Department of Surgery, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal

4 Department of Pathology, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal

5 Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Largo Prof. Abel Salazar, 4099-003 Porto, Portugal

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BMC Medicine 2010, 8:26  doi:10.1186/1741-7015-8-26

Published: 14 May 2010

Abstract

Background

Oncogenic point mutations in KIT or PDGFRA are recognized as the primary events responsible for the pathogenesis of most gastrointestinal stromal tumors (GIST), but additional genomic alterations are frequent and presumably required for tumor progression. The relative contribution of such alterations for the biology and clinical behavior of GIST, however, remains elusive.

Methods

In the present study, somatic mutations in KIT and PDGFRA were evaluated by direct sequencing analysis in a consecutive series of 80 GIST patients. For a subset of 29 tumors, comparative genomic hybridization was additionally used to screen for chromosome copy number aberrations. Genotype and genomic findings were cross-tabulated and compared with available clinical and follow-up data.

Results

We report an overall mutation frequency of 87.5%, with 76.25% of the tumors showing alterations in KIT and 11.25% in PDGFRA. Secondary KIT mutations were additionally found in two of four samples obtained after imatinib treatment. Chromosomal imbalances were detected in 25 out of 29 tumors (86%), namely losses at 14q (88% of abnormal cases), 22q (44%), 1p (44%), and 15q (36%), and gains at 1q (16%) and 12q (20%). In addition to clinico-pathological high-risk groups, patients with KIT mutations, genomic complexity, genomic gains and deletions at either 1p or 22q showed a significantly shorter disease-free survival. Furthermore, genomic complexity was the best predictor of disease progression in multivariate analysis.

Conclusions

In addition to KIT/PDGFRA mutational status, our findings indicate that secondary chromosomal changes contribute significantly to tumor development and progression of GIST and that genomic complexity carries independent prognostic value that complements clinico-pathological and genotype information.