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

BMC Medicine

Research Article

Carla Pinto¹  Isabel Veiga¹  Manuela Pinheiro¹  Mara Silva¹  Joana Vieira¹  Bárbara Mesquita¹  Franclim R Ribeiro¹  Catarina Santos¹  Manuel R Teixeira²  José Dinis³  Marta Soares³  Carlos Lopes⁴  Paula Lopes⁴  Mariana Afonso⁴  Lúcio Santos⁵ 

[1] Department of Genetics, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino Almeida, 4200-072, Porto, Portugal;Department of Genetics, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino Almeida, 4200-072, Porto, Portugal;Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Largo Prof. Abel Salazar, 4099-003, Porto, Portugal;Department of Oncology, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino Almeida, 4200-072, Porto, Portugal;Department of Pathology, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino Almeida, 4200-072, Porto, Portugal;Department of Surgery, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino Almeida, 4200-072, Porto, Portugal;

关键词: Imatinib;    Comparative Genomic Hybridization;    Gastrointestinal Stromal Tumor;    Copy Number Change;    Genomic Complexity;   

DOI  :  10.1186/1741-7015-8-26

 received in 2010-04-21, accepted in 2010-05-14,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundOncogenic 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.MethodsIn 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.ResultsWe 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.ConclusionsIn 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.

【 授权许可】

Unknown   
© Silva et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.