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

Mara Silva,Paula Lopes,Carla Pinto,José Dinis,Isabel Veiga,Manuela Pinheiro,Lúcio Santos,Bárbara Mesquita,Catarina Santos,Carlos Lopes,Franclim R Ribeiro,Marta Soares,Manuel R Teixeira,Mariana Afonso,Joana Vieira

doi:10.1186/1741-7015-8-26

Abstract

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.

Highlights

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
Clinicopathologic characteristics of the patients A total of 80 patients diagnosed with GIST were enrolled in this study
Taken together, our findings suggest that secondary chromosome changes have independent prognostic value in GIST

Summary

Introduction

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. As conventional cytogenetics and comparative genomic hybridization (CGH), have been applied in order to identify these changes Some chromosomal alterations, such as losses at 1p, 14q, and 22q, are frequent, suggesting the existence of tumor suppressor genes in these regions that could be important in tumor progression [7,8,9,10]. This cytogenetic fingerprint of GIST has been defined, the target genes involved in these regions remain undiscovered [11]. The relationship between the pattern of KIT and PDGFRA oncogenic mutations and that of cytogenetic changes has not been systematically studied, precluding a full understanding of the genetic pathways involved in GIST development

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