Title: Mitotic checkpoints and chromosome instability are strong predictors of clinical outcome in gastrointestinal stromal tumors
Authors: Lagarde, Pauline ×
Perot, Gaelle
Kauffmann, Audrey
Brulard, Celine
Dapremont, Valerie
Hostein, Isabelle
Neuville, Agnes
Wozniak, Agnieszka
Sciot, Raf
Schöffski, Patrick
Aurias, Alain
Coindre, Jean Michel
Debiec-Rychter, Maria
Chibon, Frederic #
Issue Date: Feb-2012
Publisher: Association for Cancer Research
Series Title: Clinical Cancer Research vol:18 issue:3 pages:826-838
Abstract: PURPOSE: The importance of KIT and PDGFRA mutations in the oncogenesis of gastrointestinal stromal tumors (GISTs) is well established, but the genetic basis of GIST metastasis is poorly understood. We recently published a 67 genes-expression prognostic signature related to genome complexity (CINSARC for Complexity INdex in SARComas) and asked whether it could predict outcome in GISTs.Experimental design: We performed genome and expression profiling on 67 primary untreated GISTs. RESULTS: We show and validate here that it can predict metastasis in a new dataset of 67 primary untreated GISTs. The gene whose expression was most strongly associated with metastasis was AURKA, but the AURKA locus was not amplified. Instead, we identified deletion of the p16 (CDKN2A) and retinoblastoma (RB1) genes as likely causal events leading to increased AURKA and CINSARC gene expression, to chromosome rearrangement and ultimately to metastasis. Based on these findings we established a Genomic Index that integrates the number and type of DNA copy number alterations. This index is a strong prognostic factor in GISTs. We show that CINSARC class, AURKA expression and Genomic Index all outperform the AFIP grading system in determining the prognosis of patients with GISTs. Interestingly, these signatures can identify poor prognosis patients in the group classified as intermediate-risk by the AFIP classification.CONCLUSIONS: We propose that a high Genomic Index determined by Comparative Genomic Hybridisation (CGH) from formalin-fixed paraffin-embedded samples could be used to identify AFIP intermediate-risk patients who would benefit from imatinib therapy.
ISSN: 1078-0432
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Laboratory of Experimental Oncology
Translational Cell & Tissue Research
Laboratory for Genetics of Malignant Disorders
× corresponding author
# (joint) last author

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