Abstract
Predicting responsiveness to anticancer therapy based on molecular findings at diagnosis is important to optimize treatment decisions. Although clinical outcome correlates with distinct mutations in some cancer entities, treatment responses within these lesion-stratified subgroups still remain heterogeneous, underscoring the need for additional prognosticators. We previously demonstrated that defined genetic defects at the INK4a/ARF locus, which encodes the tumor suppressors p16INK4a and ARF, not only accelerated lymphomagenesis in the Eμ-myc transgenic mouse but also interfered with treatment sensitivity. In this study, we take a nonbiased genome-wide approach to examine whether the responsiveness of these lymphomas can be further stratified based on cytogenetic information at diagnosis. Indeed, using spectral karyotyping, comparative genomic hybridization, and fluorescence in situ hybridization in 38 primary lymphomas, we find recurrent cytogenetic alterations that refine the predictive value of INK4a/ARF lesions on drug responses in vivo: gain of chromosome 14, which was never detected in INK4a/ARFnull lymphomas, defined an ARFnull subgroup with superior treatment outcome. Gain of chromosome 6 was identified as a recurrent chromosomal aberration that predisposed ARFnull tumors to their subsequent INK4a loss during therapy. These data illustrate how cytogenetic information from cancer specimens might complement established prognostic markers and may improve anticancer treatment strategies.
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Acknowledgements
We thank A Harris (Walter and Eliza Hall Institute of Medical Research, Australia), M Serrano (Centro Nacional de Investigaciones Oncológicas, Spain), and CJ Sherr (St Jude Children's Research Hospital) for mice. This work was supported by research grants from the National Cancer Institute (CA87497) to SW Lowe, from the German Federal Ministry of Educations and Research (BioFuture Award) to A Helmrich and E Schrock, and from the Deutsche Forschungsgemeinschaft and Deutsche Krebshilfe to CA Schmitt. S Lee is a fellow of the German José Carreras Leukemia Foundation (reference number F02/03).
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Helmrich, A., Lee, S., O'Brien, P. et al. Recurrent chromosomal aberrations in INK4a/ARF defective primary lymphomas predict drug responses in vivo. Oncogene 24, 4174–4182 (2005). https://doi.org/10.1038/sj.onc.1208600
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DOI: https://doi.org/10.1038/sj.onc.1208600