BACKGROUND AND PURPOSE: Recent data suggest that in vitro and in vivo derived hypoxia gene-expression signatures have prognostic power in breast and possibly other cancers. However, both tumour hypoxia and the biological adaptation to this stress are highly dynamic. Assessment of time-dependent gene-expression changes in response to hypoxia may thus provide additional biological insights and assist in predicting the impact of hypoxia on patient prognosis. MATERIALS AND METHODS: Transcriptome profiling was performed for three cell lines derived from diverse tumour-types after hypoxic exposure at eight time-points, which include a normoxic time-point. Time-dependent sets of co-regulated genes were identified from these data. Subsequently, gene ontology (GO) and pathway analyses were performed. The prognostic power of these novel signatures was assessed in parallel with previous in vitro and in vivo derived hypoxia signatures in a large breast cancer microarray meta-dataset (n=2312). RESULTS: We identified seven recurrent temporal and two general hypoxia signatures. GO and pathway analyses revealed regulation of both common and unique underlying biological processes within these signatures. None of the new or previously published in vitro signatures consisting of hypoxia-induced genes were prognostic in the large breast cancer dataset. In contrast, signatures of repressed genes, as well as the in vivo derived signatures of hypoxia-induced genes showed clear prognostic power. CONCLUSIONS: Only a subset of hypoxia-induced genes in vitro demonstrates prognostic value when evaluated in a large clinical dataset. Despite clear evidence of temporal patterns of gene-expression in vitro, the subset of prognostic hypoxia regulated genes cannot be identified based on temporal pattern alone. In vivo derived signatures appear to identify the prognostic hypoxia induced genes. The prognostic value of hypoxia-repressed genes is likely a surrogate for the known importance of proliferation in breast cancer outcome.
BACKGROUND AND PURPOSE: Recent data suggest that in vitro and in vivo derived hypoxia gene-expression signatures have prognostic power in breast and possibly other cancers. However, both tumour hypoxia and the biological adaptation to this stress are highly dynamic. Assessment of time-dependent gene-expression changes in response to hypoxia may thus provide additional biological insights and assist in predicting the impact of hypoxia on patient prognosis. MATERIALS AND METHODS: Transcriptome profiling was performed for three cell lines derived from diverse tumour-types after hypoxic exposure at eight time-points, which include a normoxic time-point. Time-dependent sets of co-regulated genes were identified from these data. Subsequently, gene ontology (GO) and pathway analyses were performed. The prognostic power of these novel signatures was assessed in parallel with previous in vitro and in vivo derived hypoxia signatures in a large breast cancer microarray meta-dataset (n=2312). RESULTS: We identified seven recurrent temporal and two general hypoxia signatures. GO and pathway analyses revealed regulation of both common and unique underlying biological processes within these signatures. None of the new or previously published in vitro signatures consisting of hypoxia-induced genes were prognostic in the large breast cancer dataset. In contrast, signatures of repressed genes, as well as the in vivo derived signatures of hypoxia-induced genes showed clear prognostic power. CONCLUSIONS: Only a subset of hypoxia-induced genes in vitro demonstrates prognostic value when evaluated in a large clinical dataset. Despite clear evidence of temporal patterns of gene-expression in vitro, the subset of prognostic hypoxia regulated genes cannot be identified based on temporal pattern alone. In vivo derived signatures appear to identify the prognostic hypoxia induced genes. The prognostic value of hypoxia-repressed genes is likely a surrogate for the known importance of proliferation in breast cancer outcome.
Authors: Philippe Lambin; Ruud G P M van Stiphout; Maud H W Starmans; Emmanuel Rios-Velazquez; Georgi Nalbantov; Hugo J W L Aerts; Erik Roelofs; Wouter van Elmpt; Paul C Boutros; Pierluigi Granone; Vincenzo Valentini; Adrian C Begg; Dirk De Ruysscher; Andre Dekker Journal: Nat Rev Clin Oncol Date: 2012-11-20 Impact factor: 66.675
Authors: Luminita Moruz; Michael R Hoopmann; Magnus Rosenlund; Viktor Granholm; Robert L Moritz; Lukas Käll Journal: J Proteome Res Date: 2013-10-11 Impact factor: 4.466
Authors: Natalie S Fox; Maud H W Starmans; Syed Haider; Philippe Lambin; Paul C Boutros Journal: BMC Bioinformatics Date: 2014-06-06 Impact factor: 3.169
Authors: Twan van den Beucken; Elizabeth Koch; Kenneth Chu; Rajesha Rupaimoole; Peggy Prickaerts; Michiel Adriaens; Jan Willem Voncken; Adrian L Harris; Francesca M Buffa; Syed Haider; Maud H W Starmans; Cindy Q Yao; Mircea Ivan; Cristina Ivan; Chad V Pecot; Paul C Boutros; Anil K Sood; Marianne Koritzinsky; Bradly G Wouters Journal: Nat Commun Date: 2014-10-29 Impact factor: 14.919
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