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Relation of a Hypoxia Metagene Derived from Head and Neck Cancer to Prognosis of Multiple Cancers

¹ Cancer Research UK Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital; ² Gray Cancer Institute, University of Oxford; ³ Department of Cellular Pathology, John Radcliffe Hospital; ⁴ Department of Otorhinolaryngology, Head and Neck Surgery, Radcliffe Infirmary, Oxford, United Kingdom; ⁵ Academic Radiation Oncology, The University of Manchester and Department of Clinical Oncology, Christie Hospital NHS Trust; ⁶ Department of Head and Neck Surgery, Manchester Royal Infirmary; ⁷ Paterson Institute for Cancer Research; and ⁸ Department of Pathology, Dental Hospital, Manchester, United Kingdom

Requests for reprints: Adrian L. Harris, Cancer Research UK Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom. Phone: 44-1865-222-457; Fax: 44-1865-222-431; E-mail: aharris.lab{at}cancer.org.uk.

Affymetrix U133plus2 GeneChips were used to profile 59 head and neck squamous cell cancers. A hypoxia metagene was obtained by analysis of genes whose in vivo expression clustered with the expression of 10 well-known hypoxia-regulated genes (e.g., CA9, GLUT1, and VEGF). To minimize random aggregation, strongly correlated up-regulated genes appearing in >50% of clusters defined a signature comprising 99 genes, of which 27% were previously known to be hypoxia associated. The median RNA expression of the 99 genes in the signature was an independent prognostic factor for recurrence-free survival in a publicly available head and neck cancer data set, outdoing the original intrinsic classifier. In a published breast cancer series, the hypoxia signature was a significant prognostic factor for overall survival independent of clinicopathologic risk factors and a trained profile. The work highlights the validity and potential of using data from analysis of in vitro stress pathways for deriving a biological metagene/gene signature in vivo. [Cancer Res 2007;67(7):3441–9]

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