Analysis of molecular intra-patient variation and delineation of a prognostic 12-gene signature in non-muscle invasive bladder cancer; technology transfer from microarrays to PCR

L Dyrskjot, T Reinert, A Novoradovsky, Tahlita Zuiverloon, Willemien Beukers, Ellen Zwarthoff, N Malats, FX Real, U Segersten, PU Malmstrom, M Knowles, C Hurst, J Sorge, M Borre, TF Orntoft

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Abstract

BACKGROUND: Multiple clinical risk factors and genetic profiles have been demonstrated to predict progression of non-muscle invasive bladder cancer; however, no easily clinical applicable gene signature has been developed to predict disease progression independent of disease stage and grade. METHODS: We measured the intra-patient variation of an 88-gene progression signature using 39 metachronous tumours from 17 patients. For delineation of the optimal quantitative reverse transcriptase PCR panel of markers, we used 115 tumour samples from patients in Denmark, Sweden, UK and Spain. RESULTS: Analysis of intra-patient variation of the molecular markers showed 71% similar classification results. A final panel of 12 genes was selected, showing significant correlation with outcome. In multivariate Cox regression analysis, we found that the 12-gene signature was an independent prognostic factor (hazard ratio = 7.4 (95% confidence interval: 3.4-15.9), P < 0.001) when adjusting for stage, grade and treatment. Independent validation of the 12-gene panel and the determined cut-off v CONCLUSION: Intra-patient marker variation in metachronous tumours is present. Therefore, to increase test sensitivity, it may be necessary to test several metachronous tumours from a patient's disease course. A PCR-based 12-gene signature significantly predicts disease progression in patients with non-muscle invasive bladder cancer. British Journal of Cancer (2012) 107, 1392-1398. doi:10.1038/bjc.2012.412 www.bjcancer.com Published online 13 September 2012 (C) 2012 Cancer Research UK
Original languageUndefined/Unknown
Pages (from-to)1392-1398
Number of pages7
JournalBritish Journal of Cancer
Volume107
Issue number8
DOIs
Publication statusPublished - 2012

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