Microarray analysis identifies a death-from-cancer signature predicting therapy failure in patients with multiple types of cancer
Gennadi V. Glinsky, … , Olga Berezovska, Anna B. Glinskii
Gennadi V. Glinsky, … , Olga Berezovska, Anna B. Glinskii
Published June 1, 2005
Citation Information: J Clin Invest. 2005;115(6):1503-1521. https://doi.org/10.1172/JCI23412.
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Research Article Oncology

Microarray analysis identifies a death-from-cancer signature predicting therapy failure in patients with multiple types of cancer

Abstract

Activation in transformed cells of normal stem cells’ self-renewal pathways might contribute to the survival life cycle of cancer stem cells and promote tumor progression. The BMI-1 oncogene–driven gene expression pathway is essential for the self-renewal of hematopoietic and neural stem cells. We applied a mouse/human comparative translational genomics approach to identify an 11-gene signature that consistently displays a stem cell–resembling expression profile in distant metastatic lesions as revealed by the analysis of metastases and primary tumors from a transgenic mouse model of prostate cancer and cancer patients. To further validate these results, we examined the prognostic power of the 11-gene signature in several independent therapy-outcome sets of clinical samples obtained from 1,153 cancer patients diagnosed with 11 different types of cancer, including 5 epithelial malignancies (prostate, breast, lung, ovarian, and bladder cancers) and 5 nonepithelial malignancies (lymphoma, mesothelioma, medulloblastoma, glioma, and acute myeloid leukemia). Kaplan-Meier analysis demonstrated that a stem cell–like expression profile of the 11-gene signature in primary tumors is a consistent powerful predictor of a short interval to disease recurrence, distant metastasis, and death after therapy in cancer patients diagnosed with 11 distinct types of cancer. These data suggest the presence of a conserved BMI-1–driven pathway, which is similarly engaged in both normal stem cells and a highly malignant subset of human cancers diagnosed in a wide range of organs and uniformly exhibiting a marked propensity toward metastatic dissemination as well as a high probability of unfavorable therapy outcome.

Authors

Gennadi V. Glinsky, Olga Berezovska, Anna B. Glinskii

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Figure 2

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Distant metastatic lesions in the TRAMP transgenic mouse model of prosta...
Distant metastatic lesions in the TRAMP transgenic mouse model of prostate cancer exhibit stem cell–like expression signatures of the BMI-1 pathway. Transcripts differentially regulated in distant metastatic lesions of 6-month-old TRAMP mice (MTTS signature) were compared with the BMI-1–regulated genes in neural stem cells (3) in search of intersection of lists. (A) Expression profiles and the corresponding Pearson correlation coefficient for 199 genes (141 upregulated and 58 downregulated) comprising concordant differentially regulated sets of transcripts in metastatic TRAMP samples and PNS neurospheres are shown. Small gene expression signatures comprising transcripts with a high level of expression correlation in metastatic cancer cells and stem cells (the selection threshold for small signatures was arbitrarily set at Pearson correlation coefficients greater than 0.95) were selected from large concordant sets. The reduction in the signature transcript number was terminated when further elimination of a transcript did not increase the value of the Pearson correlation coefficient. Using this approach, a single candidate prognostic gene expression signature was selected for each binary intersection of the MTTS signature and parent stem cell signatures (Figure 3). Consecutive steps of selection from the 199-gene concordant set of a subset of 20 genes (A and B) and a small MTTS/PNS 11-gene signature (C and D) are shown. In D, r = 0.9897, P < 0.0001 between gene groups, and n = 11 per group. Complete lists of genes and corresponding concordant subsets are shown in Supplemental Table 2. See text, Figure 3, and Table 3 for details.