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 7

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Classification of patients diagnosed with 4 different types of epithelia...
Classification of patients diagnosed with 4 different types of epithelial cancer into subgroups with distinct therapy outcome based on expression profile of the 11-gene MTTS/PNS signa-ture. Kaplan-Meier analysis of the probability that patients would remain metastasis-free (for the breast cancer group) or survive after therapy (for the other groups) among 97 early-stage breast cancer patients (A–D), 125 lung adenocarcinoma patients of all stages (E–G), 35 lung adenocarcinoma patients diagnosed with stage 1A disease (H), 37 ovarian cancer patients of all stages (I–K), and 31 bladder cancer patients (L–N), according to whe-ther they had a good-prognosis or a poor-prognosis signature as defined by the expression profiles of the 11-gene MTTS/PNS signature. For each type of cancer, the patient’s stratification cutoff value was defined in the training set, validated in a test set, and confirmed in an entire cohort. D and I–K show the Kaplan-Meier survival curves for 97 breast cancer patients and 37 ovarian cancer patients, respectively, stratified into distinct subgroups using a weighted survival predictor score algorithm.