Robust prognostic value of a knowledge-based proliferation signature across large patient microarray studies spanning different cancer types

Abstract

Tumour proliferation is one of the main biological phenotypes limiting cure in oncology. Extensive research is being performed to unravel the key players in this process. To exploit the potential of published gene expression data, creation of a signature for proliferation can provide valuable information on tumour status, prognosis and prediction. This will help individualising treatment and should result in better tumour control, and more rapid and cost-effective research and development. From in vitro published microarray studies, two proliferation signatures were compiled. The prognostic value of these signatures was tested in five large clinical microarray data sets. More than 1000 patients with breast, renal or lung cancer were included. One of the signatures (110 genes) had significant prognostic value in all data sets. Stratifying patients in groups resulted in a clear difference in survival (P-values o0.05). Multivariate Cox-regression analyses showed that this signature added substantial value to the clinical factors used for prognosis. Further patient stratification was compared to patient stratification with several well-known published signatures. Contingency tables and Cramer's V statistics indicated that these primarily identify the same patients as the proliferation signature does. The proliferation signature is a strong prognostic factor, with the potential to be converted into a predictive test. Furthermore, evidence is provided that supports the idea that many published signatures track the same biological processes and that proliferation is one of them.

Pretreatment microRNA Expression Impacting on Epithelial-to-Mesenchymal Transition Predicts Intrinsic Radiosensitivity in Head and Neck Cancer Cell Lines and Patients

“…We further tested the correlation between radiosensitivity and processes known to influence radiotherapy response in the 32 cell lines, by using published gene sets for reactive oxygen species (31), hypoxia (32,33), proliferation (34), stem cells (single marker CD44 and the set from ref. 35), p53 (constructed ourselves, Supplementary Table S5), DNA repair (constructed ourselves, Supplementary Table S5), and intrinsic radiosensitivity (8,9).…”

A Comprehensive Analysis of Human Gene Expression Profiles Identifies Stromal Immunoglobulin κ C as a Compatible Prognostic Marker in Human Solid Tumors

“…Mainly proliferation-related signatures have been shown to be transferable (29). Likewise the immunohistochemical analysis of the proliferation marker Ki-67 is of clinical importance in a variety of cancer entities.…”

CD44 Expression Predicts Local Recurrence after Radiotherapy in Larynx Cancer

“…For each of these processes, individual markers (mainly immunohistochemical) have been investigated and found to be of predictive value (10)(11)(12), although none have been sufficiently validated or are in routine use. Since many genes are involved in each process, in addition to single markers representing these processes, sets of markers (gene sets) for hypoxia (13,14), intrinsic radiosensitivity (15)(16)(17) and repopulation (18) have also been defined. Another factor more recently hypothesized to play a role in response to therapy is the number of stem cells, ultimately determining repopulation of the tumor (19,20) and so eradication of this subpopulation is of prime importance.…”