Abstract
BackgroundRobust transcriptional signatures in cancer can be identified by data similarity-driven meta-analysis of gene expression profiles. An unbiased data integration and interrogation strategy has not previously been available.Methods and FindingsWe implemented and performed a large meta-analysis of breast cancer gene expression profiles from 223 datasets containing 10,581 human breast cancer samples using a novel data similarity-based approach (iterative EXALT). Cancer gene expression signatures extracted from individual datasets were clustered by data similarity and consolidated into a meta-signature with a recurrent and concordant gene expression pattern. A retrospective survival analysis was performed to evaluate the predictive power of a novel meta-signature deduced from transcriptional profiling studies of human breast cancer. Validation cohorts consisting of 6,011 breast cancer patients from 21 different breast cancer datasets and 1,110 patients with other malignancies (lung and prostate cancer) were used to test the robustness of our findings. During the iterative EXALT analysis, 633 signatures were grouped by their data similarity and formed 121 signature clusters. From the 121 signature clusters, we identified a unique meta-signature (BRmet50) based on a cluster of 11 signatures sharing a phenotype related to highly aggressive breast cancer. In patients with breast cancer, there was a significant association between BRmet50 and disease outcome, and the prognostic power of BRmet50 was independent of common clinical and pathologic covariates. Furthermore, the prognostic value of BRmet50 was not specific to breast cancer, as it also predicted survival in prostate and lung cancers.ConclusionsWe have established and implemented a novel data similarity-driven meta-analysis strategy. Using this approach, we identified a transcriptional meta-signature (BRmet50) in breast cancer, and the prognostic performance of BRmet50 was robust and applicable across a wide range of cancer-patient populations.
Highlights
Breast cancer is the most common type of cancer in women and the second-leading cause of cancer death among women in the United States
We identified a transcriptional meta-signature (BRmet50) in breast cancer, and the prognostic performance of BRmet50 was robust and applicable across a wide range of cancer-patient populations
We identified a specific meta-signature consisting of 50 genes (BRmet50) that is robustly predictive of cancer prognosis in 6,011 breast cancer patients from 21 different breast cancer datasets as well as in other malignancies including lung and prostate cancer
Summary
Some signatures have utility as transcriptional biomarkers for classifying patients with significantly different survival outcomes in breast cancer [2,3]. Transcriptional profiling of primary breast cancer has been used previously to identify a 70-gene signature (marketed as MammaPrint but designated here as BRsig70) [3], a distinct 76-gene signature (BRsig76) [2], and others (Oncotype DX [4,5], TAMR13 [6], Genius [7], GGI [8], PAM50 [9] and PIK3CAGS278 [10]). Robust transcriptional signatures in cancer can be identified by data similarity-driven meta-analysis of gene expression profiles. An unbiased data integration and interrogation strategy has not previously been available
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