A comprehensive analysis of prognostic signatures reveals the high predictive capacity of the Proliferation, Immune response and RNA splicing modules in breast cancer

Department of Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Breast cancer research: BCR (Impact Factor: 5.49). 12/2008; 10(6):R93. DOI: 10.1186/bcr2192
Source: PubMed


Several gene expression signatures have been proposed and demonstrated to be predictive of outcome in breast cancer. In the present article we address the following issues: Do these signatures perform similarly? Are there (common) molecular processes reported by these signatures? Can better prognostic predictors be constructed based on these identified molecular processes?
We performed a comprehensive analysis of the performance of nine gene expression signatures on seven different breast cancer datasets. To better characterize the functional processes associated with these signatures, we enlarged each signature by including all probes with a significant correlation to at least one of the genes in the original signature. The enrichment of functional groups was assessed using four ontology databases.
The classification performance of the nine gene expression signatures is very similar in terms of assigning a sample to either a poor outcome group or a good outcome group. Nevertheless the concordance in classification at the sample level is low, with only 50% of the breast cancer samples classified in the same outcome group by all classifiers. The predictive accuracy decreases with the number of poor outcome assignments given to a sample. The best classification performance was obtained for the group of patients with only good outcome assignments. Enrichment analysis of the enlarged signatures revealed 11 functional modules with prognostic ability. The combination of the RNA-splicing and immune modules resulted in a classifier with high prognostic performance on an independent validation set.
The study revealed that the nine signatures perform similarly but exhibit a large degree of discordance in prognostic group assignment. Functional analyses indicate that proliferation is a common cellular process, but that other functional categories are also enriched and show independent prognostic ability. We provide new evidence of the potentially promising prognostic impact of immunity and RNA-splicing processes in breast cancer.

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Available from: Andrew E Teschendorff
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    • "Most studies evaluating various signatures [14-18] have been carried out on relatively small scales. Compatibility between the signatures and the targeted cohorts with respect to biological and pathological characteristics (Additional file 1: Table S1) is often ignored [16]. Use of validation sets not completely independent of the original training sets may have influenced the results leading to biased interpretation [14]. "
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    ABSTRACT: The aim was to assess and compare prognostic power of nine breast cancer gene signatures (Intrinsic, PAM50, 70-gene, 76-gene, Genomic-Grade-Index, 21-gene-Recurrence-Score, EndoPredict, Wound-Response and Hypoxia) in relation to ER status and follow-up time. A gene expression dataset from 947 breast tumors was used to evaluate the signatures for prediction of Distant Metastasis Free Survival (DMFS). A total of 912 patients had available DMFS status. The recently published METABRIC cohort was used as an additional validation set. Survival predictions were fairly concordant across most signatures. Prognostic power declined with follow-up time. During the first 5 years of followup, all signatures except for Hypoxia were predictive for DMFS in ER-positive disease, and 76-gene, Hypoxia and Wound-Response were prognostic in ER-negative disease. After 5 years, the signatures had little prognostic power. Gene signatures provide significant prognostic information beyond tumor size, node status and histological grade. Generally, these signatures performed better for ER-positive disease, indicating that risk within each ER stratum is driven by distinct underlying biology. Most of the signatures were strong risk predictors for DMFS during the first 5 years of follow-up. Combining gene signatures with histological grade or tumor size, could improve the prognostic power, perhaps also of long-term survival.
    Full-text · Article · Mar 2014 · BMC Cancer
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    • "Analyses of the prognostic information that lies in the 70-gene signature and other multigene signatures have shown that a large portion of the prognostic information lies in proliferation-related genes [42]. In fact, reanalyses of these signatures showed that the signature with proliferation-related genes had greater prognostic value than the original signature [43]–[45], and that the proliferation signature was correlated with the MAI (correlation coefficient, 0.968) [44]. One study showed that the non-proliferative genes had no prognostic power [43]. "
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    ABSTRACT: The overall survival rate is good for lymph-node-negative breast cancer patients, but they still suffer from serious over- and some undertreatments. Prognostic and predictive gene signatures for node-negative breast cancer have a high number of genes related to proliferation. The prognostic value of gene sets from commercial gene-expression assays were compared with proliferation markers. Illumina WG6 mRNA microarray analysis was used to examine 94 fresh-frozen tumour samples from node-negative breast cancer patients. The patients were divided into low- and high-risk groups for distant metastasis based on the MammaPrint-related genes, and into low-, intermediate- and high-risk groups based on the recurrence score algorithm with genes included in Oncotype DX. These data were then compared to proliferation status, as measured by the mitotic activity index, the expressions of phosphohistone H3 (PPH3), and Ki67. Kaplan-Meier survival analysis for distant-metastasis-free survival revealed that patients with weak and strong PPH3 expressions had 14-year survival rates of 87% (n = 45), and 65% (n = 49, p = 0.014), respectively. Analysis of the MammaPrint classification resulted in 14-year survival rates of 80% (n = 45) and 71% (n = 49, p = 0.287) for patients with low and high risks of recurrence, respectively. The Oncotype DX categorization yielded 14-year survival rates of 83% (n = 18), 79% (n = 42) and 68% (n = 34) for those in the low-, intermediate- and high-risk groups, respectively (p = 0.52). Supervised hierarchical cluster analysis for distant-metastasis-free survival in the subgroup of patients with strong PPH3 expression revealed that the genes involved in Notch signalling and cell adhesion were expressed at higher levels in those patients with distant metastasis. This pilot study indicates that proliferation has greater prognostic value than the expressions of either MammaPrint- or Oncotype-DX-related genes. Furthermore, in the subgroup of patients with high proliferation, Notch signalling pathway genes appear to be expressed at higher levels in patients who develop distant metastasis.
    Full-text · Article · Mar 2014 · PLoS ONE
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    • "Again, using microarray Alizadeh and coworkers identified new subtypes of diffuse large B-cell lymphoma (DLBCL) that correlated with long-term (8–10 year) patient survival [5]. In breast cancer, expression profiling has helped in the identification of ER (estrogen-receptor)-positive and ER-negative cancers as fundamentally distinct diseases at the molecular level [6, 7] as well as shown that prognosis of patients with ER-positive disease is largely determined by the expression of proliferation-related genes [8]. Based on the gene signatures identified from gene expression studies two diagnostic chips have been developed which are now used extensively to take clinical decisions in breast cancer; the FDA-approved MammaPrint assay (Agendia, The Netherlands) and Oncotype DX (Genomic Health, Redwood City, CA) [9, 10]. "
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