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. 2016 Apr 19;7(16):21686-98.
doi: 10.18632/oncotarget.7774.

Gene modules associated with breast cancer distant metastasis-free survival in the PAM50 molecular subtypes

Rong Liu  1   2 , Wei Zhang  1   2 , Zhao-Qian Liu  1   2 , Hong-Hao Zhou  1   2
Affiliations

Gene modules associated with breast cancer distant metastasis-free survival in the PAM50 molecular subtypes

Rong Liu et al. Oncotarget. .

Abstract

To identify PAM50 subtype-specific associations between distant metastasis-free survival (DMFS) in breast cancer (BC) patients and gene modules describing potentially targetable oncogenic pathways, a comprehensive analysis evaluating the prognostic efficacy of published gene signatures in 2027 BC patients from 13 studies was conducted. We calculated 21 gene modules and computed hazard ratios (HRs) for DMFS for one-unit increases in module score, with and without adjustment for clinical characteristics. By comparing gene expression to survival outcomes, we derived four subtype-specific prognostic signatures for BC. Univariate and multivariate analyses showed that in the luminal A subgroup, E2F3, PTEN and GGI gene module scores were associated with clinical outcome. In the luminal B tumors, RAS was associated with DMFS and in the basal-like tumors, ER was associated with DMFS. Our defined gene modules predicted high-risk patients in multivariate analyses for the basal-like (HR: 2.19, p=2.5×10-4), luminal A (HR: 3.03, p=7.2×10-5), luminal B (HR: 3.00, p=2.4×10-10) and HER2+ (HR: 5.49, p=9.7×10-10) subgroups. We found that different modules are associated with DMFS in different BC subtypes. The results of this study could help to identify new therapeutic strategies for specific molecular subgroups of BC, and could enhance efforts to improve patient-specific therapy options.

Keywords: PAM50 subtype; breast cancer; distant metastasis-free survival; gene expression profiling.

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Conflict of interest statement

None of the authors has any conflict of interest regarding this study.

Figures

Figure 1
Figure 1. A heat map presents pair-wise correlations between different modules in the cohort with 2027 BC patients
The cells are colored on the basis of Pearson's correlation coefficient values, with green and red indicative of positive and negative correlations, respectively.
Figure 2
Figure 2. Hazard ratios for DMFS for one-unit increase in module score in a Cox regression model with the data set as stratum indicator for all patients
A. and the basal-like B. luminal A C. luminal B D. and HER2+ E. subtypes. Horizontal bars represent the 95% CIs, the dimension of the square in inverse proportion to the SE of HRs; Modules with significant association (FDR<0.05) are shown in orange. FDR, false discovery rate.
Figure 3
Figure 3. Hazard ratios for DMFS for one-unit increase of module score in a Cox regression model with the data set as stratum indicator for all patients after adjustment for clinical nodal status, histologic grade and treatment
A. basal-like subtype after adjustment for age and treatment B. luminal A subtype after adjustment for histologic grade C. and luminal B subtype after adjustment for clinical nodal status D. Horizontal bars represent the 95% CIs, the dimension of the square in inverse proportion to the SE of HRs; Modules with significant association (FDR<0.05) are shown in orange. FDR, false discovery rate.
Figure 4
Figure 4. Kaplan-Meier curves of significant module scores in the univariate analysis for the PAM50 molecular subgroups
Patients were grouped according to the median of the module score: basal subgroup A. luminal A subgroup B. luminal B subgroup C. and HER2+ subgroup D. P-values were obtained from the log-rank test.
Figure 5
Figure 5. Study flow chart
DMFS, distant metastasis free survival.
See this image and copyright information in PMC

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