J Breast Cancer.  2018 Sep;21(3):277-287. 10.4048/jbc.2018.21.e39.

Long Noncoding RNA Signature and Disease Outcome in Estrogen Receptor-Positive Breast Cancer Patients Treated with Tamoxifen

Affiliations
  • 1Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. kwshen@medmail.com.cn

Abstract

PURPOSE
Recent data have shown that the expression levels of long noncoding RNAs (lncRNAs) are associated with tamoxifen sensitivity in estrogen receptor (ER)-positive breast cancer. Herein, we constructed an lncRNA-based model to predict disease outcomes of ER-positive breast cancer patients treated with tamoxifen.
METHODS
LncRNA expression information was acquired from Gene Expression Omnibus by re-mapping pre-existing microarrays of patients with ER-positive breast cancer treated with tamoxifen. The distant metastasis-free survival (DMFS) predictive signature was subsequently built based on a Cox proportional hazard regression model in discover cohort patients, which was further evaluated in another independent validation dataset.
RESULTS
Six lncRNAs were found to be associated with DMFS in the discover cohort, which were used to construct a tamoxifen efficacy-related lncRNA signature (TLS). There were 133 and 362 patients with TLS high- and low-risk signatures in the discover cohort. Both univariate and multivariate analysis demonstrated that TLS was associated with DMFS. TLS high-risk patients had worse outcomes than low-risk patients, with a hazard ratio of 4.04 (95% confidence interval, 2.83-5.77; p < 0.001). Both subgroup analysis and receiver operating characteristic analysis indicated that TLS performed better in lymph node-negative, luminal B, 21-gene recurrence score high-risk, and 70-gene prognosis signature high-risk patients. Moreover, in a comparison of the 21-gene recurrence score and 70-gene prognosis signature, TLS showed a similar area under receiver operating characteristic curve in all patients. Gene Set Enrichment Analysis indicated that TLS high-risk patients showed different gene expression patterns related to the cell cycle and nucleotide metabolism from those of low-risk patients.
CONCLUSION
This six-lncRNA signature was associated with disease outcome in ER-positive breast cancer patients treated with tamoxifen, which is comparable to previous messenger RNA signatures and requires further clinical evaluation.

Keyword

Breast neoplasms; Long noncoding RNA; Neoplasm metastasis; Prognosis; Tamoxifen

MeSH Terms

Breast Neoplasms*
Breast*
Cell Cycle
Cohort Studies
Dataset
Estrogens*
Gene Expression
Humans
Metabolism
Multivariate Analysis
Neoplasm Metastasis
Phenobarbital
Prognosis
Recurrence
RNA, Long Noncoding*
RNA, Messenger
ROC Curve
Tamoxifen*
Estrogens
Phenobarbital
RNA, Long Noncoding
RNA, Messenger
Tamoxifen

Figure

  • Figure 1 The diagram of the construction and validation of the tamoxifen efficacy-related long noncoding RNA (lncRNA) signature.ROC=receiver operating characteristic.

  • Figure 2 The six lncRNAs selected for the construction of the tamoxifen efficacy-related long noncoding RNA (lncRNA) signature. Six lncRNAs were identified with p-value less than 0.002 in the univariate Cox proportional hazards regression analysis of distant metastasis-free survival (DMFS) for the discover dataset. Each of them successfully divided patients in the discover dataset into high-risk and low-risk groups. (A) RP11-189B4.7, (B) RP11-59H7.3, (C) CTD-2090|13.1, (D) LINC01399, (E) RP11-119F7.5, and (F) RP11-193F5.1.HR=hazard ratio.

  • Figure 3 The prediction performance of the tamoxifen efficacy-related long noncoding RNA (lncRNA) signature (TLS) in the discover dataset after optimization. The TLS was optimized with best cutoff value. After that, the performance of TLS and expression profile of lncRNAs in TLS was analyzed in the discover dataset. (A) In the discover dataset, receiver operating characteristic (ROC) curve for the performance of TLS in distant metastasis-free survival (DMFS) was plotted with the corresponding area under the ROC curve (AUC) and the best cutoff for TLS score was determined. (B) The expression profile of the six lncRNAs in TLS, the risk score of TLS and patients' DMFS were integrated and then evaluated in the discover cohort. (C) Patients classified by TLS with optimized cutoff value were evaluated in Kaplan-Meier analysis in the discover dataset.HR=hazard ratio.

  • Figure 4 The evaluation of prediction capability of the tamoxifen efficacy-related long noncoding RNA (lncRNA) signature (TLS) in the validation dataset. (A) The expression profile of lncRNAs in TLS, the risk score of TLS and patients' distant metastasis-free survival (DMFS) were integrated and then evaluated in the validation cohort. (B) Patients classified by TLS with optimized cutoff value were evaluated in Kaplan-Meier analysis in the validation dataset.HR=hazard ratio.

  • Figure 5 The evaluation of prediction power of the tamoxifen efficacy-related long noncoding RNA signature (TLS) in different subgroups of all tamoxifen treated breast cancer patients. Survival analysis of distant metastasis-free survival (DMFS) was performed to assess the prediction power of TLS in all tamoxifen treated patients, lymph node-negative subgroup, lymph node-positive subgroup, luminal A subgroup, luminal B subgroup, 21-gene recurrence score low-risk subgroup, 21-gene recurrence score medium-risk subgroup, 21-gene recurrence score high-risk subgroup, 70-gene prognosis signature low-risk subgroup and 70-gene prognosis signature high-risk subgroup.HR=hazard ratio; CI=confidence interval.

  • Figure 6 The comparison of the predictive power among 21-gene recurrence score (Gene21), 70-gene prognosis signature (Gene70), the tamoxifen efficacy-related long noncoding RNA signature (TLS), the integrated model of Gene21 with TLS and the integrated model of Gene70 with TLS in different subgroups of all patients. The receiver operating characteristic (ROC) of Gene21, Gene70, TLS, the integrated model of Gene21 with TLS and the integrated model of Gene70 with TLS were plotted and corresponding area under the ROC curve (AUC) was calculated in total tamoxifen treated breast cancer patients (A), all lymph node-negative patients (B), all lymph node-positive patients (C), all luminal A patients (D), and all luminal B patients (E).


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