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Construction and validation of N6-methyladenosine long non-coding RNAs signature of prognostic value for early biochemical recurrence of prostate cancer

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Abstract

Purpose

Early biochemical recurrence (eBCR) indicated a high risk for potential recurrence and metastasis in prostate cancer. The N6-methyladenosine (m6A) methylation modification played an important role in prostate cancer progression. This study aimed to develop a m6A lncRNA signature to accurately predict eBCR in prostate cancer.

Methods

Pearson correlation analysis was first conducted to explore m6A lncRNAs and univariate Cox regression analysis was further performed to identify m6A lncRNAs of prognostic roles for predicting eBCR in prostate cancer. The m6A lncRNA signature was constructed by least absolute shrinkage and selection operator analysis (LASSO) in training cohort and further validated in test cohort. Furthermore, half maximal inhibitory concentration (IC50) values were utilized to explore potential effective drugs for high-risk group in this study.

Results

Five hundred and thirty-eighth m6A lncRNAs were searched out through Pearson correlation analysis and 25 out of 538 m6A lncRNAs were identified to pose prediction roles for eBCR in prostate cancers. An m6A lncRNA signature including 5 lncRNAs was successfully built in training cohort. The high-risk group derived from m6A lncRNA signature could efficiently predict eBCR occurrence in both training (p < 0.001) and test cohort (p = 0.002). ROC analysis also confirmed that lncRNA signature in this study posed more accurate prediction roles for eBCR occurrence when compared with PSA, TNM stages and Gleason scores. Drug sensitivity analysis further discovered that various drugs could be potentially utilized to treat high-risk samples in this study.

Conclusions

The m6A lncRNA signature in this study could be utilized to efficiently predict eBCR occurrence, various clinical characteristic and immune microenvironment for prostate cancer.

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Data availability

All public data analysed in this study were from database of TCGA (https://portal.gdc.cancer.gov/). All procedure in this study followed corresponding guidelines and relative policies of above public database.

Abbreviations

TCGA:

The cancer genome atlas

m6A:

N6-methyladenosine

lncRNA:

Long non-coding RNAs

PD-1:

Immune checkpoint programmed cell death 1

PD-L1:

Immune checkpoint programmed cell death 1 ligand

DEGs:

Differentially expressed genes

CTLA-4:

Cytotoxic T lymphocyte antigen 4

LASSO:

Least absolute shrinkage and selection operator analysis

ROC:

Receiver operating characteristic

GSVA:

Gene set variation analysis

eBCR:

Early biochemical recurrence

PSA:

Prostate-specific antigen

IC50:

The half maximal inhibitory concentration

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Funding

This work was not supported by external funders.

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Authors and Affiliations

  1. Department of Urology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, No. 1 DaHua Road, Dong Dan, Beijing, 100730, China

    Jingchao Liu, Wei Zhang, Jiawen Wang, Zhengtong Lv, Haoran Xia, Zhipeng Zhang, Yaoguang Zhang & Jianye Wang

  2. Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, 9 DongDan SANTIAO, Beijing, 100730, China

    Jingchao Liu, Wei Zhang, Jiawen Wang, Zhengtong Lv, Haoran Xia, Yaoguang Zhang & Jianye Wang

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  1. Jingchao Liu
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  2. Wei Zhang
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Contributions

JCL and JYW provied the conceptualization. WZ and JWW performed the methodology and formal analysis. HRX and ZTL prepared figures 1-7. JCL and ZPZ writed the original draft. YGZ edited the tables. All authors reviewed the manuscript.

Corresponding authors

Correspondence to Yaoguang Zhang or Jianye Wang.

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Supplementary Information

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Supplementary file1 The expression matrix of 23 m6A-related genes (TXT 122 KB)

Supplementary file2 The detailed expressions of m6A-related lncRNAs (TXT 2706 KB)

Supplementary file3 The lncRNAs expressions and clinical information of 473 prostate cancer samples (TXT 2358 KB)

Supplementary file4 Clustering results basing on 25 prognostic lncRNAs (TXT 7 KB)

Supplementary file5 Detailed clinical files for prostate samples (TXT 21 KB)

Supplementary file6 The referenced marker documents of various immune cells (TXT 143 KB)

Supplementary file7 Infiltrations of 22 immune cells in prostate cancer samples by CIBERSORT analysis (TXT 176 KB)

Supplementary file8 The detailed immune scores of prostate samples through ESTIMATE methods (TXT 40 KB)

Supplementary file9 The risk grouping information in training cohort (TXT 24 KB)

Supplementary file10 The risk grouping information in test cohort (TXT 24 KB)

432_2022_4040_MOESM11_ESM.jpg

Supplementary file11 Relationships between expressions of 25 prognostic lncRNAs and immune checkpoints. A–C Prognostic lncRNAs significantly correlated with PD1, PD-L1 and CTLA-4 in prostate cancers (JPG 2381 KB)

432_2022_4040_MOESM12_ESM.jpg

Supplementary file12 GSEA analysis. A–F Significantly enriched activities in GSEA analysis for cluster 2. (p < 0.01) G–L Significantly enriched activities in GSEA analysis for cluster 1. (p < 0.05) (JPG 2451 KB)

432_2022_4040_MOESM13_ESM.jpg

Supplementary file13 The lncRNA risk signature poses excellent predictive performance for eBCR-free survivals in various subgroups. A–B High risk group tended to obtain significantly poorer eBCR-free survivals in patients with both PSA ≥ 4 ng/ml and PSA < 4ng/ml. C–D High risk group tended to obtain significantly poorer eBCR-free survivals in patients with both Gleason score 6-7 and Gleason score 8–10 (JPG 871 KB)

432_2022_4040_MOESM14_ESM.jpg

Supplementary file14 Risk score significantly correlated with infiltrations of various immune cells. A–C The risk score positively correlated with infiltrations of activated memory CD4 T cells, resting memory CD4 T cells and M1 Macrophages. D–E Risk score negatively correlated with infiltrations of resting mast cells and Neutrophils (JPG 630 KB)

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Liu, J., Zhang, W., Wang, J. et al. Construction and validation of N6-methyladenosine long non-coding RNAs signature of prognostic value for early biochemical recurrence of prostate cancer. J Cancer Res Clin Oncol 149, 1969–1983 (2023). https://doi.org/10.1007/s00432-022-04040-y

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