Smoking-related epigenetic modiﬁcations are associated with the prognosis and chemotherapeutics of patients with bladder cancer

Sep 24, 2026

Study objective: determine smoking-related epigenetic modifications and clarify their effects on prognosis and chemotherapy in bladder cancer. DNA methylation, transcriptome, and clinical profiles from TCGA were analyzed using TCGAbiolinks, limma, pheatmap, Cytoscape, LASSO modeling, Kaplan–Meier with log-rank, prognostic nomograms, GSEA, and oncoPredict. Findings link smoking to poor outcome and define methylation- and non-coding RNA–based risk with differential drug sensitivities.

LanguageEnglish

CategoryHealthcare

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Pages12

Reading Time30 min

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Abstract

Objective

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Introduction

Original Research Article Smoking-related epigenetic modiﬁcations are associated with the prognosis and chemotherapeutics of patients with bladder cancer International Journal of Immunopathology and Pharmacology Volume 37: 1–12 © The Author(s) 2023 Article reuse guidelines: [sagepub.com/journals-permissions](sagepub.com/journals-permissions) [DOI: 10.1177/03946320231166774](DOI: 10.1177/03946320231166774) [journals.sagepub.com/home/iji](journals.sagepub.com/home/iji) Ya Ling 1,* 􀀁, Jindong Li2,* and Lijuan Zhou 1 Abstract Objective: Epidemiologic studies have linked smoking to various malignancies, including bladder cancer, but its underlying biological functions remain elusive. Currently, we aimed to identify the smoking-related epigenetic modiﬁcations and disclose their impacts on prognosis and therapies in bladder cancer. Methods: DNA methylation, transcriptome, and clinical proﬁles were acquired from The Cancer Genome Atlas (TCGA) using “TCGAbiolinks” Differential expression analyses were performed with “limma” and visualized by the “pheatmap”package. Smoking-related interactions were displayed using Cytoscape. Least absolute shrinkage and selection operator (LASSO) algorithm was for generation of a smoking-related prognostic model. Kaplan–Meier analysis with log-rank test was for survival analysis, followed by a prognostic nomogram. The Gene Set Enrichment Analysis (GSEA) was used for functional analysis. The “oncoPredict” package was applied for drug sensitivity analysis. Results: We recruited all types of bladder cancers and found that smoking was involved in poor prognosis, with the hazard ratio (HR) of 1.600 (95%CI: 1.028–2.491). A total of 1078 smoking-related DNA methylations (526 hypermethylation and 552 hypomethylation) were identiﬁed and 9 methylation-driven genes differentially expressed in bladder cancer. Also, 506 lncRNAs (448 upregulated and 58 downregulated lncRNAs) and 102 miRNAs (74 upregulated and 28 downregulated miRNAs) were determined as smoking-related ncRNAs. We then calculated the smoking-related risk score and observed that cases of high risk were predicted with poor prognosis. We constructed a prognostic nomogram to predict the 1-, 3-, and 5-year overall survival rates. Several cancer-related pathways were enriched in the high-risk group, and patients with high-risk were more sensitive to Gemcitabine, Wnt-C59, JAK1_ 8709, KRAS (G12C) Inhibitor-12, and LY2109761. Whereas, those with low-risk were more sensitive to Cisplatin, AZ960, and Buparlisib. Conclusions: Totally, we initially identiﬁed the smoking-related epigenetic modiﬁcations in bladder cancer and constructed a corresponding prognostic model, which was also linked to disparate sensitivities to chemotherapeutics. Our ﬁndings would provide novel insights into the carcinogenesis, prognosis, and therapies in bladder cancer. Keywords The Cancer Genome Atlas, smoking behavior, bladder cancer, epigenetic modiﬁcation, chemotherapies, prognosis Date received: 31 August 2022; accepted: 14 March 2023 Introduction Epidemiology data show that bladder cancer is still involved in high morbidity and mortality, with an estimated 573,000 new cases and 213,000 deaths in 2020 worldwide. 1 The ﬁrst Afﬁliated Hospital of Soochow University, Suzhou, China 2Taizhou People’s Hospital, Taizhou, China *These authors contributed equally to this work. Corresponding author: Lijuan Zhou, The ﬁrst Afﬁliated Hospital of Soochow University, Jiangsu, Suzhou 215006, China. Email: [zhouzhouzlj427@163.com](zhouzhouzlj427@163.com) Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ([https://creativecommons.org/licenses/by-nc/4.0/](https://creativecommons.org/licenses/by-nc/4.0/)) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as speciﬁe

FAQs

What was the study’s main objective in bladder cancer research?

To identify smoking-related epigenetic modifications and determine how they influence prognosis and chemotherapy outcomes in bladder cancer.

How were smoking-related epigenetic signatures and risk models constructed?

Using TCGA DNA methylation and transcriptome data, the study applied differential expression analyses, Cytoscape interaction visualization, LASSO for a smoking-related prognostic model, and Kaplan–Meier survival analysis with log-rank testing plus a prognostic nomogram.

What therapies showed different sensitivity between high- and low-risk groups?

High-risk patients were more sensitive to drugs such as Gemcitabine, Wnt-C59, JAK1_8709, KRAS(G12C) Inhibitor-12, and LY2109761, while low-risk patients were more sensitive to Cisplatin, AZ960, and Buparlisib.

Sep 24, 2026

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