A pyroptosis-related gene signature for prognostic and immunological evaluation in breast cancer

Yue Zhong; Fu Peng; Xiaoru Luo; Xuan Wang; Bowen Yang; Xinglinzi Tang; Zheng Xu; Linlin Ren; Zhiyu Wang; Cheng Peng; Neng Wang

doi:10.3389/fonc.2022.964508

A pyroptosis-related gene signature for prognostic and immunological evaluation in breast cancer

Front Oncol. 2022 Dec 23:12:964508. doi: 10.3389/fonc.2022.964508. eCollection 2022.

Authors

Yue Zhong¹, Fu Peng^{2

3}, Xiaoru Luo¹, Xuan Wang^{4

5

6}, Bowen Yang^{4

5

6}, Xinglinzi Tang¹, Zheng Xu¹, Linlin Ren¹, Zhiyu Wang^{4

5

6}, Cheng Peng², Neng Wang¹

Affiliations

¹ Integrative Medicine Research Center, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
² State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
³ Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, West China School of Pharmacy, Sichuan University, Chengdu, China.
⁴ State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
⁵ Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangdong Provincial Academy of Chinese Medical Sciences, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, China.
⁶ Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.

Abstract

Purpose: Pyroptosis exerts an undesirable impact on the clinical outcome of breast cancer. Since any single gene is insufficient to be an appropriate marker for pyroptosis, our aim is to develop a pyroptosis-related gene (PRG) signature to predict the survival status and immunological landscape for breast cancer patients.

Methods: The information of breast cancer patients was retrieved from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to verify the gene expressions of this signature in breast cancer. Its prognostic value was evaluated by univariate Cox analysis, least absolute shrinkage and selection operator (LASSO) regression analysis, receiver operating characteristics (ROCs), univariate/multivariate analysis, and nomogram. Analyses of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed to explore its potential biological function in breast cancer. The potential correlation between this signature and tumor immunity was revealed based on single sample gene set enrichment analysis (ssGSEA), ESTIMATE and CIBERSORT algorithms.

Results: A PRG signature containing GSDMC, GZMB, IL18, and TP63 was created in a TCGA training cohort and validated in two validation GEO cohorts GSE58812 and GSE37751. Compared with a human mammary epithelial cell line MCF-10A, the expression levels of GSDMC, GZMB and IL18 were upregulated, while TP63 was found with lower expression level in breast cancer cells SK-BR-3, BT-549, MCF-7, and MDA-MB-231 using RT-qPCR assay. Based on univariate and multivariate Cox models, ROC curve, nomogram as well as calibration curve, it was revealed that this signature with high-risk score could independently predict poor clinical outcomes in breast cancer. Enrichment analyses demonstrated that the involved mechanism was tightly linked to immune-related processes. SsGSEA, ESTIMATE and CIBERSORT algorithms further pointed out that the established model might exert an impact on immune cell abundance, immune cell types and immune-checkpoint markers. Furthermore, individuals with breast cancer responded differently to these therapeutic agents based on this signature.

Conclusions: Our data suggested that this PRG signature with high risk was tightly associated with impaired immune function, possibly resulting in an unfavorable outcome for breast cancer patients.

Keywords: 4-gene signature; breast cancer; immunological landscape; pyroptosis; survival status.

Grants and funding

This study was supported by the National Natural Science Foundation of China [81973526; 81873306; 82004132]; Guangdong Traditional Chinese Medicine Bureau Project (20211114); the State Key Laboratory of Dampness Syndrome of Chinese Medicine [SZ2021ZZ19]; the 2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund (Guangdong-Hong Kong-Macau Joint Lab) [2020B1212030006]; the Science and Technology Planning Project of Guangdong Province [2017B030314166]; Guangdong Science and Technology Department [2021A0505030059]; Guangzhou Science and Technology Project [202102010316]; Open Research Fund of Chengdu University of Traditional Chinese Medicine State Key Laboratory of Characteristic Chinese Medicine Resources in Southwest China [XZYZ-20201224-1945] and Funding for Young Scholars of Guangzhou University of Chinese Medicine [QNYC20190101].