Pyroptosis-related Gene Signature: A Predictor for Overall Survival, Immunotherapy Response, and Chemosensitivity in Patients with Pancreatic Adenocarcinoma

Overview

Journal Heliyon

Specialty Social Sciences

Date 2023 Dec 21

PMID 38125471

Authors

Jieting Zhou

Jian Fan

Binxiao Li

Jiayu Sun

Jingchao Wang

Affiliations

Soon will be listed here.

Abstract

Background: Pancreatic adenocarcinoma (PAAD) is a lethal malignancy with high levels of heterogeneity. Pyroptosis is thought to influence the development of various tumors. Nevertheless, the role of pyroptosis-related genes (PRGs) in prognostic risk stratification and therapeutic guidance for PAAD remains ambiguously.

Methods: Transcriptome profile and clinical information of PAAD patients were retrieved from The Cancer Genome Atlas (TCGA) as well as Gene Expression Omnibus (GEO) databases, followed by differential analysis. Patients were divided into distinct pyroptosis phenotype subtypes based on the characteristic of differently expressed PRGs (DEPRGs). Then a PRG signature was established through univariate analysis and LASSO algorithm in the training set to assess the prognostic risk, and its reliability was verified in the validation set using receiver operating characteristic(ROC) curve. The correlation of risk score with tumor microenvironment(TME), TMB and chemotherapeutic drug sensitivity were also analyzed. In addition, a nomogram was constructed to promote better clinical application.

Results: A total of 28 DEPRGs were determined in the integrated TCGA-GEO datasets. Patients were divided into three pyroptosis phenotype subtypes, Kaplan-Meier curve suggested patients in cluster B had a worse prognosis than those in cluster A and C. Then a price signature comprised of 8 PRGs was generated. TME analysis suggested that the low-risk subgroup displayed potential stronger antitumor immune effect and might respond better to immune checkpoint inhibitors (ICIs) therapy. Furthermore, PRG signature exhibited favorable discriminatory ability for TMB status and the sensitivity of multiple conventional chemotherapeutic agents including paclitaxel. Ultimately, we constructed a promising nomogram according to the risk score and N stage with good predictive accuracy compared with the actual overall survival (OS) probabilities.

Conclusion: We established an 8-gene signature that could be regarded as an independent prognostic risk factor for PAAD patients. The 8-gene signature could provide rationale for immunotherapy and chemotherapy, which might help clinicians make precise individualized treatment regimens.

References

Ru Y, Kechris K, Tabakoff B, Hoffman P, Radcliffe R, Bowler R . The multiMiR R package and database: integration of microRNA-target interactions along with their disease and drug associations. Nucleic Acids Res. 2014; 42(17):e133. PMC: 4176155. DOI: 10.1093/nar/gku631. View

Yu G, Li F, Qin Y, Bo X, Wu Y, Wang S . GOSemSim: an R package for measuring semantic similarity among GO terms and gene products. Bioinformatics. 2010; 26(7):976-8. DOI: 10.1093/bioinformatics/btq064. View

Gutteridge R, Ndiaye M, Liu X, Ahmad N . Plk1 Inhibitors in Cancer Therapy: From Laboratory to Clinics. Mol Cancer Ther. 2016; 15(7):1427-35. PMC: 4936921. DOI: 10.1158/1535-7163.MCT-15-0897. View

Rueda C, Moreno-Fernandez M, Jackson C, Kallapur S, Jobe A, Chougnet C . Neonatal regulatory T cells have reduced capacity to suppress dendritic cell function. Eur J Immunol. 2015; 45(9):2582-92. PMC: 4666291. DOI: 10.1002/eji.201445371. View

Hou J, Zhao R, Xia W, Chang C, You Y, Hsu J . PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis. Nat Cell Biol. 2020; 22(10):1264-1275. PMC: 7653546. DOI: 10.1038/s41556-020-0575-z. View

Shi F, Wei B, Lan T, Xiao Y, Quan X, Chen J . Low NLRP3 expression predicts a better prognosis of colorectal cancer. Biosci Rep. 2021; 41(4). PMC: 8055799. DOI: 10.1042/BSR20210280. View

Birnbaum D, Finetti P, Lopresti A, Gilabert M, Poizat F, Turrini O . Prognostic value of PDL1 expression in pancreatic cancer. Oncotarget. 2016; 7(44):71198-71210. PMC: 5342072. DOI: 10.18632/oncotarget.11685. View

Chiappa M, Petrella S, Damia G, Broggini M, Guffanti F, Ricci F . Present and Future Perspective on PLK1 Inhibition in Cancer Treatment. Front Oncol. 2022; 12:903016. PMC: 9201472. DOI: 10.3389/fonc.2022.903016. View

Ying H, Dey P, Yao W, Kimmelman A, Draetta G, Maitra A . Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 2016; 30(4):355-85. PMC: 4762423. DOI: 10.1101/gad.275776.115. View

10.

Ruhl S, Shkarina K, Demarco B, Heilig R, Santos J, Broz P . ESCRT-dependent membrane repair negatively regulates pyroptosis downstream of GSDMD activation. Science. 2018; 362(6417):956-960. DOI: 10.1126/science.aar7607. View

11.

Leek J, Johnson W, Parker H, Jaffe A, Storey J . The sva package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics. 2012; 28(6):882-3. PMC: 3307112. DOI: 10.1093/bioinformatics/bts034. View

12.

Yang G, Guan W, Cao Z, Guo W, Xiong G, Zhao F . Integrative Genomic Analysis of Gemcitabine Resistance in Pancreatic Cancer by Patient-derived Xenograft Models. Clin Cancer Res. 2021; 27(12):3383-3396. DOI: 10.1158/1078-0432.CCR-19-3975. View

13.

Frank D, Vince J . Pyroptosis versus necroptosis: similarities, differences, and crosstalk. Cell Death Differ. 2018; 26(1):99-114. PMC: 6294779. DOI: 10.1038/s41418-018-0212-6. View

14.

Broz P, Pelegrin P, Shao F . The gasdermins, a protein family executing cell death and inflammation. Nat Rev Immunol. 2019; 20(3):143-157. DOI: 10.1038/s41577-019-0228-2. View

15.

Wang Y, Gao W, Shi X, Ding J, Liu W, He H . Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature. 2017; 547(7661):99-103. DOI: 10.1038/nature22393. View

16.

Rawla P, Sunkara T, Gaduputi V . Epidemiology of Pancreatic Cancer: Global Trends, Etiology and Risk Factors. World J Oncol. 2019; 10(1):10-27. PMC: 6396775. DOI: 10.14740/wjon1166. View

17.

Petsalaki E, Dandoulaki M, Zachos G . The ESCRT protein Chmp4c regulates mitotic spindle checkpoint signaling. J Cell Biol. 2018; 217(3):861-876. PMC: 5839794. DOI: 10.1083/jcb.201709005. View

18.

Locy H, de Mey S, de Mey W, De Ridder M, Thielemans K, Maenhout S . Immunomodulation of the Tumor Microenvironment: Turn Foe Into Friend. Front Immunol. 2019; 9:2909. PMC: 6297829. DOI: 10.3389/fimmu.2018.02909. View

19.

Wang Y, Liu X, Zhao R . Induction of Pyroptosis and Its Implications in Cancer Management. Front Oncol. 2019; 9:971. PMC: 6775187. DOI: 10.3389/fonc.2019.00971. View

20.

Lu L, Risch E, Halaban R, Zhen P, Bacchiocchi A, Risch H . Dynamic changes of circulating soluble PD-1/PD-L1 and its association with patient survival in immune checkpoint blockade-treated melanoma. Int Immunopharmacol. 2023; 118:110092. DOI: 10.1016/j.intimp.2023.110092. View