Skip to main content
Top
Published in: BMC Pulmonary Medicine 1/2021

Open Access 01-12-2021 | Research

A novel ferroptosis-related genes model for prognosis prediction of lung adenocarcinoma

Authors: Fei Li, Dongcen Ge, Shu-lan Sun

Published in: BMC Pulmonary Medicine | Issue 1/2021

Login to get access

Abstract

Background

Ferroptosis is a newly discovered form of cell death characterized by iron-dependent lipid peroxidation. This study aims to investigate the potential correlation between ferroptosis and the prognosis of lung adenocarcinoma (LUAD).

Methods

RNA-seq data were collected from the LUAD dataset of The Cancer Genome Atlas (TCGA) database. Based on ferroptosis-related genes, differentially expressed genes (DEGs) between LUAD and paracancerous specimens were identified. The univariate Cox regression analysis was performed to screen key genes associated with the prognosis of LUAD. LUAD patients were divided into the training set and validation set. Then, we screened out key genes and built a prognostic prediction model involving 5 genes using the least absolute shrinkage and selection operator (LASSO) regression with tenfold cross-validation and the multivariate Cox regression analysis. After dividing LUAD patients based on the median level of risk score as cut-off value, the generated prognostic prediction model was validated in the validation set. Moreover, we analyzed the somatic mutations, and estimated the scores of immune infiltration in the high-risk and low-risk groups. Functional enrichment analysis of DEGs was performed as well.

Results

High-risk scores indicated the worse prognosis of LUAD. The maximum area under curve (AUC) of the training set and the validation set in this study was 0.7 and 0.69, respectively. Moreover, we integrated the age, gender, and tumor stage to construct the composite nomogram. The charts indicated that the AUC of LUAD cases with the survival time of 1, 3 and 5 years was 0.698, 0.71 and 0.73, respectively. In addition, the mutation frequency of LUAD patients in the high-risk group was significantly higher than that in the low-risk group. Simultaneously, DEGs were mainly enriched in ferroptosis-related pathways by analyzing the functional results.

Conclusions

This study constructs a novel LUAD prognosis prediction model involving 5 ferroptosis-related genes, which can be used as a promising tool for decision-making of clinical therapeutic strategies of LUAD.
Appendix
Available only for authorised users
Literature
1.
go back to reference Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060–72.CrossRef Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060–72.CrossRef
2.
go back to reference Yang WS, Stockwell BR. Ferroptosis: death by lipid peroxidation. Trends Cell Biol. 2016;26(3):165–76.CrossRef Yang WS, Stockwell BR. Ferroptosis: death by lipid peroxidation. Trends Cell Biol. 2016;26(3):165–76.CrossRef
3.
go back to reference Xia X, Fan X, Zhao M, Zhu P. The relationship between ferroptosis and tumors: a novel landscape for therapeutic approach. Curr Gene Ther. 2019;19(2):117–24.CrossRef Xia X, Fan X, Zhao M, Zhu P. The relationship between ferroptosis and tumors: a novel landscape for therapeutic approach. Curr Gene Ther. 2019;19(2):117–24.CrossRef
4.
go back to reference Hassannia B, Vandenabeele P, Vanden BT. Targeting ferroptosis to iron out cancer. Cancer Cell. 2019;35(6):830–49.CrossRef Hassannia B, Vandenabeele P, Vanden BT. Targeting ferroptosis to iron out cancer. Cancer Cell. 2019;35(6):830–49.CrossRef
5.
go back to reference Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553(7689):446–54.CrossRef Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553(7689):446–54.CrossRef
6.
go back to reference Santarpia M, Aguilar A, Chaib I, et al. Non-small-cell lung cancer signaling pathways, metabolism, and PD-1/PD-L1 antibodies. Cancers (Basel). 2020;12(6). Santarpia M, Aguilar A, Chaib I, et al. Non-small-cell lung cancer signaling pathways, metabolism, and PD-1/PD-L1 antibodies. Cancers (Basel). 2020;12(6).
7.
go back to reference Allemani C, Matsuda T, Di Carlo V, et al. Global surveillance of trends in cancer survival 2000–14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet. 2018;391(10125):1023–75.CrossRef Allemani C, Matsuda T, Di Carlo V, et al. Global surveillance of trends in cancer survival 2000–14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet. 2018;391(10125):1023–75.CrossRef
8.
go back to reference Ji X, Qian J, Rahman SMJ, et al. xCT (SLC7A11)-mediated metabolic reprogramming promotes non-small cell lung cancer progression. Oncogene. 2018;37(36):5007–19.CrossRef Ji X, Qian J, Rahman SMJ, et al. xCT (SLC7A11)-mediated metabolic reprogramming promotes non-small cell lung cancer progression. Oncogene. 2018;37(36):5007–19.CrossRef
9.
go back to reference Lai Y, Zhang Z, Li J, et al. STYK1/NOK correlates with ferroptosis in non-small cell lung carcinoma. Biochem Biophys Res Commun. 2019;519(4):659–66.CrossRef Lai Y, Zhang Z, Li J, et al. STYK1/NOK correlates with ferroptosis in non-small cell lung carcinoma. Biochem Biophys Res Commun. 2019;519(4):659–66.CrossRef
10.
go back to reference Alvarez SW, Sviderskiy VO, Terzi EM, et al. NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis. Nature. 2017;551(7682):639–43.CrossRef Alvarez SW, Sviderskiy VO, Terzi EM, et al. NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis. Nature. 2017;551(7682):639–43.CrossRef
11.
go back to reference Wu G, Wang Q, Xu Y, Li Q, Cheng L. A new survival model based on ferroptosis-related genes for prognostic prediction in clear cell renal cell carcinoma. Aging (Albany NY). 2020;12(14):14933–48.CrossRef Wu G, Wang Q, Xu Y, Li Q, Cheng L. A new survival model based on ferroptosis-related genes for prognostic prediction in clear cell renal cell carcinoma. Aging (Albany NY). 2020;12(14):14933–48.CrossRef
12.
go back to reference Liang JY, Wang DS, Lin HC, et al. A novel ferroptosis-related gene signature for overall survival prediction in patients with hepatocellular carcinoma. Int J Biol Sci. 2020;16(13):2430–41.CrossRef Liang JY, Wang DS, Lin HC, et al. A novel ferroptosis-related gene signature for overall survival prediction in patients with hepatocellular carcinoma. Int J Biol Sci. 2020;16(13):2430–41.CrossRef
13.
go back to reference Stockwell BR, Friedmann Angeli JP, Bayir H, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017;171(2):273–85.CrossRef Stockwell BR, Friedmann Angeli JP, Bayir H, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017;171(2):273–85.CrossRef
14.
go back to reference Bersuker K, Hendricks JM, Li Z, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature. 2019;575(7784):688–92.CrossRef Bersuker K, Hendricks JM, Li Z, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature. 2019;575(7784):688–92.CrossRef
15.
go back to reference Doll S, Freitas FP, Shah R, et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature. 2019;575(7784):693–8.CrossRef Doll S, Freitas FP, Shah R, et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature. 2019;575(7784):693–8.CrossRef
16.
go back to reference Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12):550.CrossRef Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12):550.CrossRef
17.
go back to reference Simon N, Friedman J, Hastie T, Tibshirani R. Regularization paths for cox’s proportional hazards model via coordinate descent. J Stat Softw. 2011;39(5):1–13.CrossRef Simon N, Friedman J, Hastie T, Tibshirani R. Regularization paths for cox’s proportional hazards model via coordinate descent. J Stat Softw. 2011;39(5):1–13.CrossRef
18.
go back to reference Tibshirani R. The lasso method for variable selection in the Cox model. Stat Med. 1997;16(4):385–95.CrossRef Tibshirani R. The lasso method for variable selection in the Cox model. Stat Med. 1997;16(4):385–95.CrossRef
19.
go back to reference Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012;16(5):284–7.CrossRef Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012;16(5):284–7.CrossRef
20.
go back to reference Rooney MS, Shukla SA, Wu CJ, Getz G, Hacohen N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell. 2015;160(1–2):48–61.CrossRef Rooney MS, Shukla SA, Wu CJ, Getz G, Hacohen N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell. 2015;160(1–2):48–61.CrossRef
21.
go back to reference Hanzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics. 2013;14:7.CrossRef Hanzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics. 2013;14:7.CrossRef
22.
go back to reference Mayakonda A, Lin DC, Assenov Y, Plass C, Koeffler HP. Maftools: efficient and comprehensive analysis of somatic variants in cancer. Genome Res. 2018;28(11):1747–56.CrossRef Mayakonda A, Lin DC, Assenov Y, Plass C, Koeffler HP. Maftools: efficient and comprehensive analysis of somatic variants in cancer. Genome Res. 2018;28(11):1747–56.CrossRef
23.
go back to reference Magtanong L, Ko PJ, To M, et al. Exogenous monounsaturated fatty acids promote a ferroptosis-resistant cell state. Cell Chem Biol. 2019;26(3):420–32.CrossRef Magtanong L, Ko PJ, To M, et al. Exogenous monounsaturated fatty acids promote a ferroptosis-resistant cell state. Cell Chem Biol. 2019;26(3):420–32.CrossRef
24.
go back to reference Muller T, Dewitz C, Schmitz J, et al. Necroptosis and ferroptosis are alternative cell death pathways that operate in acute kidney failure. Cell Mol Life Sci. 2017;74(19):3631–45.CrossRef Muller T, Dewitz C, Schmitz J, et al. Necroptosis and ferroptosis are alternative cell death pathways that operate in acute kidney failure. Cell Mol Life Sci. 2017;74(19):3631–45.CrossRef
25.
go back to reference Doll S, Proneth B, Tyurina YY, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2017;13(1):91–8.CrossRef Doll S, Proneth B, Tyurina YY, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2017;13(1):91–8.CrossRef
26.
go back to reference Wenzel SE, Tyurina YY, Zhao J, et al. PEBP1 wardens ferroptosis by enabling lipoxygenase generation of lipid death signals. Cell. 2017;171(3):628–41.CrossRef Wenzel SE, Tyurina YY, Zhao J, et al. PEBP1 wardens ferroptosis by enabling lipoxygenase generation of lipid death signals. Cell. 2017;171(3):628–41.CrossRef
27.
go back to reference Zou Y, Li H, Graham ET, et al. Cytochrome P450 oxidoreductase contributes to phospholipid peroxidation in ferroptosis. Nat Chem Biol. 2020;16(3):302–9.CrossRef Zou Y, Li H, Graham ET, et al. Cytochrome P450 oxidoreductase contributes to phospholipid peroxidation in ferroptosis. Nat Chem Biol. 2020;16(3):302–9.CrossRef
28.
go back to reference Weigand I, Schreiner J, Rohrig F, et al. Active steroid hormone synthesis renders adrenocortical cells highly susceptible to type II ferroptosis induction. Cell Death Dis. 2020;11(3):192.CrossRef Weigand I, Schreiner J, Rohrig F, et al. Active steroid hormone synthesis renders adrenocortical cells highly susceptible to type II ferroptosis induction. Cell Death Dis. 2020;11(3):192.CrossRef
29.
go back to reference Rowe SE, Wagner NJ, Li L, et al. Reactive oxygen species induce antibiotic tolerance during systemic Staphylococcus aureus infection. Nat Microbiol. 2020;5(2):282–90.CrossRef Rowe SE, Wagner NJ, Li L, et al. Reactive oxygen species induce antibiotic tolerance during systemic Staphylococcus aureus infection. Nat Microbiol. 2020;5(2):282–90.CrossRef
30.
go back to reference Becci PJ, McDowell EM, Trump BF. The respiratory epithelium. VI. Histogenesis of lung tumors induced by benzo[a]pyrene-ferric oxide in the hamster. J Natl Cancer Inst. 1978;61(2):607–18.PubMed Becci PJ, McDowell EM, Trump BF. The respiratory epithelium. VI. Histogenesis of lung tumors induced by benzo[a]pyrene-ferric oxide in the hamster. J Natl Cancer Inst. 1978;61(2):607–18.PubMed
31.
go back to reference Infante AA, Infante D, Chan MC, et al. Ferritin associates with marginal band microtubules. Exp Cell Res. 2007;313(8):1602–14.CrossRef Infante AA, Infante D, Chan MC, et al. Ferritin associates with marginal band microtubules. Exp Cell Res. 2007;313(8):1602–14.CrossRef
Metadata
Title
A novel ferroptosis-related genes model for prognosis prediction of lung adenocarcinoma
Authors
Fei Li
Dongcen Ge
Shu-lan Sun
Publication date
01-12-2021
Publisher
BioMed Central
Published in
BMC Pulmonary Medicine / Issue 1/2021
Electronic ISSN: 1471-2466
DOI
https://doi.org/10.1186/s12890-021-01588-2

Other articles of this Issue 1/2021

BMC Pulmonary Medicine 1/2021 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.