Pan Wenjing,Zhao Jindu,Gao Qun.A ferroptosis-based prognostic signature for soft tissue sarcoma: a study integrating bioinformatics analysis and experimental validation[J].Journal of Clinical Pediatric Surgery,,():584-590.[doi:10.3760/cma.j.cn101785-20251105-00045]
A ferroptosis-based prognostic signature for soft tissue sarcoma: a study integrating bioinformatics analysis and experimental validation
- Keywords:
- Solt Tissue Sarcoma; Bioinformatics; Ferroptosis; Genes; Prognosis; Risk Factors
- Abstract:
- Objective To develop a prognostic signature based upon ferroptosis-related genes (FRGs) for soft tissue sarcoma (STS),aiming to provide theoretical rationales for prognostic assessments and personalized treatments. Methods This study was conducted using a retrospective cohort analysis based upon public databases plus in vitro cell experiments.Transcriptomic and clinical data from the TCGA-SARC dataset within the item of sarcoma of The Cancer Genome Atlas (TCGA) were utilized as training cohort.A multi-gene prognostic signature was constructed through univariate Cox regression,LASSO regression and multivariate Cox regression analyses.The GSE30929 dataset from the Gene Expression Omnibus (GEO) database served as an independent validation cohort.Finally,RT-qPCR was performed for validating the expression of core genes in rhabdomyosarcoma cell line (A-204) and normal human skeletal muscle cell line (HSKMC). Results A six-gene prognostic signature comprising ADIPOR1,SLC16A1,KAT5,HNRNPD,ACTL6A and NFKB2 was successfully established.In training cohort,high-risk group exhibited significantly shorter overall survival (Log-rank P<0.001).And time-dependent receiver operating characteristic (ROC) analysis revealed that areas under the curve (AUC) for predicting 1/3/5-year survival rates were 0.862,0.822 and 0.845.Concordance index (C-index) was 0.783 and significant difference existed in risk score distribution between high- and low-risk groups.These findings were consistently confirmed in validation cohort.RT-qPCR results indicated that the relative expression levels of six genes in rhabdomyosarcoma cell line A-204 (experimental group) and normal human skeletal muscle cell line HSKMC (control group) were as follows (presented as mean±standard deviation): ACTL6A (1.000±0.011) vs. (0.485±0.036); SLC16A1 (1.003±0.091) vs. (0.678±0.046); HNRNPD (1.001±0.055) vs. (0.794±0.038); NFKB2 (1.003±0.092) vs. (2.135±0.097); KAT5 (0.430±0.033) vs. (1.003±0.097); ADIPOR1 (0.471±0.010) vs. (1.000±0.018).All differences were statistically significant (P<0.01). Conclusions This study has established a multi-gene prognostic model that not only highlighting potential interplay between ferroptosis and tumor microenvironment remodeling but also proving to be a reliable predictor of survival with significant risk stratification power in STS.These findings offer a promising new avenue for prognostic assessments and advancing precision medicine for STS.
References:
[1] Fletcher CDM.The evolving classification of soft tissue tumours-an update based on the new 2013 WHO classification[J].Histopathology,2014,64(1):2-11.DOI:10.1111/his.12267.
[2] Siegel RL,Miller KD,Fuchs HE,et al.Cancer statistics,2022[J].CA Cancer J Clin,2022,72(1): 7-33.DOI:10.3322/caac.21708.
[3] Bessen T,Caughey GE,Shakib S,et al.A population-based study of soft tissue sarcoma incidence and survival in Australia: an analysis of 26,970 cases[J].Cancer Epidemiol,2019,63:101590.DOI: 10.1016/j.canep.2019.101590.
[4] Kim HS,Nam CM,Jang SY,et al.Characteristics and treatment patterns of patients with advanced soft tissue sarcoma in Korea[J].Cancer Res Treat,2019,51(4):1380-1391.DOI:10.4143/crt.2018.476.
[5] Kollár A,Rothermundt C,Klenke F,et al.Incidence,mortality,and survival trends of soft tissue and bone sarcoma in Switzerland between 1996 and 2015[J].Cancer Epidemiol,2019,63:101596.DOI:10.1016/j.canep.2019.101596.
[6] Drilon A,Laetsch TW,Kummar S,et al.Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children[J].N Engl J Med,2018,378(8):731-739.DOI:10.1056/NEJMoa1714448.
[7] Tawbi HA,Burgess M,Bolejack V,et al.Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre,two-cohort,single-arm,open-label,phase 2 trial[J].Lancet Oncol,2017,18(11):1493-1501.DOI:10.1016/S1470-2045(17)30624-1.
[8] Gounder M,Sch?ffski P,Jones RL,et al.Tazemetostat in advanced epithelioid sarcoma with loss of INI1/SMARCB1: an international,open-label,phase 2 basket study[J].Lancet Oncol,2020,21(11): 1423-1432.DOI:10.1016/S1470-2045(20)30451-4.
[9] Farzaliyev F,Steinau HU,Ring A,et al.Outcome of surgery as part of palliative care of patients with symptomatic advanced or metastatic extra-abdominal high-grade soft tissue sarcoma[J].Palliat Med Rep,2023,3(1):64-70.DOI:10.1089/pmr.2022.0063.
[10] Dixon SJ,Lemberg KM,Lamprecht MR,et al.Ferroptosis: an iron-dependent form of nonapoptotic cell death[J].Cell,2012,149(5):1060-1072.DOI:10.1016/j.cell.2012.03.042.
[11] Yu HT,Guo PY,Xie XZ,et al.Ferroptosis,a new form of cell death,and its relationships with tumourous diseases[J].J Cell Mol Med,2017,21(4):648-657.DOI:10.1111/jcmm.13008.
[12] Jiang L,Kon N,Li TY,et al.Ferroptosis as a p53-mediated activity during tumour suppression[J].Nature,2015,520(7545):57-62.DOI:10.1038/nature14344.
[13] Wang WM,Green M,Choi JE,et al.CD8+ T cells regulate tumo-ur ferroptosis during cancer immunotherapy[J].Nature,2019,569(7755):270-274.DOI:10.1038/s41586-019-1170-y.
[14] Friedmann Angeli JP,Krysko DV,Conrad M.Ferroptosis at the crossroads of cancer-acquired drug resistance and immune evasion[J].Nat Rev Cancer,2019,19(7):405-414.DOI:10.1038/s41568-019-0149-1.
[15] Zhang HM,Ma JL,Hou CY,et al.A ROS-mediated oxidation-O-GlcNAcylation cascade governs ferroptosis[J].Nat Cell Biol,2025,27(8):1288-1300.DOI:10.1038/s41556-025-01722-w.
[16] Viswanathan VS,Ryan MJ,Dhruv HD,et al.Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway[J].Nature,2017,547(7664):453-457.DOI:10.1038/nature23007.
[17] Umeda K,Miyamura T,Yamada K,et al.Prognostic and therapeutic factors influencing the clinical outcome of metastatic Ewing sarcoma family of tumors: a retrospective report from the Japan Ewing Sarcoma Study Group[J].Pediatr Blood Cancer,2021,68(3):e28844.DOI:10.1002/pbc.28844.
[18] Koscielniak E,Stegmaier S,Ljungman G,et al.Prognostic factors in patients with localized and metastatic alveolar rhabdomyosarcoma.A report from two studies and two registries of the Cooperative Weichteilsarkom Studiengruppe CWS[J].Cancer Med,2025,14(1):e70215.DOI:10.1002/cam4.70215.
[19] Gronchi A,Miah AB,Dei Tos AP,et al.Soft tissue and visceral sarcomas:ESMO-EURACAN-GENTURIS Clinical Practice Guidelines for diagnosis,treatment and follow-up[J].Ann Oncol,2021,32(11):1348-1365.DOI:10.1016/j.annonc.2021.07.006.
[20] Italiano A,Mathoulin-Pelissier S,Cesne AL,et al.Trends in survival for patients with metastatic soft-tissue sarcoma[J].Cancer,2011,117(5):1049-1054.DOI:10.1002/cncr.25538.
[21] Zhang Y,Tan H,Daniels JD,et al.Imidazole ketone erastin induces ferroptosis and slows tumor growth in a mouse lymphoma model[J].Cell Chem Biol,2019,26(5):623-633.e9.DOI:10.1016/j.chembiol.2019.01.008.
[22] Sun W,Wang WC,Lei J,et al.Actin-like protein 6A is a novel prognostic indicator promoting invasion and metastasis in osteosarcoma[J].Oncol Rep,2017,37(4):2405-2417.DOI:10.3892/or.2017.5473.
Memo
收稿日期:2025-11-5。
基金项目:安徽省卫生健康科研项目(AHWJ2024Ab0085)
通讯作者:高群,Email:gaoqun@ahmu.edu.cn