Defining Three Ferroptosis-based Molecular Subtypes and Developing a Prognostic Risk Model for High-grade Serous Ovarian Cancer

Overview

Journal Aging (Albany NY)

Specialty Geriatrics

Date 2024 May 25

PMID 38795391

Authors

Xiang Sun

Wenbin He

Baohua Lin

Weiming Huang

Danping Ye

Affiliations

Soon will be listed here.

Abstract

Background: As a newly defined regulated cell death, ferroptosis is a potential biomarker in ovarian cancer (OV). However, its underlying mechanism in tumor microenvironment (TME) and clinical prediction significance in OV remained to be elucidated.

Methods: The transcriptome data of high-grade serous OV from The Cancer Genome Atlas (TCGA) database were downloaded. Molecular subtypes were classified based on ferroptosis-correlated genes from the FerrDb database by performing consensus clustering analysis. The associations between the subtypes and clinicopathologic characteristics, mutation, regulatory pathways and immune landscape were assessed. A ferroptosis-related prognostic model was constructed and verified using International Cancer Genome Consortium (ICGC) cohort and GSE70769.

Results: Three molecular subtypes of OV were defined. Patients in subtype C3 tended to have the most favorable prognosis, while subtype C1 showing more mesenchymal cells, increased immune infiltration of Macrophages_M2, lower tumor purity, and epithelial-to-mesenchymal transition (EMT) features had the poorest prognosis. A ferroptosis-related risk model was constructed using 8 genes (PDP1, FCGBP, EPHA4, GAS1, SLC7A11, BLOC1S1, SPOCK2, and CXCL9) and manifested a strong prediction performance. High-risk patients had enriched EMT pathways, more Macrophages_M2, less plasma cells and CD8 cell infiltration, greater tendency of immune escape and worse prognosis. The risk score has negatively correlated relation with LAG3, TIGIT, CTLA4, IDO1, CD27, ICOS, and IL2RB but positively correlated with PVR, CD276, and CD28. Moreover, low-risk patients were more sensitive to Cisplatin and Gefitinib, Gemcitabine.

Conclusions: Our results could improve the understanding of ferroptosis in OV, providing promising insights for the clinical targeted therapy for the cancer.

Citing Articles

Keratin-15 high expression links with lymph node metastasis and poor survival prognosis in epithelial ovarian cancer patients.

Feng X, Wang Q Discov Oncol. 2024; 15(1):555.

PMID: 39402426 PMC: 11473747. DOI: 10.1007/s12672-024-01404-3.

Ferroptosis: mechanism, immunotherapy and role in ovarian cancer.

Guo K, Lu M, Bi J, Yao T, Gao J, Ren F Front Immunol. 2024; 15:1410018.

PMID: 39192972 PMC: 11347334. DOI: 10.3389/fimmu.2024.1410018.

References

Rhee I . Diverse macrophages polarization in tumor microenvironment. Arch Pharm Res. 2016; 39(11):1588-1596. DOI: 10.1007/s12272-016-0820-y. View

Matulonis U, Shapira-Frommer R, Santin A, Lisyanskaya A, Pignata S, Vergote I . Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. Ann Oncol. 2019; 30(7):1080-1087. DOI: 10.1093/annonc/mdz135. View

Bagaev A, Kotlov N, Nomie K, Svekolkin V, Gafurov A, Isaeva O . Conserved pan-cancer microenvironment subtypes predict response to immunotherapy. Cancer Cell. 2021; 39(6):845-865.e7. DOI: 10.1016/j.ccell.2021.04.014. View

Dongre A, Weinberg R . New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat Rev Mol Cell Biol. 2018; 20(2):69-84. DOI: 10.1038/s41580-018-0080-4. View

Jiang P, Gu S, Pan D, Fu J, Sahu A, Hu X . Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nat Med. 2018; 24(10):1550-1558. PMC: 6487502. DOI: 10.1038/s41591-018-0136-1. View

Calvo F, Ranftl R, Hooper S, Farrugia A, Moeendarbary E, Bruckbauer A . Cdc42EP3/BORG2 and Septin Network Enables Mechano-transduction and the Emergence of Cancer-Associated Fibroblasts. Cell Rep. 2015; 13(12):2699-714. PMC: 4700053. DOI: 10.1016/j.celrep.2015.11.052. View

Beroukhim R, Mermel C, Porter D, Wei G, Raychaudhuri S, Donovan J . The landscape of somatic copy-number alteration across human cancers. Nature. 2010; 463(7283):899-905. PMC: 2826709. DOI: 10.1038/nature08822. View

Li L, Wang X . Identification of gastric cancer subtypes based on pathway clustering. NPJ Precis Oncol. 2021; 5(1):46. PMC: 8172826. DOI: 10.1038/s41698-021-00186-z. View

Hanzelmann S, Castelo R, Guinney J . GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics. 2013; 14:7. PMC: 3618321. DOI: 10.1186/1471-2105-14-7. View

10.

Lu N, Liu J, Xu M, Liang J, Wang Y, Wu Z . CSMD3 is Associated with Tumor Mutation Burden and Immune Infiltration in Ovarian Cancer Patients. Int J Gen Med. 2021; 14:7647-7657. PMC: 8575319. DOI: 10.2147/IJGM.S335592. View

11.

Cao L, Che X, Qiu X, Li Z, Yang B, Wang S . M2 macrophage infiltration into tumor islets leads to poor prognosis in non-small-cell lung cancer. Cancer Manag Res. 2019; 11:6125-6138. PMC: 6613613. DOI: 10.2147/CMAR.S199832. View

12.

Silwal-Pandit L, Langerod A, Borresen-Dale A . TP53 Mutations in Breast and Ovarian Cancer. Cold Spring Harb Perspect Med. 2016; 7(1). PMC: 5204332. DOI: 10.1101/cshperspect.a026252. View

13.

Lei G, Zhuang L, Gan B . Targeting ferroptosis as a vulnerability in cancer. Nat Rev Cancer. 2022; 22(7):381-396. PMC: 10243716. DOI: 10.1038/s41568-022-00459-0. View

14.

Mao Y, Feng Q, Zheng P, Yang L, Liu T, Xu Y . Low tumor purity is associated with poor prognosis, heavy mutation burden, and intense immune phenotype in colon cancer. Cancer Manag Res. 2018; 10:3569-3577. PMC: 6149864. DOI: 10.2147/CMAR.S171855. View

15.

Hamanishi J, Mandai M, Ikeda T, Minami M, Kawaguchi A, Murayama T . Safety and Antitumor Activity of Anti-PD-1 Antibody, Nivolumab, in Patients With Platinum-Resistant Ovarian Cancer. J Clin Oncol. 2015; 33(34):4015-22. DOI: 10.1200/JCO.2015.62.3397. View

16.

Auslander N, Zhang G, Lee J, Frederick D, Miao B, Moll T . Robust prediction of response to immune checkpoint blockade therapy in metastatic melanoma. Nat Med. 2018; 24(10):1545-1549. PMC: 6693632. DOI: 10.1038/s41591-018-0157-9. View

17.

Ribatti D, Tamma R, Annese T . Epithelial-Mesenchymal Transition in Cancer: A Historical Overview. Transl Oncol. 2020; 13(6):100773. PMC: 7182759. DOI: 10.1016/j.tranon.2020.100773. View

18.

Wang Y, Wei Z, Pan K, Li J, Chen Q . The function and mechanism of ferroptosis in cancer. Apoptosis. 2020; 25(11-12):786-798. DOI: 10.1007/s10495-020-01638-w. View

19.

Thompson L, Oliveira T, Hermann E, Chowanadisai W, Clarke S, Montgomery M . Distinct TP53 Mutation Types Exhibit Increased Sensitivity to Ferroptosis Independently of Changes in Iron Regulatory Protein Activity. Int J Mol Sci. 2020; 21(18). PMC: 7555626. DOI: 10.3390/ijms21186751. View

20.

Bebber C, Muller F, Prieto Clemente L, Weber J, von Karstedt S . Ferroptosis in Cancer Cell Biology. Cancers (Basel). 2020; 12(1). PMC: 7016816. DOI: 10.3390/cancers12010164. View