Genome Instability-Derived Genes Are Novel Prognostic Biomarkers for Triple-Negative Breast Cancer

Overview

Journal Front Cell Dev Biol

Specialty Cell Biology

Date 2021 Jul 29

PMID 34322487

Citations 8

Authors

Maoni Guo

San Ming Wang

Affiliations

Soon will be listed here.

Abstract

Background: Triple-negative breast cancer (TNBC) is an aggressive disease. Recent studies have identified genome instability-derived genes for patient outcomes. However, most of the studies mainly focused on only one or a few genome instability-related genes. Prognostic potential and clinical significance of genome instability-associated genes in TNBC have not been well explored.

Methods: In this study, we developed a computational approach to identify TNBC prognostic signature. It consisted of (1) using somatic mutations and copy number variations (CNVs) in TNBC to build a binary matrix and identifying the top and bottom 25% mutated samples, (2) comparing the gene expression between the top and bottom 25% samples to identify genome instability-related genes, and (3) performing univariate Cox proportional hazards regression analysis to identify survival-associated gene signature, and Kaplan-Meier, log-rank test, and multivariate Cox regression analyses to obtain overall survival (OS) information for TNBC outcome prediction.

Results: From the identified 111 genome instability-related genes, we extracted a genome instability-derived gene signature (GIGenSig) of 11 genes. Through survival analysis, we were able to classify TNBC cases into high- and low-risk groups by the signature in the training dataset (log-rank test = 2.66e-04), validated its prognostic performance in the testing (log-rank test = 2.45e-02) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) (log-rank test = 2.57e-05) datasets, and further validated the predictive power of the signature in five independent datasets.

Conclusion: The identified novel signature provides a better understanding of genome instability in TNBC and can be applied as prognostic markers for clinical TNBC management.

Citing Articles

RIOK1: A Novel Oncogenic Driver in Hepatocellular Carcinoma.

Ruan C, Shang T, Zhang S, Ru W, Yang Y, Shen Y Cancer Med. 2025; 14(3):e70597.

PMID: 39865406 PMC: 11761428. DOI: 10.1002/cam4.70597.

Emerging role and function of SPDL1 in human health and diseases.

Feng Y, Tang D, Wang J Open Med (Wars). 2024; 19(1):20240922.

PMID: 38623460 PMC: 11017184. DOI: 10.1515/med-2024-0922.

FEN1 Inhibition as a Potential Novel Targeted Therapy against Breast Cancer and the Prognostic Relevance of FEN1.

Berfelde J, Hildebrand L, Kuhlmann L, Fietkau R, Distel L Int J Mol Sci. 2024; 25(4).

PMID: 38396787 PMC: 10889347. DOI: 10.3390/ijms25042110.

Genome instability-derived genes as a novel prognostic signature for lung adenocarcinoma.

Zhang X, Lam T, Ting H Front Cell Dev Biol. 2023; 11:1224069.

PMID: 37655157 PMC: 10467266. DOI: 10.3389/fcell.2023.1224069.

The NF-κB Transcriptional Network Is a High-Dose Vitamin C-Targetable Vulnerability in Breast Cancer.

Mussa A, Afolabi H, Syed N, Talib M, Murtadha A, Hajissa K Biomedicines. 2023; 11(4).

PMID: 37189677 PMC: 10135907. DOI: 10.3390/biomedicines11041060.

References

Chen M, Pockaj B, Andreozzi M, Barrett M, Krishna S, Eaton S . JAK2 and PD-L1 Amplification Enhance the Dynamic Expression of PD-L1 in Triple-negative Breast Cancer. Clin Breast Cancer. 2018; 18(5):e1205-e1215. DOI: 10.1016/j.clbc.2018.05.006. View

Wang S, Beeghly-Fadiel A, Cai Q, Cai H, Guo X, Shi L . Gene expression in triple-negative breast cancer in relation to survival. Breast Cancer Res Treat. 2018; 171(1):199-207. PMC: 7195858. DOI: 10.1007/s10549-018-4816-9. View

Lyons T . Targeted Therapies for Triple-Negative Breast Cancer. Curr Treat Options Oncol. 2019; 20(11):82. DOI: 10.1007/s11864-019-0682-x. View

Sabatier R, Finetti P, Cervera N, Lambaudie E, Esterni B, Mamessier E . A gene expression signature identifies two prognostic subgroups of basal breast cancer. Breast Cancer Res Treat. 2010; 126(2):407-20. DOI: 10.1007/s10549-010-0897-9. View

Suo H, Tao Z, Zhang L, Jin Z, Li X, Ma W . Coexpression Network Analysis of Genes Related to the Characteristics of Tumor Stemness in Triple-Negative Breast Cancer. Biomed Res Int. 2020; 2020:7575862. PMC: 7374213. DOI: 10.1155/2020/7575862. View

Evan G, Vousden K . Proliferation, cell cycle and apoptosis in cancer. Nature. 2001; 411(6835):342-8. DOI: 10.1038/35077213. View

Guo L, Li W, Zhu X, Ling Y, Qiu T, Dong L . PD-L1 expression and CD274 gene alteration in triple-negative breast cancer: implication for prognostic biomarker. Springerplus. 2016; 5(1):805. PMC: 4916110. DOI: 10.1186/s40064-016-2513-x. View

Hatzis C, Pusztai L, Valero V, Booser D, Esserman L, Lluch A . A genomic predictor of response and survival following taxane-anthracycline chemotherapy for invasive breast cancer. JAMA. 2011; 305(18):1873-81. PMC: 5638042. DOI: 10.1001/jama.2011.593. View

Desrichard A, Snyder A, Chan T . Cancer Neoantigens and Applications for Immunotherapy. Clin Cancer Res. 2015; 22(4):807-12. DOI: 10.1158/1078-0432.CCR-14-3175. View

10.

Qian J, Chen H, Ji X, Eisenberg R, Chakravarthy A, Mayer I . A 3q gene signature associated with triple negative breast cancer organ specific metastasis and response to neoadjuvant chemotherapy. Sci Rep. 2017; 7:45828. PMC: 5384279. DOI: 10.1038/srep45828. View

11.

Denkert C, Liedtke C, Tutt A, von Minckwitz G . Molecular alterations in triple-negative breast cancer-the road to new treatment strategies. Lancet. 2016; 389(10087):2430-2442. DOI: 10.1016/S0140-6736(16)32454-0. View

12.

Suzuki K, Ohnami S, Tanabe C, Sasaki H, Yasuda J, Katai H . The genomic damage estimated by arbitrarily primed PCR DNA fingerprinting is useful for the prognosis of gastric cancer. Gastroenterology. 2003; 125(5):1330-40. DOI: 10.1016/j.gastro.2003.07.006. View

13.

Rao C, Asch A, Yamada H . Frequently mutated genes/pathways and genomic instability as prevention targets in liver cancer. Carcinogenesis. 2016; 38(1):2-11. PMC: 5219050. DOI: 10.1093/carcin/bgw118. View

14.

Song H, Cicek M, Dicks E, Harrington P, Ramus S, Cunningham J . The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. Hum Mol Genet. 2014; 23(17):4703-9. PMC: 4119409. DOI: 10.1093/hmg/ddu172. View

15.

Mermel C, Schumacher S, Hill B, Meyerson M, Beroukhim R, Getz G . GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 2011; 12(4):R41. PMC: 3218867. DOI: 10.1186/gb-2011-12-4-r41. View

16.

Johansson A, Andersson T, Hsieh C, Jirstrom K, Cnattingius S, Fredriksson I . Tumor characteristics and prognosis in women with pregnancy-associated breast cancer. Int J Cancer. 2017; 142(7):1343-1354. DOI: 10.1002/ijc.31174. View

17.

Kalimutho M, Nones K, Srihari S, Duijf P, Waddell N, Khanna K . Patterns of Genomic Instability in Breast Cancer. Trends Pharmacol Sci. 2019; 40(3):198-211. DOI: 10.1016/j.tips.2019.01.005. View

18.

Si L, Fu J, Liu W, Hayashi T, Mizuno K, Hattori S . Silibinin-induced mitochondria fission leads to mitophagy, which attenuates silibinin-induced apoptosis in MCF-7 and MDA-MB-231 cells. Arch Biochem Biophys. 2020; 685:108284. DOI: 10.1016/j.abb.2020.108284. View

19.

Senfter D, Samadaei M, Mader R, Gojo J, Peyrl A, Krupitza G . High impact of miRNA-4521 on FOXM1 expression in medulloblastoma. Cell Death Dis. 2019; 10(10):696. PMC: 6754377. DOI: 10.1038/s41419-019-1926-1. View

20.

Abuderman A, Harb O, Gertallah L . Prognostic and clinicopathological values of tissue expression of MFAP5 and ITM2A in triple-negative breast cancer: an immunohistochemical study. Contemp Oncol (Pozn). 2020; 24(2):87-95. PMC: 7403766. DOI: 10.5114/wo.2020.97520. View