NetPSig: Computationally guided neutrophil extracellular trap-associated signature significantly predicts the prognosis and therapeutic response in breast cancer

Abstract Background: Considerable evidence suggests that neutrophil extracellular traps (NETs) are involved in cancer development and metastasis dissemination. Equally important, the yet to be defined role of NETs in resistance to cancer therapies. Results: Herein, we investigated the expression alterations and genetic variations (mutations, SNPs) in NETs-associated genes and related them to the clinical outcomes in breast cancer (BC) patients. To strengthen our analysis, we established a novel prognostic signature (named as, NetPSig) and confirmed its robust performance using several independent BC cohorts and publicly available BC gene-based signatures. Our analysis clearly demonstrated that: 1) expression and genetic variation of NETs-associated genes significantly contribute to the prognosis of BC; 2) NetPSig complements BC-related clinically valuable variables such as age, PAM50 and tumor stage; 3) the biological disparities in high- and low-risk groups identified by NetPSig confer prognostic values (p-value ≤ 0.01), in particular, the high-risk group showed worse prognosis with enrichment of P53mutations, 4) NetPSig performed positively in predicting the therapeutic response and identified five potential drugs (AZD7762, Bosutinib, DMOG, Docetaxel and Sunitinib) for the treatment of BC patients with lower risk score category. Conclusion: In summary, a novel prognostic signature (NetPSig) presented in this study provides more robust and better predictive performance compared to the existing BC gene-based signatures. Besides, we support the notion that NET-associated genes represent an opportunity to further improve the efficacy of cancer therapy.