Identification of a novel necroptosis-related classifier to predict prognosis and guide immunotherapy in breast invasive carcinoma

Abstract

BackgroundNecroptosis plays a crucial function in the progression of breast invasive carcinoma (BRCA). It may be triggered in cancer therapy to enhance anti-tumor immunity. However, the functions of necroptosis in tumors and its relationship with the tumor microenvironment (TME) remain largely unclear.MethodsNecroptosis-related genes (NRGs) were collated from high-quality literature reviews. A robust risk model was constructed to systematically evaluate the clinical value, functional status, effects exerted by the risk model on the TME, and the genomic variations based on the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) meta-cohorts.ResultsA risk model was constructed which comprised of six NRGs, including TNF receptor-associated factor 5 (TRAF5), Toll-like receptor 3 (TLR3), a riboflavin kinase (RFK), Fas ligand (FASLG), Fas-associated protein with death domain (FADD), and baculoviral IAP repeat-containing 3 (BIRC3). The stability and accuracy of the risk model were demonstrated for both the training and validation cohorts and its utility as an independent prognostic model for BRCA was verified. Patients in the low-risk group exhibited “hot” tumors having active immune and cell killing functions, while those in the high-risk group showed “cold” tumors having active tumor proliferation and immunosuppression. Moreover, patients in the high-risk group had a greater number of CNV events in their genome, while the somatic mutations were fewer. Furthermore, patients in the low-risk group showed high sensitivity toward immunotherapy and chemotherapy.ConclusionA reliable risk model based on NRGs to assess patient prognoses and guide clinical decision-making was constructed and validated. Our findings may contribute to the understanding of necroptosis and aid clinical management, along with precision treatment in BRCA.

VDX‐111, a novel small molecule, induces necroptosis to inhibit ovarian cancer progression

“…12 While there are limited studies of the antitumor potential of inciting necroptosis in immune-compromised and immune-intact ovarian cancer models, multiple studies reveal that necroptosis-related gene signatures predict improved responses to immune therapy. [13][14][15] In this work, evaluation of VDX-111 in both a patient-derived xenograft and a syngeneic ovarian cancer murine model demonstrated survival benefit and antitumoral effects. While both necroptosis and apoptosis effectors were changed in response to drug treatment, we focused on necroptosis-related cell death due to its consistent induction across all models and its limited understanding in ovarian cancer.…”

“…Necroptosis is mediated in a caspase‐independent fashion through Receptor Interacting Protein Kinases (RIPK1/3) and Mixed Lineage Kinase domain‐like (MLKL) and leads to a robust inflammatory response and immune activation 12 . While there are limited studies of the antitumor potential of inciting necroptosis in immune‐compromised and immune‐intact ovarian cancer models, multiple studies reveal that necroptosis‐related gene signatures predict improved responses to immune therapy 13–15 …”

Single‑cell RNA‑seq necroptosis‑related genes predict the prognosis of breast cancer and affect the differentiation of CD4+ T cells in tumor immune microenvironment

“…In the majority of cases, BIRC3 is regarded as an oncogene with antiapoptotic functions; however, in BC, BIRC3 does not regulate any pathway of apoptosis ( 32 ). A recent study by Zhou et al ( 33 ) showed that BIRC3 was highly expressed in BC, and its high expression was associated with favorable prognosis. The dual function of BIRC3 may depend on the type of cancer and/or the molecular subtype of BC.…”

Determination and characterization of molecular heterogeneity and precision medicine strategies of patients with pancreatic cancer and pancreatic neuroendocrine tumor based on oxidative stress and mitochondrial dysfunction-related genes

“…MRPL14 is part of 2 intersubunit bridges in the assembled ribosome, which might be involved in the occurrence and development of thyroid tumors ( 72 ). RFK is essential for TNF-induced ROS production, which can influence the progress of breast invasive carcinoma and human prostate cancer ( 71 , 73 ). However, the role of COQ4, MCRIP2, MRPL50, MRPL14, RFK, and NMNAT3 in pancreatic tumor has not been reported.…”