Abstract
Background: Gliomas are highly lethal brain tumors. Despite multimodality therapy with surgery, radiotherapy, chemotherapy, and immunotherapy, glioma prognosis remains poor. Ferroptosis is a crucial tumor suppressor mechanism that has been proven to be effective in anticancer therapy. However, the implications of ferroptosis on the clinical prognosis, chemotherapy, and immune checkpoint inhibitor (ICI) therapy for patients with glioma still need elucidation. Methods: Consensus clustering revealed two distinct ferroptosis-related subtypes based on the Cancer Genome Atlas (TCGA) glioma dataset (n = 663). Subsequently, the ferroptosis-related gene prognostic index (FRGPI) was constructed by weighted gene co-expression network analysis (WGCNA) and “stepAIC” algorithms and validated with the Chinese Glioma Genome Atlas (CGGA) dataset (n = 404). Subsequently, the correlation among clinical, molecular, and immune features and FRGPI was analyzed. Next, the temozolomide sensitivity and ICI response for glioma were predicted using the “pRRophetic” and “TIDE” algorithms, respectively. Finally, candidate small molecular drugs were defined using the connectivity map database based on FRGPI. Results: The FRGPI was established based on the HMOX1, TFRC, JUN, and SOCS1 genes. The distribution of FRGPI varied significantly among the different ferroptosis-related subtypes. Patients with high FRGPI had a worse overall prognosis than patients with low FRGPI, consistent with the results in the CGGA dataset. The final results showed that high FRGPI was characterized by more aggressive phenotypes, high PD-L1 expression, high tumor mutational burden score, and enhanced temozolomide sensitivity; low FRGPI was associated with less aggressive phenotypes, high microsatellite instability score, and stronger response to immune checkpoint blockade. In addition, the infiltration of memory resting CD4+ T cells, regulatory T cells, M1 macrophages, M2 macrophages, and neutrophils was positively correlated with FRGPI. In contrast, plasma B cells and naïve CD4+ T cells were negatively correlated. A total of 15 potential small molecule compounds (such as depactin, physostigmine, and phenacetin) were identified. Conclusion: FRGPI is a promising gene panel for predicting the prognosis, immune characteristics, temozolomide sensitivity, and ICI response in patients with glioma.
Highlights
Gliomas, including low grade (LGG, World Health Organization grades I–II) and high grade (HGG, World Health Organization grades III–IV), are the most common and lethal solid tumors of all brain cancers (Louis et al, 2016; Aldape et al, 2019)
The final results showed that high ferroptosis-related gene prognostic index (FRGPI) was characterized by more aggressive phenotypes, high progressive disease (PD)-L1 expression, high tumor mutational burden score, and enhanced temozolomide sensitivity; low FRGPI was associated with less aggressive phenotypes, high microsatellite instability score, and stronger response to immune checkpoint blockade
Glutathione peroxidase 4 (GPX4), Ferroptosis suppressor protein 1 (FSP1), GCH1, and dihydrowhey dehydrogenase (DHODH) are key genes involved in cell ferroptosis defense (Zheng and Conrad, 2020; Mao et al, 2021)
Summary
Gliomas, including low grade (LGG, World Health Organization grades I–II) and high grade (HGG, World Health Organization grades III–IV), are the most common and lethal solid tumors of all brain cancers (Louis et al, 2016; Aldape et al, 2019). Current glioma multimodal therapy includes surgery, radiotherapy, chemotherapy, and immunotherapy. The overall prognosis remains poor, especially for glioblastomas, the most fatal of gliomas, which have 14.6 months of median survival (Tan et al, 2020). Despite multimodality therapy with surgery, radiotherapy, chemotherapy, and immunotherapy, glioma prognosis remains poor. The implications of ferroptosis on the clinical prognosis, chemotherapy, and immune checkpoint inhibitor (ICI) therapy for patients with glioma still need elucidation
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