RESUMO
Immunotherapy for neuroblastoma remains unsatisfactory due to heterogeneity and weak immunogenicity. Exploring powerful signatures for the evaluation of immunotherapy outcomes remain the primary purpose. We constructed a ferroptosis-related gene (FRG) signature by least absolute shrinkage and selection operator and Cox regression, identified 10 independent prognostic FRGs in a training cohort (GSE62564), and then verified them in an external validation cohort (TCGA). Associated with clinical factors, the signature accurately predicts overall survival of 3, 5, and 10 years. An independent prognostic nomogram, which included FRG risk, age, stage of the International Neuroblastoma Staging System, and an MYCN status, was constructed. The area under the curves showed satisfactory prognostic predicting performance. Through bulk RNA-seq and proteomics data, we revealed the relationship between hub genes and the key onco-promoter MYCN gene and then validated the results in MYCN-amplified and MYCN-non-amplified cell lines with qRT-PCR. The FRG signature significantly divided patients into high- and low-risk groups, and the differentially expressed genes between the two groups were enriched in immune actions, autophagy, and carcinogenesis behaviors. The low-risk group embodied higher positive immune component infiltration and a higher expression of immune checkpoints with a more favorable immune cytolytic activity (CYT). We verified the predictive power of this signature with data from melanoma patients undergoing immunotherapy, and the predictive power was satisfactory. Gene mutations were closely related to the signature and prognosis. AURKA and PRKAA2 were revealed to be nodal hub FRGs in the signature, and both were shown to have significantly different expressions between the INSS stage IV and other stages after immunohistochemical validation. With single-cell RNA-seq analysis, we found that genes related to T cells were enriched in TNFA signaling and interferon-γ hallmark. In conclusion, we constructed a ferroptosis-related gene signature that can predict the outcomes and work in evaluating the effects of immunotherapy.
RESUMO
BACKGROUND: Triple-negative breast cancer (TNBC) is considered to be higher grade, more aggressive and have a poorer prognosis than other types of breast cancer. Discover biomarkers in TNBC for risk stratification and treatments that improve prognosis are in dire need. METHODS: Clinical data of 195 patients with triple negative breast cancer confirmed by pathological examination and received neoadjuvant chemotherapy (NAC) were collected. The expression levels of EGFR and CK5/6 were measured before and after NAC, and the relationship between EGFR and CK5/6 expression and its effect on prognosis of chemotherapy was analyzed. RESULTS: The overall response rate (ORR) was 86.2% and the pathological complete remission rate (pCR) was 29.2%. Univariate and multivariate logistic regression analysis showed that cT (clinical Tumor stages) stage was an independent factor affecting chemotherapy outcome. Multivariate Cox regression analysis showed pCR, chemotherapy effect, ypT, ypN, histological grades, and post- NAC expression of CK5/6 significantly affected prognosis. The prognosis of CK5/6-positive patients after NAC was worse than that of CK5/6-negative patients (p=0.036). Changes in CK5/6 and EGFR expression did not significantly affect the effect of chemotherapy, but changes from positive to negative expression of these two markers are associated with a tendency to improve prognosis. CONCLUSION: For late-stage triple negative breast cancer patients receiving NAC, patients who achieved pCR had a better prognosis than those with non- pCR. Patients with the change in expression of EGFR and CK5/6 from positive to negative after neoadjuvant chemotherapy predicted a better prognosis than the change from negative to positive group.
