Identification of senescence-related subtypes, establishment of a prognosis model, and characterization of a tumor microenvironment infiltration in breast cancer

Abstract

Breast cancer is a malignancy with the highest incidence and mortality in women worldwide. Senescence is a model of arrest in the cell cycle, which plays an important role in tumor progression, while the prognostic value of cellular senescence-related genes (SRGs) in evaluating immune infiltration and clinical outcomes of breast cancer needs further investigation. In the present study, we identified two distinct molecular subtypes according to the expression profiles of 278 SRGs. We further explored the dysregulated pathways between the two subtypes and constructed a microenvironmental landscape of breast cancer. Subsequently, we established a senescence-related scoring signature based on the expression of four SRGs in the training set (GSE21653) and validated its accuracy in two validation sets (GSE20685 and GSE25055). In the training set, patients in the high-risk group had a worse prognosis than patients in the low-risk group. Multivariate Cox regression analysis showed that risk score was an independent prognostic indicator. Receiver operating characteristic curve (ROC) analysis proved the predictive accuracy of the signature. The prognostic value of this signature was further confirmed in the validation sets. We also observed that a lower risk score was associated with a higher pathological response rate in patients with neoadjuvant chemotherapy. We next performed functional experiments to validate the results above. Our study demonstrated that these cellular senescence patterns effectively grouped patients at low or high risk of disease recurrence and revealed their potential roles in the tumor–immune–stromal microenvironment. These findings enhanced our understanding of the tumor immune microenvironment and provided new insights for improving the prognosis of breast cancer patients.

Comprehensive genomics analysis of aging related gene signature to predict the prognosis and drug resistance of colon adenocarcinoma

“…A previous study has identified several senescence-associated gene signatures using transcriptome data from TCGA database, which can predict clinical outcomes and responses to immunotherapy in patients with head and neck squamous cell carcinoma (Wang et al, 2022). Another study has developed the senescence-related subtypes, established a prognostic risk model, and further revealed their potential roles in TME in breast cancer only using transcriptome data from GEO cohort (Zhou et al, 2022). In the present study, we downloaded the scRNA-seq data of 13 COAD samples from GEO database and demonstrated that senescence-related pathways were highly expressed in malignant cells than that of non-malignant cells, indicating that cellular senescence was largely associated with heterogeneity of TME in COAD at single cell level.…”

Identification of a novel senescence-associated signature to predict biochemical recurrence and immune microenvironment for prostate cancer

“…In the past decades, senescence was defined as an adaptive response of cells against unfavorable conditions. In the context of cancer, senescence-mediated life stagnation is a critical intrinsic mechanism of antitumor defense since (pre)neoplastic cells can be prevented from proliferation and progression ( 7 ). This concept has recently been queried by conflicting evidence showing that non-malignant and malignant cells with lastingly persistent senescence can acquire carcinogenic properties.…”

A cellular senescence-related genes model allows for prognosis and treatment stratification of cervical cancer: a bioinformatics analysis and external verification

“…In the past, senescence has been recognized as an adaptive response of cells to adverse conditions. In the context of cancer, senescence-mediated growth stagnation serves as an intrinsic mechanism to counteract tumor progression by preventing the proliferation of (pre)neoplastic cells [ 7 ]. Pereira et al and other researchers have shown that senescent cells can avoid immune clearance by discharging SASP factors, such as IL-6.…”