Cell Senescence-Related Pathways Are Enriched in Breast Cancer Patients With Late Toxicity After Radiotherapy and Low Radiation-Induced Lymphocyte Apoptosis
Por:
Aguado-Flor E., Fuentes-Raspall M.J., Gonzalo R., Alonso C., Ramón y Cajal T., Fisas D., Seoane A., Sánchez-Pla Á., Giralt J., Díez O., Gutiérrez-Enríquez S.
Publicada:
1 ene 2022
Resumen:
Background: Radiation-induced late effects are a common cause of morbidity among cancer survivors. The biomarker with the best evidence as a predictive test of late reactions is the radiation-induced lymphocyte apoptosis (RILA) assay. We aimed to investigate the molecular basis underlying the distinctive RILA levels by using gene expression analysis in patients with and without late effects and in whom we had also first identified differences in RILA levels. Patients and Methods: Peripheral blood mononuclear cells of 10 patients with late severe skin complications and 10 patients without symptoms, selected from those receiving radiotherapy from 1993 to 2007, were mock-irradiated or irradiated with 8 Gy. The 48-h response was analyzed in parallel by RILA assay and gene expression profiling with Affymetrix microarrays. Irradiated and non-irradiated gene expression profiles were compared between both groups. Gene set enrichment analysis was performed to identify differentially expressed biological processes. Results: Although differentially expressed mRNAs did not reach a significant adjusted p-value between patients suffering and not suffering clinical toxicity, the enriched pathways indicated significant differences between the two groups, either in irradiated or non-irradiated cells. In basal conditions, the main differentially expressed pathways between the toxicity and non-toxicity groups were the transport of small molecules, interferon signaling, and transcription. After 8 Gy, the differences lay in pathways highly related to cell senescence like cell cycle/NF-?B, G-protein-coupled receptors, and interferon signaling. Conclusion: Patients at risk of developing late toxicity have a distinctive pathway signature driven by deregulation of immune and cell cycle pathways related to senescence, which in turn may underlie their low RILA phenotype. Copyright © 2022 Aguado-Flor, Fuentes-Raspall, Gonzalo, Alonso, Ramón y Cajal, Fisas, Seoane, Sánchez-Pla, Giralt, Díez and Gutiérrez-Enríquez.
Filiaciones:
Aguado-Flor E.:
Hereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
Fuentes-Raspall M.J.:
Radiation Oncology Department, Santa Creu i Sant Pau Hospital, Barcelona, Spain
Gonzalo R.:
Statistics and Bioinformatics Unit, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
Alonso C.:
Medical Oncology Department, Santa Creu i Sant Pau Hospital, Barcelona, Spain
Ramón y Cajal T.:
Medical Oncology Department, Santa Creu i Sant Pau Hospital, Barcelona, Spain
Fisas D.:
Medical Oncology Department, Santa Creu i Sant Pau Hospital, Barcelona, Spain
Seoane A.:
Medical Physics Department, Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campu, s, Barcelona, Spain
Sánchez-Pla Á.:
Statistics and Bioinformatics Unit, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
Genetics, Microbiology and Statistics Department, Universitat de Barcelona, Barcelona, Spain
Giralt J.:
Radiation Oncology Department, Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
Radiation Oncology Group, Vall d’Hebron Institute of Oncology (VHIO, Vall d’Hebron Barcelona Hospital Campu, s, Barcelona, Spain
Díez O.:
Hereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
Area of Clinical and Molecular Genetics, Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
Gutiérrez-Enríquez S.:
Hereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
All Open Access; Gold
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