Cell Senescence-Related Pathways Are Enriched in Breast Cancer Patients With Late Toxicity After Radiotherapy and Low Radiation-Induced Lymphocyte Apoptosis
Aguado-Flor, Ester (Vall d'Hebron Institut d'Oncologia)
Fuentes-Raspall, María J. (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Gonzalo Sanz, Ricardo (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Alonso, Carmen (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Ramon y Cajal, Teresa (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Fisas, David (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Seoane, A. (Hospital Universitari Vall d'Hebron)
Sánchez, Alex (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Giralt López de Sagredo, Jordi (Vall d'Hebron Institut d'Oncologia)
Diez, Orland (Hospital Universitari Vall d'Hebron)
Gutiérrez-Enríquez, Sara (Vall d'Hebron Institut d'Oncologia)
Universitat Autònoma de Barcelona

Date:	2022
Abstract:	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-κB, 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.
Grants:	Ministerio de Economía y Competitividad CP16/00034
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Breast cancer ; Gene set enrichment analysis (GSEA) ; Late skin toxicity ; Radiation-induced lymphocyte apoptosis (RILA) ; Radiotherapy-adverse effects
Published in:	Frontiers in Oncology, Vol. 12 (24 2022) , p. 825703, ISSN 2234-943X

DOI: 10.3389/fonc.2022.825703
PMID: 35686103

10 p, 7.6 MB

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