title: TNFSF10/TRAIL regulates human T4 effector memory lymphocyte radiosensitivity and predicts radiation-induced acute and subacute dermatitis.
abstract: Sensitivity of T4 effector-memory (T4EM) lymphocytes to radiation-induced apoptosis shows heritability compatible with a Mendelian mode of transmission. Using gene expression studies and flow cytometry, we show a higher TNF-Related Apoptosis Inducing Ligand (TRAIL/TNFSF10)mRNA level and a higher level of membrane bound TRAIL (mTRAIL) on radiosensitive compared to radioresistant T4EM lymphocytes. Functionally, we show that mTRAIL mediates a pro-apoptotic autocrine signaling after irradiation of T4EM lymphocytes linking mTRAIL expression to T4EM radiosensitivity. Using single marker and multimarker Family-Based Association Testing, we identified 3 SNPs in the TRAIL gene that are significantly associated with T4EM lymphocytes radiosensitivity. Among these 3 SNPs, two are also associated with acute and subacute dermatitis after radiotherapy in breast cancer indicating that T4EM lymphocytes radiosensitivity may be used to predict response to radiotherapy. Altogether, these results show that mTRAIL level regulates the response of T4EM lymphocytes to ionizing radiation and suggest that TRAIL/TNFSF10 genetic variants hold promise as markers of individual radiosensitivity.
authors.affiliation: CEA/DRF/IRCM/SCSR, Fontenay-aux-Roses Cedex, France.|Inserm U967, Fontenay-aux-Roses Cedex, France.|Université Paris-Diderot, Paris, France.|Université Paris-Sud, Paris, France.
authors.forename: Jan
authors.initials: J
authors.lastname: Baijer
authors.affiliation: CEA/DRF/IRCM/SCSR, Fontenay-aux-Roses Cedex, France.|Inserm U967, Fontenay-aux-Roses Cedex, France.|Université Paris-Diderot, Paris, France.|Université Paris-Sud, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Déchamps
authors.affiliation: Université Paris-Saclay, Univ. Paris-Sud, Inserm, CESP, Villejuif, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Perdry
authors.affiliation: CEA/DRF/IRCM/SCSR, Fontenay-aux-Roses Cedex, France.
authors.forename: Pablo
authors.initials: P
authors.lastname: Morales
authors.affiliation: University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kerns
authors.affiliation: CEA/DRF/IRCM/SCSR, Fontenay-aux-Roses Cedex, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Vasilescu
authors.affiliation: ICGex Next-Generation Sequencing Platform, Institut Curie, Paris, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Baulande
authors.affiliation: Department of Radiation Oncology, ICM-Val d'Aurelle and INSERM U896, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.
authors.forename: David
authors.initials: D
authors.lastname: Azria
authors.affiliation: CEA/DRF/IRCM/SCSR, Fontenay-aux-Roses Cedex, France.|Inserm U967, Fontenay-aux-Roses Cedex, France.|Université Paris-Diderot, Paris, France.|Université Paris-Sud, Paris, France.
authors.forename: Paul Henri
authors.initials: PH
authors.lastname: Roméo
authors.affiliation: CEA/DRF/IRCM/SCSR, Fontenay-aux-Roses Cedex, France.
authors.forename: Annette
authors.initials: A
authors.lastname: Schmitz
mesh_terms: D000208:Acute Disease; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000528:radiation effects; D003872:Dermatitis / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D015870:Gene Expression / Q000528:radiation effects; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011836:Radiation Tolerance / Q000235:genetics; D011839:Radiation, Ionizing; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000528:radiation effects; D012867:Skin / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*
chemical_list: D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human
keywords: TRAIL; acute radiosensitivity; apoptosis; biomarker; lymphocyte