title: Evaluation of Severe Combined Immunodeficiency and Combined Immunodeficiency Pediatric Patients on the Basis of Cellular Radiosensitivity.
abstract: Pediatric patients with severe or nonsevere combined immunodeficiency have increased susceptibility to severe, life-threatening infections and, without hematopoietic stem cell transplantation, may fail to thrive. A subset of these patients have the radiosensitive (RS) phenotype, which may necessitate conditioning before hematopoietic stem cell transplantation, and this conditioning includes radiomimetic drugs, which may significantly affect treatment response. To provide statistical criteria for classifying cellular response to ionizing radiation as the measure of functional RS screening, we analyzed the repair capacity and survival of ex vivo irradiated primary skin fibroblasts from five dysmorphic and/or developmentally delayed pediatric patients with severe combined immunodeficiency and combined immunodeficiency. We developed a mathematical framework for the analysis of γ histone 2A isoform X foci kinetics to quantitate DNA-repair capacity, thus establishing crucial criteria for identifying RS. The results, presented in a diagram showing each patient as a point in a 2D RS map, were in agreement with findings from the assessment of cellular RS by clonogenic survival and from the genetic analysis of factors involved in the nonhomologous end-joining repair pathway. We provide recommendations for incorporating into clinical practice the functional assays and genetic analysis used for establishing RS status before conditioning. This knowledge would enable the selection of the most appropriate treatment regimen, reducing the risk for severe therapy-related adverse effects.
authors.affiliation: Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Pavel
authors.initials: P
authors.lastname: Lobachevsky
authors.affiliation: Sussex Centre for Genome Damage and Stability, University of Sussex-Falmer, Brighton, United Kingdom.
authors.forename: Lisa
authors.initials: L
authors.lastname: Woodbine
authors.affiliation: Department of Allergy and Immunology, Royal Children's Hospital, Melbourne, Victoria, Australia.
authors.forename: Kuang-Chih
authors.initials: KC
authors.lastname: Hsiao
authors.affiliation: Department of Allergy and Immunology, Royal Children's Hospital, Melbourne, Victoria, Australia.
authors.forename: Sharon
authors.initials: S
authors.lastname: Choo
authors.affiliation: Oncology Unit, Children's Health Services, Queensland Health, Herston, Queensland, Australia.
authors.forename: Chris
authors.initials: C
authors.lastname: Fraser
authors.affiliation: Department of Immunology and Infectious Diseases, Sydney Children's Hospital, Sydney, New South Wales, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Gray
authors.affiliation: Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Jai
authors.initials: J
authors.lastname: Smith
authors.affiliation: Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Nickala
authors.initials: N
authors.lastname: Best
authors.affiliation: Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Laura
authors.initials: L
authors.lastname: Munforte
authors.affiliation: Sussex Centre for Genome Damage and Stability, University of Sussex-Falmer, Brighton, United Kingdom.
authors.forename: Elena
authors.initials: E
authors.lastname: Korneeva
authors.affiliation: Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Roger F
authors.initials: RF
authors.lastname: Martin
authors.affiliation: Sussex Centre for Genome Damage and Stability, University of Sussex-Falmer, Brighton, United Kingdom.
authors.forename: Penny A
authors.initials: PA
authors.lastname: Jeggo
authors.affiliation: Molecular Radiation Biology Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia; Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Electronic address: olga.martin@petermac.org.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Martin
mesh_terms: D000293:Adolescent; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005260:Female; D005347:Fibroblasts / Q000473:pathology / Q000528:radiation effects; D006801:Humans; D007223:Infant; D008297:Male; D010641:Phenotype; D011836:Radiation Tolerance / Q000502:physiology*; D016511:Severe Combined Immunodeficiency / Q000175:diagnosis* / Q000473:pathology; D012867:Skin / Q000473:pathology / Q000528:radiation effects