title: Perforin polymorphism A91V and susceptibility to B-precursor childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group.
abstract: Perforin plays a key role in the cytotoxicity of natural killer and cytotoxic T cells. Genetic mutations in the perforin gene (PRF1) give rise to approximately 30% cases of familial hemophagocytic lymphohistiocytosis. A frequent polymorphism, A91V (C to T transition at position 272), may impair processing of perforin protein to the active form, and has been suggested to increase susceptibility to childhood acute lymphoblastic leukemia (ALL). To investigate the role of A91V in ALL, we genotyped 2272 children with de novo ALL registered on the Pediatric Oncology Group ALL Classification study P9900 and 655 normal controls. Allele frequencies in the controls showed a very low frequency of the variant allele in blacks, 0.7% compared to 4% in white controls. In light of this, analysis was restricted to a comparison of white cases and controls only. Overall genotype frequencies were similar in white ALL cases and normal white controls (P=0.58), indicating that in contrast to the previous report, A91V polymorphism is not associated with increased risk of childhood ALL. PRF1 A91V frequency was significantly increased in children with BCR-ABL positive ALL (24 vs 8.5%; P=0.0048); however, this observation includes a relatively small number of cases and needs further exploration.
authors.affiliation: Division of Hematology Oncology, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229, USA. parinda.mehta@ccmhc.org
authors.forename: P A
authors.initials: PA
authors.lastname: Mehta
authors.forename: S M
authors.initials: SM
authors.lastname: Davies
authors.forename: A
authors.initials: A
authors.lastname: Kumar
authors.forename: M
authors.initials: M
authors.lastname: Devidas
authors.forename: S
authors.initials: S
authors.lastname: Lee
authors.forename: T
authors.initials: T
authors.lastname: Zamzow
authors.forename: J
authors.initials: J
authors.lastname: Elliott
authors.forename: J
authors.initials: J
authors.lastname: Villanueva
authors.forename: J
authors.initials: J
authors.lastname: Pullen
authors.forename: Y
authors.initials: Y
authors.lastname: Zewge
authors.forename: A
authors.initials: A
authors.lastname: Filipovich
mesh_terms: D001483:Base Sequence; D002051:Burkitt Lymphoma / Q000235:genetics*; D002648:Child; D017931:DNA Primers; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics*; D054353:Perforin; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D052899:Pore Forming Cytotoxic Proteins; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*
chemical_list: D017931:DNA Primers; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin