title: Monoallelic mutations of the perforin gene may represent a predisposing factor to childhood anaplastic large cell lymphoma.
abstract: Anaplastic large cell lymphoma (ALCL) accounts for approximately 15% of all pediatric non-Hodgkin lymphomas. It has distinct clinical features, including frequent involvement of extranodal sites and rare localization to the central nervous system. As some presenting features of ALCL are in common with the hemophagocytic syndrome, we previously analyzed a small series of patients with ALCL for PRF1 mutations and found that 27% of them carried mutations. We now expanded our preliminary study by increasing the cohort of ALCL patients to a total of 84 consecutive cases, in whom we extended mutation analysis to the genes SH2D1A, PRF1 e UNC13D, all related to familial HLH. Furthermore, perforin expression in tumor cells was investigated on paraffin-embedded tissues by immunohistochemical analysis. Mutations were observed in 23/84 patients (27.4%). Twenty-one patients (25%) carried a total of 10 different mutations of PRF1; they were monoallelic in 20 patients, biallelic in 1. No mutations were found in the gene SH2D1A. Two additional patients had missense mutations of the UNC13D gene. These data show that monoallelic germline mutations of PRF1 are frequent in patients with childhood ALCL, suggesting that partially impaired cytotoxic machinery may represent a predisposing factor for ALCL. Involvement is less frequent for UNC13D and absent for SH2D1A.
authors.affiliation: *Pediatric Hematology-Oncology, Azienda Ospedaliero Universitaria Meyer Children Hospital, Firenze †Istituto Toscano Tumori (I.T.T.), Tuscany Pediatric Hematology Oncology Network, Florence ‡Istituto di Ricerca Pediatrico, Fondazione Città della Speranza §Clinica di Oncoematologia Pediatrica, Azienda Ospedaliera-Università di Padova ∥Department of Pathology, San Bortolo Hospital, Vicenza ¶Clinica Pediatrica, Università di Udine, Udine, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Ciambotti
authors.forename: Lara
authors.initials: L
authors.lastname: Mussolin
authors.forename: Emanuele S G
authors.initials: ES
authors.lastname: d'Amore
authors.forename: Marta
authors.initials: M
authors.lastname: Pillon
authors.forename: Elena
authors.initials: E
authors.lastname: Sieni
authors.forename: Maria L
authors.initials: ML
authors.lastname: Coniglio
authors.forename: Martina D
authors.initials: MD
authors.lastname: Ros
authors.forename: Valentina
authors.initials: V
authors.lastname: Cetica
authors.forename: Maurizio
authors.initials: M
authors.lastname: Aricò
authors.forename: Angelo
authors.initials: A
authors.lastname: Rosolen
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D000818:Animals; D019556:COS Cells; D002648:Child; D002522:Chlorocebus aethiops; D003198:Computer Simulation; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D018095:Germ-Line Mutation; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D020125:Mutation, Missense; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; C510468:PRF1 protein, human; D052899:Pore Forming Cytotoxic Proteins; C507969:UNC13D protein, human; D054353:Perforin