title: Recurrent somatic mutations of PTPN1 in primary mediastinal B cell lymphoma and Hodgkin lymphoma.
abstract: Classical Hodgkin lymphoma and primary mediastinal B cell lymphoma (PMBCL) are related lymphomas sharing pathological, molecular and clinical characteristics. Here we discovered by whole-genome and whole-transcriptome sequencing recurrent somatic coding-sequence mutations in the PTPN1 gene. Mutations were found in 6 of 30 (20%) Hodgkin lymphoma cases, in 6 of 9 (67%) Hodgkin lymphoma-derived cell lines, in 17 of 77 (22%) PMBCL cases and in 1 of 3 (33%) PMBCL-derived cell lines, consisting of nonsense, missense and frameshift mutations. We demonstrate that PTPN1 mutations lead to reduced phosphatase activity and increased phosphorylation of JAK-STAT pathway members. Moreover, silencing of PTPN1 by RNA interference in Hodgkin lymphoma cell line KM-H2 resulted in hyperphosphorylation and overexpression of downstream oncogenic targets. Our data establish PTPN1 mutations as new drivers in lymphomagenesis.
authors: 1] Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada. [2] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Jay
authors: J
authors: Gunawardana
authors: 1] Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada. [2] Bioinformatics Training Program, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Fong Chun
authors: FC
authors: Chan
authors: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors: Adèle
authors: A
authors: Telenius
authors: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors: Bruce
authors: B
authors: Woolcock
authors: 1] Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada. [2] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Robert
authors: R
authors: Kridel
authors: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors: King L
authors: KL
authors: Tan
authors: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors: Susana
authors: S
authors: Ben-Neriah
authors: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors: Anja
authors: A
authors: Mottok
authors: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors: Raymond S
authors: RS
authors: Lim
authors: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors: Merrill
authors: M
authors: Boyle
authors: Centre for High-Throughput Biology, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Sanja
authors: S
authors: Rogic
authors: Department of Pathology, University of Arizona, Tucson, Arizona, USA.
authors: Lisa M
authors: LM
authors: Rimsza
authors: INSERM U955, Créteil, France.
authors: Chrystelle
authors: C
authors: Guiter
authors: 1] INSERM U955, Créteil, France. [2] Université Paris Est, Créteil, France. [3] Département de Pathologie-Service d'Hématologie-Plateforme de Ressources Biologiques, Groupe Hospitalier Henri-MONDOR, Assistance Publique-Hôpitaux de Paris, Créteil, France.
authors: Karen
authors: K
authors: Leroy
authors: 1] INSERM U955, Créteil, France. [2] Université Paris Est, Créteil, France. [3] Département de Pathologie-Service d'Hématologie-Plateforme de Ressources Biologiques, Groupe Hospitalier Henri-MONDOR, Assistance Publique-Hôpitaux de Paris, Créteil, France.
authors: Philippe
authors: P
authors: Gaulard
authors: 1] Université Paris Est, Créteil, France. [2] Département de Pathologie-Service d'Hématologie-Plateforme de Ressources Biologiques, Groupe Hospitalier Henri-MONDOR, Assistance Publique-Hôpitaux de Paris, Créteil, France.
authors: Corinne
authors: C
authors: Haioun
authors: 1] Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada. [2] Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Marco A
authors: MA
authors: Marra
authors: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors: Kerry J
authors: KJ
authors: Savage
authors: Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors: Joseph M
authors: JM
authors: Connors
authors: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Sohrab P
authors: SP
authors: Shah
authors: 1] Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada. [2] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Randy D
authors: RD
authors: Gascoyne
authors: 1] Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia, Canada. [2] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Christian
authors: C
authors: Steidl
mesh_terms: D020869:Gene Expression Profiling / Q000379:methods; D055785:Gene Knockdown Techniques; D023281:Genomics / Q000379:methods; D057809:HEK293 Cells; D059014:High-Throughput Nucleotide Sequencing; D006689:Hodgkin Disease / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D061346:Laser Capture Microdissection; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000473:pathology; D008479:Mediastinal Neoplasms / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000235:genetics*; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1