Recurrent somatic mutations of PTPN1 in primary mediastinal B cell lymphoma and Hodgkin lymphoma

Jay Gunawardana; Fong Chun Chan; Adèle Telenius; Bruce Woolcock; Robert Kridel; King L. Tan; Susana Ben-Neriah; Anja Mottok; Raymond S. Lim; Merrill Boyle; Sanja Rogic; Lisa M. Rimsza; Chrystelle Guiter; Karen Leroy; Philippe Gaulard; Corinne Haioun; Marco A. Marra; Kerry J. Savage; Joseph M. Connors; Sohrab P. Shah; Randy D. Gascoyne; Christian Steidl

doi:10.1038/ng.2900

Recurrent somatic mutations of PTPN1 in primary mediastinal B cell lymphoma and Hodgkin lymphoma

Jay Gunawardana
, Fong Chun Chan
, Adèle Telenius
, Bruce Woolcock
, Robert Kridel
, King L. Tan
, Susana Ben-Neriah
, Anja Mottok
, Raymond S. Lim
, Merrill Boyle
, Sanja Rogic
, Lisa M. Rimsza
, Chrystelle Guiter
, Karen Leroy
, Philippe Gaulard
, Corinne Haioun
, Marco A. Marra
, Kerry J. Savage
, Joseph M. Connors
, Sohrab P. Shah

Randy D. Gascoyne, Christian Steidl

Research output: Contribution to journal › Article › peer-review

178 Scopus citations

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.

Original language	English (US)
Pages (from-to)	329-335
Number of pages	7
Journal	Nature Genetics
Volume	46
Issue number	4
DOIs	https://doi.org/10.1038/ng.2900
State	Published - Apr 2014
Externally published	Yes

ASJC Scopus subject areas

Genetics

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10.1038/ng.2900

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Gunawardana, J., Chan, F. C., Telenius, A., Woolcock, B., Kridel, R., Tan, K. L., Ben-Neriah, S., Mottok, A., Lim, R. S., Boyle, M., Rogic, S., Rimsza, L. M., Guiter, C., Leroy, K., Gaulard, P., Haioun, C., Marra, M. A., Savage, K. J., Connors, J. M., ... Steidl, C. (2014). Recurrent somatic mutations of PTPN1 in primary mediastinal B cell lymphoma and Hodgkin lymphoma. Nature Genetics, 46(4), 329-335. https://doi.org/10.1038/ng.2900

Gunawardana, J, Chan, FC, Telenius, A, Woolcock, B, Kridel, R, Tan, KL, Ben-Neriah, S, Mottok, A, Lim, RS, Boyle, M, Rogic, S, Rimsza, LM, Guiter, C, Leroy, K, Gaulard, P, Haioun, C, Marra, MA, Savage, KJ, Connors, JM, Shah, SP, Gascoyne, RD & Steidl, C 2014, 'Recurrent somatic mutations of PTPN1 in primary mediastinal B cell lymphoma and Hodgkin lymphoma', Nature Genetics, vol. 46, no. 4, pp. 329-335. https://doi.org/10.1038/ng.2900

@article{f45b2f4a7dfb4417902a650c6cd9e87e,

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.",

author = "Jay Gunawardana and Chan, \{Fong Chun\} and Ad{\`e}le Telenius and Bruce Woolcock and Robert Kridel and Tan, \{King L.\} and Susana Ben-Neriah and Anja Mottok and Lim, \{Raymond S.\} and Merrill Boyle and Sanja Rogic and Rimsza, \{Lisa M.\} and Chrystelle Guiter and Karen Leroy and Philippe Gaulard and Corinne Haioun and Marra, \{Marco A.\} and Savage, \{Kerry J.\} and Connors, \{Joseph M.\} and Shah, \{Sohrab P.\} and Gascoyne, \{Randy D.\} and Christian Steidl",

note = "Funding Information: We thank the BC Cancer Foundation and the Canada Foundation for Innovation for their support. We also thank T. Van Tol, M. Drake, R. Tong, the Genome Sciences Centre (GSC) production group and the Center for Translational and Applied Genomics (CTAG) for excellent technical support. This work is supported by a research grant from the Leukemia \& Lymphoma Society of Canada (LLSC) and by a Terry Fox Research Institute team grant (1023) to C.S. and a Scholarship award from the Michael Smith Foundation for Health Research (MSFHR) to C.S. R.D.G. is supported by a Canadian Institutes of Health Research (CIHR) grant (178536) and a Terry Fox Foundation program project grant (019001). A.M. is supported by a fellowship award from the Mildred Scheel Cancer Foundation. R.K. is supported by fellowship awards from CIHR, MSFHR and the University of British Columbia.",

year = "2014",

month = apr,

doi = "10.1038/ng.2900",

language = "English (US)",

volume = "46",

pages = "329--335",

journal = "Nature Genetics",

issn = "1061-4036",

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T1 - Recurrent somatic mutations of PTPN1 in primary mediastinal B cell lymphoma and Hodgkin lymphoma

AU - Gunawardana, Jay

AU - Chan, Fong Chun

AU - Telenius, Adèle

AU - Woolcock, Bruce

AU - Kridel, Robert

AU - Tan, King L.

AU - Ben-Neriah, Susana

AU - Mottok, Anja

AU - Lim, Raymond S.

AU - Boyle, Merrill

AU - Rogic, Sanja

AU - Rimsza, Lisa M.

AU - Guiter, Chrystelle

AU - Leroy, Karen

AU - Gaulard, Philippe

AU - Haioun, Corinne

AU - Marra, Marco A.

AU - Savage, Kerry J.

AU - Connors, Joseph M.

AU - Shah, Sohrab P.

AU - Gascoyne, Randy D.

AU - Steidl, Christian

N1 - Funding Information: We thank the BC Cancer Foundation and the Canada Foundation for Innovation for their support. We also thank T. Van Tol, M. Drake, R. Tong, the Genome Sciences Centre (GSC) production group and the Center for Translational and Applied Genomics (CTAG) for excellent technical support. This work is supported by a research grant from the Leukemia & Lymphoma Society of Canada (LLSC) and by a Terry Fox Research Institute team grant (1023) to C.S. and a Scholarship award from the Michael Smith Foundation for Health Research (MSFHR) to C.S. R.D.G. is supported by a Canadian Institutes of Health Research (CIHR) grant (178536) and a Terry Fox Foundation program project grant (019001). A.M. is supported by a fellowship award from the Mildred Scheel Cancer Foundation. R.K. is supported by fellowship awards from CIHR, MSFHR and the University of British Columbia.

PY - 2014/4

Y1 - 2014/4

N2 - 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.

AB - 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.

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VL - 46

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EP - 335

JO - Nature Genetics

JF - Nature Genetics

IS - 4

ER -

Recurrent somatic mutations of PTPN1 in primary mediastinal B cell lymphoma and Hodgkin lymphoma

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