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.

The Genetics of Nodal Marginal Zone Lymphoma

“…By compiling the results of WES, targeted resequencing (Figure 2A), and high-resolution SNP array analysis ( Figure 2B), 41 genes were recurrently affected in $3 of 35 (9%) of NMZL by mutations (n 5 32 genes) or focal CNA (n 5 9 genes), including MLL2 (also known as KMT2D, 34%), PTPRD (20%), NOTCH2 (20%), and KLF2 (17%) ( Figure 3A; supplemental Tables 3 and 4 . Prevalence of nonsynonymous PTPRD mutations among mature B-cell tumors (NMZL, nodal marginal zone lymphoma, data from this study; SMZL, splenic marginal zone lymphoma, data from this study and others 5,6,7,9 ; DLBCL, diffuse large B-cell lymphoma, data from various studies 22,37,45,47 ; BL, Burkitt lymphoma, data from various studies 40,41 ; CLL, chronic lymphocytic leukemia, data from various studies 38,39,44,49 ; MCL, mantle cell lymphoma, data from Beà et al 43 ; PMBCL, primary mediastinal large B-cell lymphoma, data from Gunawardana et al 15 ; FL, follicular lymphoma, data from various studies 37,48 ; MM, multiple myeloma, data from Chapman et al 36 ; WM, Waldenström macroglobulinemia, data from various studies 42,46 ; EMZL, extranodal marginal zone lymphoma, data from this study; PCNSL primary central nervous system lymphoma, data from various studies [52][53][54][55] ).…”

“…[5][6][7]9,15,22,[36][37][38][39][40][41][42][43][44][45][46][47][48][49] Copy number (CNA) alteration frequency of PTPRD in SMZL, EMZL, diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia, and mantle cell leukemia was derived from the following datasets: GSE50252, GSE24881, GSE15127, GSE8123, and GSE4176. MLL2 NOTCH2 PTPRD KLF2 TNFRSF14 NOL9 FAS FAT4 GPR98 LRP1B TBL1XR1 TNFAIP3 SPEN AMN CDC42BPB RCOR1 ABCA13 BCL10 ID3 RP1L1 TAF1 C6orf103 CDKN2A PARK2 PACRG SAMD5 STXBP5 ACTG1 ADD2 AOC2 CARD11 CLGN CNKSR2 FAT1 MYD88 NCOR2 PLXNB3 SCG3 TCTN2 ZNF90 RCOR1 MLL2 CREBBP EP300 TBL1XR1 NCOR2 ARID1B EP400 BAZ2A HIS1H1E HIST1H1B HIST1H1C HIST1H2BK HIST1H4L ARID1A RAI1 TRRAP INO80B SMARCB1 THAP7 TNFAIP3 BCL10 CARD11 REL BIRC3 TRAF3 NOTCH2 FBXW7 SPEN RBPJL DTX1 ITCH MAML2 Mutation Loss Gain …”

“…Mutation analysis of cytokine signaling genes that did not emerge from WES in NMZL, but are known to be mutated in lymphomas, namely PTPN1, PTPN2, SOCS1, STAT3, STAT6, and JAK1, [15][16][17][18][19][20] as well as mutation analysis of PTPRD in EMZL and in the validation cohort of NMZL, were performed by Sanger sequencing. Details are in the supplemental Appendix.…”

The immune microenvironment in Hodgkin lymphoma: T cells, B cells, and immune checkpoints

“…The mutational burden in CHL is not well established as sequencing efforts have thus far been hampered by the paucity of RS cells within CHL tumors, although this can be overcome by either flow cytometry or microdissection-based cell enrichment. 39,107 Another intriguing option for assessment of mutation burden is via assessment of cell-free DNA, which can be detected in the serum of the majority of CHL patients, 108 although it is not yet clear whether cellfree or circulating tumor DNA can be used for comprehensive whole exome sequencing. More importantly, the majority of CHL samples demonstrate a loss of beta-2 microglobulin, leading to an absence of MHC-I expression on RS cells.…”

Frequent CTLA4-CD28 gene fusion in diverse types of T-cell lymphoma

“…1,3,5,[11][12][13][14][15][16][17][18] We added three p53-related genes and five JAK-STAT signaling genes for targeted deep sequencing. The list of 70 target genes is provided in Online Supplementary Table S1.…”