{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T10:29:26Z","timestamp":1794047366888,"version":"4.8.0"},"reference-count":45,"publisher":"Ferrata Storti Foundation (Haematologica)","issue":"11","license":[{"start":{"date-parts":[[2020,9,10]],"date-time":"2020-09-10T00:00:00Z","timestamp":1599696000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["haematol"],"abstract":"<jats:p>Nodal peripheral T-cell lymphoma not otherwise specified (PTCLNOS) remains a diagnosis encompassing a heterogenous group of PTCL cases not fitting criteria for more homogeneous subtypes. They are characterized by a poor clinical outcome when treated with anthracycline-containing regimens. A better understanding of their biology could improve prognostic stratification and foster the development of novel therapeutic approaches. Recent targeted and whole exome sequencing studies have shown recurrent copy number abnormalities (CNA) with prognostic significance. Here, investigating five formalinfixed, paraffin embedded cases of PTCL-NOS by whole genome sequencing, we found a high prevalence of structural variants and complex events, such as chromothripsis likely responsible for the observed CNA. Among them, CDKN2A and PTEN deletions emerged as the most frequent aberration, as confirmed in a final cohort of 143 patients with nodal PTCL. The incidence of CDKN2A and PTEN deletions among PTCL-NOS was 46% and 26%, respectively. Furthermore, we found that co-occurrence of CDKN2A and PTEN deletions is an event associated with PTCLNOS with absolute specificity. In contrast, these deletions are rare and never co-occur in angioimmunoblastic and anaplastic lymphomas. CDKN2A deletion was associated with shorter overall survival in multivariate analysis corrected by age, International Prognostic Index, transplant eligibility and GATA3 expression (adjusted Hazard Ratio =2.53; 95% Confidence Interval: 1.006-6.3; P=0.048). These data suggest that CDKN2A deletions may be relevant for refining the prognosis of PTCLNOS and their significance should be evaluated in prospective trials.<\/jats:p>","DOI":"10.3324\/haematol.2020.262659","type":"journal-article","created":{"date-parts":[[2020,9,16]],"date-time":"2020-09-16T14:42:42Z","timestamp":1600267362000},"page":"2918-2926","source":"Crossref","is-referenced-by-count":40,"title":["&lt;i&gt;CDKN2A&lt;\/i&gt; deletion is a frequent event associated with poor outcome in patients with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS)"],"prefix":"10.3324","volume":"106","author":[{"given":"Francesco","family":"Maura","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Dodero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristiana","family":"Carniti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niccol\u00f2","family":"Bolli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Magni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Monti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonello","family":"Cabras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Leongamornlert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Abascal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Diamond","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernardo","family":"Rodriguez-Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Zamora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Butler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inigo","family":"Martincorena","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose M. C.","family":"Tubio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Campbell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annalisa","family":"Chiappella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giancarlo","family":"Pruneri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Corradini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1856","published-online":{"date-parts":[[2020,9,10]]},"reference":[{"key":"31102","doi-asserted-by":"crossref","unstructured":"de Leval L, Gaulard P. Cellular origin of T-cell lymphomas. Blood. 2014; 123(19):2909-2910.","DOI":"10.1182\/blood-2014-02-555763"},{"key":"31103","doi-asserted-by":"crossref","unstructured":"Inghirami G, Chan WC, Pileri S. the AIRC 5xMille consortium \u2018Genetics-driven targeted management of lymphoid malignancies.\u2019 Peripheral T-cell and NK cell lymphoproliferative disorders: cell of origin, clinical and pathological implications. Immunol Rev. 2015; 263(1):124-159.","DOI":"10.1111\/imr.12248"},{"key":"31104","doi-asserted-by":"crossref","unstructured":"Maura F, Dodero A, Carniti C, Bolli N. Biology of peripheral T cell lymphomas \u2013 not otherwise specified: is something finally happening?. Pathogenesis. 2016; 3(1):9-18.","DOI":"10.1016\/j.pathog.2016.02.002"},{"key":"31105","unstructured":"Swerdlow SH, Campo E, Harris NL. WHO classification of tumours of haematopoietic and lymphoid tissues. Revised 4th edition. 2017;585."},{"key":"31106","doi-asserted-by":"crossref","unstructured":"Crescenzo R, Abate F, Lasorsa E. Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma. Cancer Cell. 2015; 27(4):516-532.","DOI":"10.1016\/j.ccell.2015.03.006"},{"key":"31107","doi-asserted-by":"crossref","unstructured":"Palomero T, Couronn\u00e9 L, Khiabanian H. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nat Genet. 2014; 46(2):166-170.","DOI":"10.1038\/ng.2873"},{"key":"31108","doi-asserted-by":"crossref","unstructured":"Sakata-Yanagimoto M, Enami T, Yoshida K. Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nat Genet. 2014; 46(2):171-175.","DOI":"10.1038\/ng.2872"},{"key":"31109","doi-asserted-by":"crossref","unstructured":"Yoo HY, Sung MK, Lee SH. A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma. Nat Genet. 2014; 46(4):371-375.","DOI":"10.1038\/ng.2916"},{"key":"31110","doi-asserted-by":"crossref","unstructured":"Allen PB, Pro B. Therapy of peripheral T cell lymphoma: focus on nodal subtypes. Curr Oncol Rep. 2020; 22(5):44.","DOI":"10.1007\/s11912-020-00902-1"},{"key":"31111","doi-asserted-by":"crossref","unstructured":"Lemonnier F, Dupuis J, Sujobert P. Treatment with 5-azacytidine induces a sustained response in patients with angioimmunoblastic T-cell lymphoma. Blood. 2018; 132(21):2305-2309.","DOI":"10.1182\/blood-2018-04-840538"},{"key":"31112","doi-asserted-by":"crossref","unstructured":"Schatz JH, Horwitz SM, Teruya-Feldstein J. Targeted mutational profiling of peripheral T-cell lymphoma not otherwise specified highlights new mechanisms in a heterogeneous pathogenesis. Leukemia. 2015; 29(1):237-241.","DOI":"10.1038\/leu.2014.261"},{"key":"31113","doi-asserted-by":"crossref","unstructured":"Abate F, da Silva-Almeida AC, Zairis S. Activating mutations and translocations in the guanine exchange factor VAV1 in peripheral T-cell lymphomas. Proc Natl Acad Sci U S A. 2017; 114(4):764-769.","DOI":"10.1073\/pnas.1608839114"},{"key":"31114","doi-asserted-by":"crossref","unstructured":"Laginestra MA, Cascione L, Motta G. Whole exome sequencing reveals mutations in FAT1 tumor suppressor gene clinically impacting on peripheral T-cell lymphoma not otherwise specified. Mod Pathol. 2020; 33(2):179-187.","DOI":"10.1038\/s41379-019-0279-8"},{"key":"31115","doi-asserted-by":"crossref","unstructured":"Corradini P, Vitolo U, Rambaldi A. Intensified chemo-immunotherapy with or without stem cell transplantation in newly diagnosed patients with peripheral T-cell lymphoma. Leukemia. 2014; 28(9):1885-1891.","DOI":"10.1038\/leu.2014.79"},{"key":"31116","doi-asserted-by":"crossref","unstructured":"d\u2019Amore F, Lepp\u00e4 S, Silva MG da. Final analysis of the front-line phase III randomized ACT-1 trial in younger patients with systemic peripheral T-cell lymphoma treated with CHOP chemotherapy with or without alemtuzumab and consolidated by autologous hematopoietic stem cell transplant. Blood. 2018; 132(Suppl 1):S998-998.","DOI":"10.1182\/blood-2018-99-110429"},{"key":"31117","doi-asserted-by":"crossref","unstructured":"Iqbal J, Wright G, Wang C. Gene expression signatures delineate biological and prognostic subgroups in peripheral Tcell lymphoma. Blood. 2014; 123(19):2915-2923.","DOI":"10.1182\/blood-2013-11-536359"},{"key":"31118","doi-asserted-by":"crossref","unstructured":"Wang T, Feldman AL, Wada DA. GATA-3 expression identifies a high-risk subset of PTCL, NOS with distinct molecular and clinical features. Blood. 2014; 123(19):3007-3015.","DOI":"10.1182\/blood-2013-12-544809"},{"key":"31119","doi-asserted-by":"crossref","unstructured":"Amador C, Greiner TC, Heavican TB. Reproducing the molecular subclassification of peripheral T-cell lymphoma-NOS by Immunohistochemistry. Blood. 2019; 134(24):2159-2170.","DOI":"10.1182\/blood.2019000779"},{"key":"31120","doi-asserted-by":"crossref","unstructured":"Heavican TB, Bouska A, Yu J. Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma. Blood. 2019; 133(15):1664-1676.","DOI":"10.1182\/blood-2018-09-872549"},{"key":"31121","doi-asserted-by":"crossref","unstructured":"Watatani Y, Sato Y, Miyoshi H. Molecular heterogeneity in peripheral T-cell lymphoma, not otherwise specified revealed by comprehensive genetic profiling. Leukemia. 2019; 33(12):2867-2883.","DOI":"10.1038\/s41375-019-0473-1"},{"key":"31122","doi-asserted-by":"crossref","unstructured":"The ICGC\/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-cancer analysis of whole genomes. Nature. 2020; 578(7793):82-93.","DOI":"10.1038\/s41586-020-1969-6"},{"key":"31123","doi-asserted-by":"crossref","unstructured":"Munchel S, Hoang Y, Zhao Y. Targeted or whole genome sequencing of formalin fixed tissue samples: potential applications in cancer genomics. Oncotarget. 2015; 6(28):25943-25961.","DOI":"10.18632\/oncotarget.4671"},{"key":"31124","doi-asserted-by":"crossref","unstructured":"Maura F, Bolli N, Angelopoulos N. Genomic landscape and chronological reconstruction of driver events in multiple myeloma. Nat Commun. 2019; 10(1):3835.","DOI":"10.1038\/s41467-019-11680-1"},{"key":"31125","doi-asserted-by":"crossref","unstructured":"Jones D, Raine KM, Davies H. cgpCaVEManWrapper: simple execution of CaVEMan in order to detect somatic single nucleotide variants in NGS data. 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A practical guide for mutational signature analysis in hematological malignancies. Nat Commun. 2019; 10(1):2969.","DOI":"10.1038\/s41467-019-11037-8"},{"key":"31130","doi-asserted-by":"crossref","unstructured":"PCAWG Mutational Signatures Working Group PCAWG Consortium, Alexandrov LB. The repertoire of mutational signatures in human cancer. Nature. 2020; 578(7793):94-101.","DOI":"10.1038\/s41586-020-1943-3"},{"key":"31131","doi-asserted-by":"crossref","unstructured":"Roberti A, Dobay MP, Bisig B. Type II enteropathy-associated T-cell lymphoma features a unique genomic profile with highly recurrent SETD2 alterations. Nat Commun. 2016; 7(1):12602.","DOI":"10.1038\/ncomms12602"},{"key":"31132","doi-asserted-by":"crossref","unstructured":"Wang M, Zhang S, Chuang S-S. Angioimmunoblastic T cell lymphoma: novel molecular insights by mutation profiling. Oncotarget. 2017; 8(11):17763-17770.","DOI":"10.18632\/oncotarget.14846"},{"key":"31133","doi-asserted-by":"crossref","unstructured":"Boi M, Rinaldi A, Kwee I. PRDM1\/BLIMP1 is commonly inactivated in anaplastic large T-cell lymphoma. Blood. 2013; 122(15):2683-2693.","DOI":"10.1182\/blood-2013-04-497933"},{"key":"31134","doi-asserted-by":"crossref","unstructured":"Hartmann S, Gesk S, Scholtysik R. High resolution SNP array genomic profiling of peripheral T cell lymphomas, not otherwise specified, identifies a subgroup with chromosomal aberrations affecting the REL locus. Br J Haematol. 2010; 148(3):402-412.","DOI":"10.1111\/j.1365-2141.2009.07956.x"},{"key":"31135","doi-asserted-by":"crossref","unstructured":"Wang K, Li M, Hadley D. PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res. 2007; 17(11):1665-1674.","DOI":"10.1101\/gr.6861907"},{"key":"31136","doi-asserted-by":"crossref","unstructured":"Korbel JO, Campbell PJ. Criteria for inference of chromothripsis in cancer genomes. Cell. 2013; 152(6):1226-1236.","DOI":"10.1016\/j.cell.2013.02.023"},{"key":"31137","doi-asserted-by":"crossref","unstructured":"Alhejaily A, Day AG, Feilotter HE, Baetz T, LeBrun DP. Inactivation of the CDKN2A tumor-suppressor gene by deletion or methylation is common at diagnosis in follicular lymphoma and associated with poor clinical outcome. Clin Cancer Res. 2014; 20(6):1676-1686.","DOI":"10.1158\/1078-0432.CCR-13-2175"},{"key":"31138","doi-asserted-by":"crossref","unstructured":"Pasqualucci L, Khiabanian H, Fangazio M. Genetics of follicular lymphoma transformation. Cell Rep. 2014; 6(1):130-140.","DOI":"10.1016\/j.celrep.2013.12.027"},{"key":"31139","doi-asserted-by":"crossref","unstructured":"Dodero A, Spina F, Narni F. Allogeneic transplantation following a reduced-intensity conditioning regimen in relapsed\/refractory peripheral T-cell lymphomas: long-term remissions and response to donor lymphocyte infusions support the role of a graft-versus- lymphoma effect. Leukemia. 2012; 26(3):520-526.","DOI":"10.1038\/leu.2011.240"},{"key":"31140","doi-asserted-by":"crossref","unstructured":"Kataoka K, Nagata Y, Kitanaka A. Integrated molecular analysis of adult T cell leukemia\/lymphoma. Nat Genet. 2015; 47(11):1304-1315.","DOI":"10.1038\/ng.3428"},{"key":"31141","doi-asserted-by":"crossref","unstructured":"Reddy A, Zhang J, Davis NS. Genetic and functional drivers of diffuse large B cell lymphoma. Cell. 2017; 171(2):481-494.","DOI":"10.1016\/j.cell.2017.09.027"},{"key":"31142","doi-asserted-by":"crossref","unstructured":"Karube K, Enjuanes A, Dlouhy I. Integrating genomic alterations in diffuse large B-cell lymphoma identifies new relevant pathways and potential therapeutic targets. Leukemia. 2018; 32(3):675-684.","DOI":"10.1038\/leu.2017.251"},{"key":"31143","doi-asserted-by":"crossref","unstructured":"Bolli N, Li Y, Sathiaseelan V. A DNA target-enrichment approach to detect mutations, copy number changes and immunoglobulin translocations in multiple myeloma. Blood Cancer J. 2016; 6(9):e467.","DOI":"10.1038\/bcj.2016.72"},{"key":"31144","doi-asserted-by":"crossref","unstructured":"Bolli N, Manes N, McKerrell T. Characterization of gene mutations and copy number changes in acute myeloid leukemia using a rapid target enrichment protocol. Haematologica. 2015; 100(2):214-222.","DOI":"10.3324\/haematol.2014.113381"},{"key":"31145","doi-asserted-by":"crossref","unstructured":"McKerrell T, Moreno T, Ponstingl H. Development and validation of a comprehensive genomic diagnostic tool for myeloid malignancies. Blood. 2016; 128(1):e1-9.","DOI":"10.1182\/blood-2015-11-683334"},{"key":"31146","doi-asserted-by":"crossref","unstructured":"Liu X, Karnell JL, Yin B. Distinct roles for PTEN in prevention of T cell lymphoma and autoimmunity in mice. 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