{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T12:09:26Z","timestamp":1790770166085,"version":"4.1.0"},"reference-count":53,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2020,4,17]],"date-time":"2020-04-17T00:00:00Z","timestamp":1587081600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Department of Pathology at Northwestern University"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Genes Chromosomes &amp; Cancer"],"published-print":{"date-parts":[[2020,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Aggressive morphologic variants of mantle cell lymphoma (MCL), including blastoid and pleomorphic (B\/P\u2010MCL), are rare and associated with poor clinical outcomes. The genomic landscape of these variants remains incompletely explored. In this multi\u2010institutional study, we describe recurrent mutations and novel genomic copy number alterations (CNAs) in B\/P\u2010MCL, using next generation sequencing and SNP\u2010array. Chromothripsis, a recently described phenomenon of massive chromosomal rearrangements, was identified in eight of 13 (62%) B\/P MCL cases, and a high degree of genomic complexity with frequent copy number gains and losses was also seen. In contrast, a comparative cohort of nine cases of conventional MCL (C\u2010MCL) showed no chromothripsis and less complexity. Twelve of 13 (92%) B\/P\u2010MCL cases showed loss of <jats:italic>CDKN2A<\/jats:italic>\/<jats:italic>B<\/jats:italic> (6 biallelic and 6 monoallelic losses); while only one C\u2010MCL showed monoallelic <jats:italic>CDKN2A<\/jats:italic>\/<jats:italic>B<\/jats:italic> loss. In B\/P\u2010MCL, <jats:italic>TP53<\/jats:italic> was the most commonly mutated gene, with mutations present in eight cases (62%), six of which showed concurrent loss of chromosome 17p. Of the eight cases with chromothripsis, six (85%) harbored <jats:italic>TP53<\/jats:italic> mutations. Other recurrent mutations in B\/P\u2010MCL included <jats:italic>ATM<\/jats:italic> (7, 53%), <jats:italic>CCND1<\/jats:italic> (5, 38%), <jats:italic>NOTCH1<\/jats:italic> (2, 18%), <jats:italic>NOTCH2<\/jats:italic>, and <jats:italic>BIRC3<\/jats:italic> (each in 3, 23%). Here, we describe high genomic instability associated with chromothripsis and a high frequency of <jats:italic>CDKN2A\/B<\/jats:italic> and <jats:italic>TP53<\/jats:italic> alterations in the aggressive variants of MCL. The nonrandom chromothripsis events observed in B\/P\u2010MCL may be an indicator of clinically aggressive MCL. In addition, frequent <jats:italic>CDKN2A<\/jats:italic> deletion and high genomic instability may provide potential targets for alternative treatment.<\/jats:p>","DOI":"10.1002\/gcc.22849","type":"journal-article","created":{"date-parts":[[2020,4,11]],"date-time":"2020-04-11T05:34:36Z","timestamp":1586583276000},"page":"484-494","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Aggressive morphologic variants of mantle cell lymphoma characterized with high genomic instability showing frequent chromothripsis, <scp>CDKN2A<\/scp>\/B loss, and <scp>TP53<\/scp> mutations: A multi\u2010institutional study"],"prefix":"10.1002","volume":"59","author":[{"given":"Lukas","family":"Streich","sequence":"first","affiliation":[{"name":"Department of Pathology, Northwestern Memorial Hospital Northwestern University Feinberg School of Medicine  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madina","family":"Sukhanova","sequence":"additional","affiliation":[{"name":"Department of Pathology, Northwestern Memorial Hospital Northwestern University Feinberg School of Medicine  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyan","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Northwestern Memorial Hospital Northwestern University Feinberg School of Medicine  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi\u2010Hua","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Northwestern Memorial Hospital Northwestern University Feinberg School of Medicine  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Girish","family":"Venkataraman","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Chicago Hospitals  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Mathews","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine University of North Carolina School of Medicine  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanxiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Indiana University School of Medicine  Bloomington Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katalin","family":"Kelemen","sequence":"additional","affiliation":[{"name":"Department of Pathology Mayo Clinic  Phoenix Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Segal","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Chicago Hospitals  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juehua","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Pathology, Northwestern Memorial Hospital Northwestern University Feinberg School of Medicine  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leo","family":"Gordon","sequence":"additional","affiliation":[{"name":"Division of Hematology\u2010Oncology, Department of Medicine, Northwestern Memorial Hospital Northwestern University Feinberg School of Medicine  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Northwestern Memorial Hospital Northwestern University Feinberg School of Medicine  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3944-2792","authenticated-orcid":false,"given":"Amir","family":"Behdad","sequence":"additional","affiliation":[{"name":"Department of Pathology, Northwestern Memorial Hospital Northwestern University Feinberg School of Medicine  Chicago Illinois USA"},{"name":"Division of Hematology\u2010Oncology, Department of Medicine, Northwestern Memorial Hospital Northwestern University Feinberg School of Medicine  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,4,17]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI61272"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2013.52.2466"},{"key":"e_1_2_8_4_1","first-page":"285","volume-title":"WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues","author":"Swerdlow SH","year":"2017"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0142(19980201)82:3<567::AID-CNCR20>3.0.CO;2-Z"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2402272"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2018.36.15_suppl.e19548"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.2870020310"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1994.tb06655.x"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1209147"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-07-517177"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1314608110"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-11-391474"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0510441103"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3435"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2230"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2007.06526.x"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V98.12.3479"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.22123"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2006.08.4251"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-03-344069"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0148972"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-09-738161"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-018-0035-y"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cancergen.2016.05.048"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-08-737502"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V87.8.3351.bloodjournal8783351"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-8049(02)00456-2"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0609.2005.00409.x"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2011.055715"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmoldx.2016.07.012"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.02.023"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.11.055"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3027"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.03.021"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-04-779736"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03485"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2017.180497"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a026286"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200905057"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2014.09.030"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-018-0034-3"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-14-0240"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-18-0919"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-02-628792"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1080\/10428194.2016.1228925"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1164266"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2018027672"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2013.12.027"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/nos114"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2011.08.047"},{"issue":"8","key":"e_1_2_8_52_1","first-page":"2997","article-title":"PD\u20100332991, a potent and selective inhibitor of cyclin\u2010dependent kinase 4\/6, demonstrates inhibition of proliferation in renal cell carcinoma at nanomolar concentrations and molecular markers predict for sensitivity","volume":"33","author":"Logan JE","year":"2013","journal-title":"Anticancer Res"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.2016-0310"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.3747\/co.22.2700"}],"container-title":["Genes, Chromosomes and Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fgcc.22849","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/gcc.22849","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/gcc.22849","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/gcc.22849","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,4]],"date-time":"2023-09-04T13:58:12Z","timestamp":1693835892000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/gcc.22849"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,17]]},"references-count":53,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2020,8]]}},"alternative-id":["10.1002\/gcc.22849"],"URL":"https:\/\/doi.org\/10.1002\/gcc.22849","archive":["Portico"],"relation":{},"ISSN":["1045-2257","1098-2264"],"issn-type":[{"value":"1045-2257","type":"print"},{"value":"1098-2264","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,17]]},"assertion":[{"value":"2020-02-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-03-20","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-04-17","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}