{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T10:29:24Z","timestamp":1794047364785,"version":"4.8.0"},"reference-count":50,"publisher":"Ferrata Storti Foundation (Haematologica)","issue":"10","license":[{"start":{"date-parts":[[2020,8,27]],"date-time":"2020-08-27T00:00:00Z","timestamp":1598486400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/legalcode"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["haematol"],"abstract":"<jats:p>In situ follicular neoplasia (ISFN) is the earliest morphologically identifiable precursor of follicular lymphoma (FL). Although it is genetically less complex than FL and has low risk for progression, ISFN already harbors secondary genetic alterations, in addition to the defining t(14;18)(q32;q21) translocation. FL, in turn, frequently progresses to diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBL). By BCL2 staining of available reactive lymphoid tissue obtained at any time point in patients with aggressive B-cell lymphoma (BCL), we identified ten paired cases of ISFN and DLBCL\/HGBL, including six de novo tumors and four tumors transformed from FL as an intermediate step, and investigated their clonal evolution using microdissection and next-generation sequencing. A clonal relationship between ISFN and aggressive BCL was established by immunoglobulin and\/or BCL2 rearrangements and\/or the demonstration of shared somatic mutations for all ten cases. Targeted sequencing revealed CREBBP, KMT2D, EZH2, TNFRSF14 and BCL2 as the genes most frequently mutated already in ISFN. Based on the distribution of private and shared mutations, two patterns of clonal evolution were evident. In most cases, the aggressive lymphoma, ISFN and, when present, FL revealed divergent evolution from a common progenitor, whereas linear evolution with sequential accumulation of mutations was less frequent. In conclusion, we demonstrate for the first time that t(14;18)+ aggressive BCL can arise from ISFN without clinically evident FL as an intermediate step and that during this progression, branched evolution is common.<\/jats:p>","DOI":"10.3324\/haematol.2020.254854","type":"journal-article","created":{"date-parts":[[2020,8,27]],"date-time":"2020-08-27T13:20:30Z","timestamp":1598534430000},"page":"2673-2681","source":"Crossref","is-referenced-by-count":33,"title":["Genetic evolution of &lt;i&gt;in situ&lt;\/i&gt; follicular neoplasia to aggressive B-cell lymphoma of germinal center subtype"],"prefix":"10.3324","volume":"106","author":[{"family":"Antonio Vogelsberg","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Julia Steinhilber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Barbara Mankel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Birgit Federmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Janine Schmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Ivonne A. Montes-Mojarro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Katrin H\u00fcttl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Maria Rodriguez-Pinilla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Praveen Baskaran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Sven Nahnsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Miguel A. Piris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"German Ott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Leticia Quintanilla-Martinez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Irina Bonzheim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Falko Fend","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1856","published-online":{"date-parts":[[2020,8,27]]},"reference":[{"key":"30074","doi-asserted-by":"crossref","unstructured":"Alizadeh AA, Eisen MB, Davis RE. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000; 403(6769):503-511.","DOI":"10.1038\/35000501"},{"key":"30075","doi-asserted-by":"crossref","unstructured":"Hans CP, Weisenburger DD, Greiner TC. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004; 103(1):275-282.","DOI":"10.1182\/blood-2003-05-1545"},{"key":"30076","unstructured":"Swerdlow SH, Campo E, Harris NL. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised 4th ed. 2017."},{"key":"30077","doi-asserted-by":"crossref","unstructured":"Tsujimoto Y, Gorham J, Cossman J, Jaffe E, Croce CM. The t(14;18) chromosome translocations involved in B-cell neoplasms result from mistakes in VDJ joining. Science. 1985; 229(4720):1390-1393.","DOI":"10.1126\/science.3929382"},{"key":"30078","doi-asserted-by":"crossref","unstructured":"McDonnell TJ, Deane N, Platt FM. bcl- 2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell. 1989; 57(1):79-88.","DOI":"10.1016\/0092-8674(89)90174-8"},{"key":"30079","doi-asserted-by":"crossref","unstructured":"Smith KG, Light A, O'Reilly LA, Ang SM, Strasser A, Tarlinton D. bcl-2 transgene expression inhibits apoptosis in the germinal center and reveals differences in the selection of memory B cells and bone marrow antibody-forming cells. J Exp Med. 2000; 191(3):475-484.","DOI":"10.1084\/jem.191.3.475"},{"key":"30080","doi-asserted-by":"crossref","unstructured":"Kridel R, Mottok A, Farinha P. Cell of origin of transformed follicular lymphoma. Blood. 2015; 126(18):2118-2127.","DOI":"10.1182\/blood-2015-06-649905"},{"key":"30081","doi-asserted-by":"crossref","unstructured":"D\u00f6lken G, D\u00f6lken L, Hirt C, Fusch C, Rabkin CS, Sch\u00fcler F. Age-dependent prevalence and frequency of circulating t(14;18)- positive cells in the peripheral blood of healthy individuals. J Natl Cancer Inst Monogr. 2008; 39:44-47.","DOI":"10.1093\/jncimonographs\/lgn005"},{"key":"30082","doi-asserted-by":"crossref","unstructured":"Roulland S, Lebailly P, Lecluse Y, Heutte N, Nadel B, Gauduchon P. Long-term clonal persistence and evolution of t(14;18)-bearing B cells in healthy individuals. Leukemia. 2006; 20(1):158-162.","DOI":"10.1038\/sj.leu.2404035"},{"key":"30083","doi-asserted-by":"crossref","unstructured":"Roulland S, Kelly RS, Morgado E. t(14;18) Translocation: a predictive blood biomarker for follicular lymphoma. J Clin Oncol. 2014; 32(13):1347-1355.","DOI":"10.1200\/JCO.2013.52.8190"},{"key":"30084","doi-asserted-by":"crossref","unstructured":"Cong P, Raffeld M, Teruya-Feldstein J, Sorbara L, Pittaluga S, Jaffe ES. In situ localization of follicular lymphoma: description and analysis by laser capture microdissection. Blood. 2002; 99(9):3376-3382.","DOI":"10.1182\/blood.V99.9.3376"},{"key":"30085","doi-asserted-by":"crossref","unstructured":"Jegalian AG, Eberle FC, Pack SD. Follicular lymphoma in situ: clinical implications and comparisons with partial involvement by follicular lymphoma. Blood. 2011; 118(11):2976-2984.","DOI":"10.1182\/blood-2011-05-355255"},{"key":"30086","doi-asserted-by":"crossref","unstructured":"Henopp T, Quintanilla-Martinez L, Fend F, Adam P. Prevalence of follicular lymphoma in situ in consecutively analysed reactive lymph nodes. Histopathology. 2011; 59(1):139-142.","DOI":"10.1111\/j.1365-2559.2011.03897.x"},{"key":"30087","doi-asserted-by":"crossref","unstructured":"Schmidt J, Salaverria I, Haake A. Increasing genomic and epigenomic complexity in the clonal evolution from in situ to manifest t(14;18)-positive follicular lymphoma. Leukemia. 2014; 28(5):1103-1112.","DOI":"10.1038\/leu.2013.307"},{"key":"30088","doi-asserted-by":"crossref","unstructured":"Schmidt J, Ramis-Zaldivar JE, Bonzheim I. CREBBP gene mutations are frequently detected in in situ follicular neoplasia. Blood. 2018; 132(25):2687-2690.","DOI":"10.1182\/blood-2018-03-837039"},{"key":"30089","doi-asserted-by":"crossref","unstructured":"Mamessier E, Song JY, Eberle FC. Early lesions of follicular lymphoma: a genetic perspective. Haematologica. 2014; 99(3):481-488.","DOI":"10.3324\/haematol.2013.094474"},{"key":"30090","doi-asserted-by":"crossref","unstructured":"Agopian J, Navarro JM, Gac AC. Agricultural pesticide exposure and the molecular connection to lymphomagenesis. J Exp Med. 2009; 206(7):1473-1483.","DOI":"10.1084\/jem.20082842"},{"key":"30091","doi-asserted-by":"crossref","unstructured":"Mamessier E, Drevet C, Broussais-Guillaumot F. Contiguous follicular lymphoma and follicular lymphoma in situ harboring N-glycosylated sites. Haematologica. 2015; 100(4):e155-157.","DOI":"10.3324\/haematol.2014.115782"},{"key":"30092","doi-asserted-by":"crossref","unstructured":"Kosmidis P, Bonzheim I, Dufke C. Next generation sequencing of the clonal IGH rearrangement detects ongoing mutations and interfollicular trafficking in in situ follicular neoplasia. PLoS One. 2017; 12(6):e0178503.","DOI":"10.1371\/journal.pone.0178503"},{"key":"30093","doi-asserted-by":"crossref","unstructured":"Coelho V, Krysov S, Ghaemmaghami AM. Glycosylation of surface Ig creates a functional bridge between human follicular lymphoma and microenvironmental lectins. Proc Natl Acad Sci U S A. 2010; 107(43):18587-18592.","DOI":"10.1073\/pnas.1009388107"},{"key":"30094","doi-asserted-by":"crossref","unstructured":"Greeve J, Philipsen A, Krause K. Expression of activation-induced cytidine deaminase in human B-cell non-Hodgkin lymphomas. Blood. 2003; 101(9):3574-3580.","DOI":"10.1182\/blood-2002-08-2424"},{"key":"30095","doi-asserted-by":"crossref","unstructured":"Loeffler M, Kreuz M, Haake A. Genomic and epigenomic co-evolution in follicular lymphomas. Leukemia. 2015; 29(2):456-463.","DOI":"10.1038\/leu.2014.209"},{"key":"30096","doi-asserted-by":"crossref","unstructured":"Morin RD, Mendez-Lago M, Mungall AJ. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature. 2011; 476(7360):298-303.","DOI":"10.1038\/nature10351"},{"key":"30097","doi-asserted-by":"crossref","unstructured":"Aukema SM, Kreuz M, Kohler CW. Biological characterization of adult MYCtranslocation- positive mature B-cell lymphomas other than molecular Burkitt lymphoma. Haematologica. 2014; 99(4):726-735.","DOI":"10.3324\/haematol.2013.091827"},{"key":"30098","doi-asserted-by":"crossref","unstructured":"van Dongen JJ, Langerak AW, Bruggemann M. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia. 2003; 17(12):2257-2317.","DOI":"10.1038\/sj.leu.2403202"},{"key":"30099","doi-asserted-by":"crossref","unstructured":"Lee AY, Connors JM, Klimo P, O'Reilly SE, Gascoyne RD. Late relapse in patients with diffuse large-cell lymphoma treated with MACOP-B. J Clin Oncol. 1997; 15(5):1745-1753.","DOI":"10.1200\/JCO.1997.15.5.1745"},{"key":"30100","doi-asserted-by":"crossref","unstructured":"Arber DA, George TI. Bone marrow biopsy involvement by non-Hodgkin's lymphoma: frequency of lymphoma types, patterns, blood involvement, and discordance with other sites in 450 specimens. Am J Surg Pathol. 2005; 29(12):1549-1557.","DOI":"10.1097\/01.pas.0000182405.65041.8b"},{"key":"30101","doi-asserted-by":"crossref","unstructured":"Brudno J, Tadmor T, Pittaluga S, Nicolae A, Polliack A, Dunleavy K. Discordant bone marrow involvement in non-Hodgkin lymphoma. Blood. 2016; 127(8):965-970.","DOI":"10.1182\/blood-2015-06-651968"},{"key":"30102","doi-asserted-by":"crossref","unstructured":"Kremer M, Spitzer M, Mandl-Weber S. Discordant bone marrow involvement in diffuse large B-cell lymphoma: comparative molecular analysis reveals a heterogeneous group of disorders. Lab Invest. 2003; 83(1):107-114.","DOI":"10.1097\/01.LAB.0000050762.61660.27"},{"key":"30103","doi-asserted-by":"crossref","unstructured":"Schmitz R, Wright GW, Huang DW. Genetics and pathogenesis of diffuse large Bcell lymphoma. N Engl J Med. 2018; 378(15):1396-1407.","DOI":"10.1056\/NEJMoa1801445"},{"key":"30104","doi-asserted-by":"crossref","unstructured":"Chapuy B, Stewart C, Dunford AJ. Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med. 2018; 24(5):679-690.","DOI":"10.1038\/s41591-018-0016-8"},{"key":"30105","doi-asserted-by":"crossref","unstructured":"Yamamoto K, Okamura A, Inui Y. Cryptic insertion of BCL2 gene into immunoglobulin heavy locus in follicular lymphoma with t(6;9)(p23;p13). Leuk Res. 2012; 36(9):e202-205.","DOI":"10.1016\/j.leukres.2012.05.002"},{"key":"30106","doi-asserted-by":"crossref","unstructured":"Bonzheim I, Salaverria I, Haake A. A unique case of follicular lymphoma provides insights to the clonal evolution from follicular lymphoma in situ to manifest follicular lymphoma. Blood. 2011; 118(12):3442-3444.","DOI":"10.1182\/blood-2011-07-368944"},{"key":"30107","doi-asserted-by":"crossref","unstructured":"Juskevicius D, Lorber T, Gsponer J. Distinct genetic evolution patterns of relapsing diffuse large B-cell lymphoma revealed by genome-wide copy number aberration and targeted sequencing analysis. Leukemia. 2016; 30(12):2385-2395.","DOI":"10.1038\/leu.2016.135"},{"key":"30108","doi-asserted-by":"crossref","unstructured":"Weigert O, Kopp N, Lane AA. Molecular ontogeny of donor-derived follicular lymphomas occurring after hematopoietic cell transplantation. Cancer Discov. 2012; 2(1):47-55.","DOI":"10.1158\/2159-8290.CD-11-0208"},{"key":"30109","doi-asserted-by":"crossref","unstructured":"Araf S, Wang J, Ashton-Key M. Transmission of diffuse large B-cell lymphoma by an allogeneic stem-cell transplant. Haematologica. 2019; 104(4):e174-e177.","DOI":"10.3324\/haematol.2018.196907"},{"key":"30110","doi-asserted-by":"crossref","unstructured":"Okosun J, Bodor C, Wang J. Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nat Genet. 2014; 46(2):176-181.","DOI":"10.1038\/ng.2856"},{"key":"30111","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":"30112","doi-asserted-by":"crossref","unstructured":"Saito M, Novak U, Piovan E. BCL6 suppression of BCL2 via Miz1 and its disruption in diffuse large B cell lymphoma. Proc Natl Acad Sci U S A. 2009; 106(27):11294-11299.","DOI":"10.1073\/pnas.0903854106"},{"key":"30113","doi-asserted-by":"crossref","unstructured":"Schuetz JM, Johnson NA, Morin RD. BCL2 mutations in diffuse large B-cell lymphoma. Leukemia. 2012; 26(6):1383-1390.","DOI":"10.1038\/leu.2011.378"},{"key":"30114","doi-asserted-by":"crossref","unstructured":"Pasqualucci L, Bhagat G, Jankovic M. AID is required for germinal center-derived lymphomagenesis. Nat Genet. 2008; 40(1):108-112.","DOI":"10.1038\/ng.2007.35"},{"key":"30115","doi-asserted-by":"crossref","unstructured":"Sungalee S, Mamessier E, Morgado E. Germinal center reentries of BCL2-overexpressing B cells drive follicular lymphoma progression. J Clin Invest. 2014; 124(12):5337-5351.","DOI":"10.1172\/JCI72415"},{"key":"30116","doi-asserted-by":"crossref","unstructured":"Cheung MC, Bailey D, Pennell N. In situ localization of follicular lymphoma: evidence for subclinical systemic disease with detection of an identical BCL-2\/IGH fusion gene in blood and lymph node. Leukemia. 2009; 23(6):1176-1179.","DOI":"10.1038\/leu.2009.9"},{"key":"30117","doi-asserted-by":"crossref","unstructured":"Green MR, Gentles AJ, Nair RV. Hierarchy in somatic mutations arising during genomic evolution and progression of follicular lymphoma. Blood. 2013; 121(9):1604-1611.","DOI":"10.1182\/blood-2012-09-457283"},{"key":"30118","doi-asserted-by":"crossref","unstructured":"Green MR, Kihira S, Liu CL. Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation. Proc Natl Acad Sci U S A. 2015; 112(10):E1116-1125.","DOI":"10.1073\/pnas.1501199112"},{"key":"30119","doi-asserted-by":"crossref","unstructured":"Kridel R, Chan FC, Mottok A. Histological transformation and progression in follicular lymphoma: a clonal evolution study. PLoS Med. 2016; 13(12):e1002197.","DOI":"10.1371\/journal.pmed.1002197"},{"key":"30120","doi-asserted-by":"crossref","unstructured":"Pasqualucci L, Dominguez-Sola D, Chiarenza A. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature. 2011; 471(7337):189-195.","DOI":"10.1038\/nature09730"},{"key":"30121","doi-asserted-by":"crossref","unstructured":"Zhang J, Vlasevska S, Wells VA. The CREBBP acetyltransferase is a haploinsufficient tumor suppressor in B-cell lymphoma. Cancer Discov. 2017; 7(3):322-337.","DOI":"10.1158\/2159-8290.CD-16-1417"},{"key":"30122","doi-asserted-by":"crossref","unstructured":"Jiang Y, Redmond D, Nie K. Deep sequencing reveals clonal evolution patterns and mutation events associated with relapse in B-cell lymphomas. Genome Biol. 2014; 15(8):432.","DOI":"10.1186\/PREACCEPT-6612547881370092"},{"key":"30123","doi-asserted-by":"crossref","unstructured":"Correia C, Schneider PA, Dai H. BCL2 mutations are associated with increased risk of transformation and shortened survival in follicular lymphoma. Blood. 2015; 125(4):658-667.","DOI":"10.1182\/blood-2014-04-571786"}],"container-title":["Haematologica"],"original-title":[],"link":[{"URL":"https:\/\/haematologica.org\/article\/download\/9914\/71496","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/haematologica.org\/article\/download\/9914\/71497","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/haematologica.org\/article\/download\/9914\/71496","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T09:58:03Z","timestamp":1794045483000},"score":1,"resource":{"primary":{"URL":"https:\/\/haematologica.org\/article\/view\/9914"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,27]]},"references-count":50,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10,1]]}},"URL":"https:\/\/doi.org\/10.3324\/haematol.2020.254854","relation":{},"ISSN":["1592-8721","0390-6078"],"issn-type":[{"value":"1592-8721","type":"electronic"},{"value":"0390-6078","type":"print"}],"subject":[],"published":{"date-parts":[[2020,8,27]]}}}