{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T02:52:17Z","timestamp":1775011937537,"version":"3.50.1"},"reference-count":43,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,10,25]],"date-time":"2017-10-25T00:00:00Z","timestamp":1508889600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,10,25]],"date-time":"2017-10-25T00:00:00Z","timestamp":1508889600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>We investigated clinical and genetic characteristics of high-risk follicular lymphoma (FL), that lacked evidence of large cell transformation at diagnosis, in the rituximab era. First, we retrospectively analysed the clinical features of 100 patients with non-transformed FL that were consecutively treated with rituximab-containing therapies in a discovery cohort. The presence of either peripheral blood and\/or bone involvement was associated with short progression-free survival. This was confirmed in a validation cohort of 66 FL patients. Then, whole exome sequencing was performed on randomly selected 5 high- and 9 standard-risk FL tumours. The most common mutational signature was a CG\u2009&gt;\u2009TG substitution-enriched signature associated with spontaneous deamination of 5-methylcytosine at CpG, but mutations in WA and WRC(Y) motifs (so-called activation-induced cytidine deaminase (AID) motifs) were also enriched throughout the whole exome. We found clustered mutations in target sequences of AID in the <jats:italic>IG<\/jats:italic> and <jats:italic>BCL2<\/jats:italic> loci. Importantly, high-risk FLs harboured more somatic mutations (mean 190 vs. 138, <jats:italic>P<\/jats:italic>\u2009=\u20090.04), including mutations in WA (33 vs. 22, <jats:italic>P<\/jats:italic>\u2009=\u20090.038), WRC (34 vs. 22, <jats:italic>P<\/jats:italic>\u2009=\u20090.016) and WRCY motifs (17 vs. 11, <jats:italic>P<\/jats:italic>\u2009=\u20090.004). These results suggest that genomic instability that allows for emergence of distinct mutations through AID activity underlies development of the high-risk FL phenotype.<\/jats:p>","DOI":"10.1038\/s41598-017-14150-0","type":"journal-article","created":{"date-parts":[[2017,10,19]],"date-time":"2017-10-19T10:36:11Z","timestamp":1508409371000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["High-risk follicular lymphomas harbour more somatic mutations including those in the AID-motif"],"prefix":"10.1038","volume":"7","author":[{"given":"Taku","family":"Tsukamoto","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masakazu","family":"Nakano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryuichi","family":"Sato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroko","family":"Adachi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miki","family":"Kiyota","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eri","family":"Kawata","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nobuhiko","family":"Uoshima","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satoru","family":"Yasukawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshiaki","family":"Chinen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinsuke","family":"Mizutani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuji","family":"Shimura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsutomu","family":"Kobayashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shigeo","family":"Horiike","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akio","family":"Yanagisawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masafumi","family":"Taniwaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kei","family":"Tashiro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junya","family":"Kuroda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2017,10,25]]},"reference":[{"key":"14150_CR1","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1182\/blood-2013-03-491514","volume":"122","author":"D Tan","year":"2013","unstructured":"Tan, D. et al. Improvements in observed and relative survival in follicular grade 1-2 lymphoma during 4 decades: the Stanford University experience. Blood \n                           122, 981\u2013987, https:\/\/doi.org\/10.1182\/blood-2013-03-491514 (2013).","journal-title":"Blood"},{"key":"14150_CR2","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/S0140-6736(10)62175-7","volume":"377","author":"G Salles","year":"2011","unstructured":"Salles, G. et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. The Lancet \n                           377, 42\u201351, https:\/\/doi.org\/10.1016\/s0140-6736(10)62175-7 (2011).","journal-title":"The Lancet"},{"key":"14150_CR3","doi-asserted-by":"publisher","first-page":"3725","DOI":"10.1182\/blood-2005-01-0016","volume":"106","author":"W Hiddemann","year":"2005","unstructured":"Hiddemann, W. et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood \n                           106, 3725\u20133732, https:\/\/doi.org\/10.1182\/blood-2005-01-0016 (2005).","journal-title":"Blood"},{"key":"14150_CR4","doi-asserted-by":"publisher","first-page":"1388","DOI":"10.1038\/leu.2014.91","volume":"28","author":"W Hiddemann","year":"2014","unstructured":"Hiddemann, W. & Cheson, B. D. How we manage follicular lymphoma. Leukemia \n                           28, 1388\u20131395, https:\/\/doi.org\/10.1038\/leu.2014.91 (2014).","journal-title":"Leukemia"},{"key":"14150_CR5","doi-asserted-by":"publisher","first-page":"3272","DOI":"10.1200\/JCO.2012.48.3990","volume":"31","author":"BK Link","year":"2013","unstructured":"Link, B. K. et al. Rates and outcomes of follicular lymphoma transformation in the immunochemotherapy era: a report from the University of Iowa\/MayoClinic Specialized Program of Research Excellence Molecular Epidemiology Resource. J Clin Oncol \n                           31, 3272\u20133278, https:\/\/doi.org\/10.1200\/JCO.2012.48.3990 (2013).","journal-title":"J Clin Oncol"},{"key":"14150_CR6","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1182\/blood-2015-01-621375","volume":"126","author":"ND Wagner-Johnston","year":"2015","unstructured":"Wagner-Johnston, N. D. et al. Outcomes of transformed follicular lymphoma in the modern era: a report from the National LymphoCare Study (NLCS). Blood \n                           126, 851\u2013857, https:\/\/doi.org\/10.1182\/blood-2015-01-621375 (2015).","journal-title":"Blood"},{"key":"14150_CR7","doi-asserted-by":"publisher","first-page":"2516","DOI":"10.1200\/JCO.2014.59.7534","volume":"33","author":"C Casulo","year":"2015","unstructured":"Casulo, C. et al. Early Relapse of Follicular Lymphoma After Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Defines Patients at High Risk for Death: An Analysis From the National LymphoCare Study. J Clin Oncol \n                           33, 2516\u20132522, https:\/\/doi.org\/10.1200\/JCO.2014.59.7534 (2015).","journal-title":"J Clin Oncol"},{"key":"14150_CR8","doi-asserted-by":"publisher","first-page":"1258","DOI":"10.1182\/blood-2003-12-4434","volume":"104","author":"P Solal-Celigny","year":"2004","unstructured":"Solal-Celigny, P. et al. Follicular lymphoma international prognostic index. Blood \n                           104, 1258\u20131265, https:\/\/doi.org\/10.1182\/blood-2003-12-4434 (2004).","journal-title":"Blood"},{"key":"14150_CR9","doi-asserted-by":"publisher","first-page":"4555","DOI":"10.1200\/JCO.2008.21.3991","volume":"27","author":"M Federico","year":"2009","unstructured":"Federico, M. et al. Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project. J Clin Oncol \n                           27, 4555\u20134562, https:\/\/doi.org\/10.1200\/JCO.2008.21.3991 (2009).","journal-title":"J Clin Oncol"},{"key":"14150_CR10","doi-asserted-by":"publisher","first-page":"E1116","DOI":"10.1073\/pnas.1501199112","volume":"112","author":"MR Green","year":"2015","unstructured":"Green, M. R. et al. Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation. Proc Natl Acad Sci USA \n                           112, E1116\u20131125, https:\/\/doi.org\/10.1073\/pnas.1501199112 (2015).","journal-title":"Proc Natl Acad Sci USA"},{"key":"14150_CR11","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1038\/nature10351","volume":"476","author":"RD Morin","year":"2011","unstructured":"Morin, R. D. et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature \n                           476, 298\u2013303, https:\/\/doi.org\/10.1038\/nature10351 (2011).","journal-title":"Nature"},{"key":"14150_CR12","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1038\/ng.2856","volume":"46","author":"J Okosun","year":"2014","unstructured":"Okosun, J. et al. Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nat Genet \n                           46, 176\u2013181, https:\/\/doi.org\/10.1038\/ng.2856 (2014).","journal-title":"Nat Genet"},{"key":"14150_CR13","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1016\/j.celrep.2013.12.027","volume":"6","author":"L Pasqualucci","year":"2014","unstructured":"Pasqualucci, L. et al. Genetics of follicular lymphoma transformation. Cell Rep \n                           6, 130\u2013140, https:\/\/doi.org\/10.1016\/j.celrep.2013.12.027 (2014).","journal-title":"Cell Rep"},{"key":"14150_CR14","doi-asserted-by":"publisher","first-page":"1487","DOI":"10.1182\/blood-2013-05-500264","volume":"123","author":"H Li","year":"2014","unstructured":"Li, H. et al. Mutations in linker histone genes HIST1H1 B, C, D, and E; OCT2 (POU2F2); IRF8; and ARID1A underlying the pathogenesis of follicular lymphoma. Blood \n                           123, 1487\u20131498, https:\/\/doi.org\/10.1182\/blood-2013-05-500264 (2014).","journal-title":"Blood"},{"key":"14150_CR15","doi-asserted-by":"publisher","first-page":"3812","DOI":"10.1093\/nar\/gkg509","volume":"31","author":"PC Ng","year":"2003","unstructured":"Ng, P. C. SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Research \n                           31, 3812\u20133814, https:\/\/doi.org\/10.1093\/nar\/gkg509 (2003).","journal-title":"Nucleic Acids Research"},{"key":"14150_CR16","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1038\/nmeth0410-248","volume":"7","author":"IA Adzhubei","year":"2010","unstructured":"Adzhubei, I. A. et al. A method and server for predicting damaging missense mutations. 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Peripheral blood involvement in patients with follicular lymphoma: a rare disease manifestation associated with poor prognosis. Br J Haematol \n                           164, 659\u2013667, https:\/\/doi.org\/10.1111\/bjh.12675 (2014).","journal-title":"Br J Haematol"},{"key":"14150_CR21","doi-asserted-by":"publisher","first-page":"3165","DOI":"10.1182\/blood-2013-04-496893","volume":"122","author":"C Bodor","year":"2013","unstructured":"Bodor, C. et al. EZH2 mutations are frequent and represent an early event in follicular lymphoma. Blood \n                           122, 3165\u20133168, https:\/\/doi.org\/10.1182\/blood-2013-04-496893 (2013).","journal-title":"Blood"},{"key":"14150_CR22","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1182\/blood-2014-06-582650","volume":"125","author":"M Yildiz","year":"2015","unstructured":"Yildiz, M. et al. Activating STAT6 mutations in follicular lymphoma. 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