{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:35:43Z","timestamp":1760236543291,"version":"build-2065373602"},"reference-count":58,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T00:00:00Z","timestamp":1638316800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002848","name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo","doi-asserted-by":"publisher","award":["2016-72170683"],"award-info":[{"award-number":["2016-72170683"]}],"id":[{"id":"10.13039\/501100002848","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010751","name":"Fondecyt","doi-asserted-by":"publisher","award":["1180882"],"award-info":[{"award-number":["1180882"]}],"id":[{"id":"10.13039\/501100010751","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002847","name":"Ministry of Education","doi-asserted-by":"publisher","award":["MAG1895"],"award-info":[{"award-number":["MAG1895"]}],"id":[{"id":"10.13039\/501100002847","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Activation-induced deaminase (AID) is required for somatic hypermutation in immunoglobulin genes, but also induces off-target mutations. Follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL), the most frequent types of indolent B-cell tumors, are exposed to AID activity during lymphomagenesis. We designed a workflow integrating de novo mutational signatures extraction and fitting of COSMIC (Catalogue Of Somatic Mutations In Cancer) signatures, with tridimensional chromatin conformation data (Hi-C). We applied the workflow to exome sequencing data from lymphoma samples. In 33 FL and 30 CLL samples, 42% and 34% of the contextual mutations could be traced to a known AID motif. We demonstrate that both CLL and FL share mutational processes dominated by spontaneous deamination, failures in DNA repair, and AID activity. The processes had equiproportional distribution across active and nonactive chromatin compartments in CLL. In contrast, canonical AID activity and failures in DNA repair pathways in FL were significantly higher within the active chromatin compartment. Analysis of DNA repair genes revealed a higher prevalence of base excision repair gene mutations (p = 0.02) in FL than CLL. These data indicate that AID activity drives the genetic landscapes of FL and CLL. However, the final result of AID-induced mutagenesis differs between these lymphomas depending on chromatin compartmentalization and mutations in DNA repair pathways.<\/jats:p>","DOI":"10.3390\/ijms222313015","type":"journal-article","created":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T02:40:02Z","timestamp":1638412802000},"page":"13015","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Integration of Mutational Signature Analysis with 3D Chromatin Data Unveils Differential AID-Related Mutagenesis in Indolent Lymphomas"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6354-3609","authenticated-orcid":false,"given":"Julieta H.","family":"Sepulveda-Yanez","sequence":"first","affiliation":[{"name":"Department of Hematology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands"},{"name":"School of Medicine, University of Magallanes, Punta Arenas 6210427, Chile"},{"name":"Centro Asistencial Docente y de Investigaci\u00f3n, University of Magallanes, Punta Arenas 6210005, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0753-274X","authenticated-orcid":false,"given":"Diego","family":"Alvarez-Saravia","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Magallanes, Punta Arenas 6210427, Chile"},{"name":"Centro Asistencial Docente y de Investigaci\u00f3n, University of Magallanes, Punta Arenas 6210005, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5349-4348","authenticated-orcid":false,"given":"Jose","family":"Fernandez-Goycoolea","sequence":"additional","affiliation":[{"name":"Department of Physics and Mathematics, University of Magallanes, Punta Arenas 6210427, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3491-6589","authenticated-orcid":false,"given":"Jacqueline","family":"Aldridge","sequence":"additional","affiliation":[{"name":"Department of Computer Engineering, University of Magallanes, Punta Arenas 6210427, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6386-4517","authenticated-orcid":false,"given":"Cornelis A. M.","family":"van Bergen","sequence":"additional","affiliation":[{"name":"Department of Hematology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ward","family":"Posthuma","sequence":"additional","affiliation":[{"name":"Department of Oncology, Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9519-8862","authenticated-orcid":false,"given":"Roberto","family":"Uribe-Paredes","sequence":"additional","affiliation":[{"name":"Department of Computer Engineering, University of Magallanes, Punta Arenas 6210427, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9108-3125","authenticated-orcid":false,"given":"Hendrik","family":"Veelken","sequence":"additional","affiliation":[{"name":"Department of Hematology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2044-9548","authenticated-orcid":false,"given":"Marcelo A.","family":"Navarrete","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Magallanes, Punta Arenas 6210427, Chile"},{"name":"Centro Asistencial Docente y de Investigaci\u00f3n, University of Magallanes, Punta Arenas 6210005, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1093\/carcin\/22.3.367","article-title":"Patterns of p53 G\u2013>T transversions in lung cancers reflect the primary mutagenic signature of DNA-damage by tobacco smoke","volume":"22","author":"Hainaut","year":"2001","journal-title":"Carcinogenesis"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1038\/nature07943","article-title":"The cancer genome","volume":"458","author":"Stratton","year":"2009","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/nature12477","article-title":"Signatures of mutational processes in human cancer","volume":"500","author":"Alexandrov","year":"2013","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.celrep.2012.12.008","article-title":"Deciphering signatures of mutational processes operative in human cancer","volume":"3","author":"Alexandrov","year":"2013","journal-title":"Cell Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/nature00862","article-title":"AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification","volume":"418","author":"Harris","year":"2002","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1038\/nature00981","article-title":"Altering the pathway of immunoglobulin hypermutation by inhibiting uracil-DNA glycosylase","volume":"419","author":"Neuberger","year":"2002","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1098\/rstb.2000.0742","article-title":"Altered spectra of hypermutation in DNA repair-deficient mice","volume":"356","author":"Winter","year":"2001","journal-title":"Philos. 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