{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:32:15Z","timestamp":1760059935868,"version":"build-2065373602"},"reference-count":37,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T00:00:00Z","timestamp":1752796800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Follicular lymphoma (FL) is one of the most common types of non-Hodgkin\u2019s lymphomas. The tumor is characterized by a wide range of clinical manifestations, ranging from indolent forms to early transformation and progression with a poor prognosis. The search for clinically significant genetic changes is essential for personalized risk assessment and treatment selection. The CREBBP gene is frequently mutated in this type of lymphoma, with changes occurring at the level of the earliest tumor precursor cells. However, the prognostic and diagnostic significance of the CREBBP gene mutation status in FL has not been fully established. In this study, we analyzed sequencing data of exons 22\u201330 of the CREBBP gene in 86 samples from patients with different grades of FL (1\u20133B), including those in the 3A\u20133B subgroup without the t(14;18) translocation. We also investigated the prognostic significance of CREBBP gene mutations in relation to the treatment options, namely high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HDCT\/auto-HSCT) and conventional chemotherapy programs (CCT). It was found that FL patients with a single missense mutation in the KAT domain of the CREBBP gene experienced an extremely low number of early adverse events related to lymphoma and had better long-term survival rates, regardless of treatment option. In contrast, when comparing patients with FL without a missense mutation in the KAT domain or those with multiple mutations in the CREBBP gene, overall and progression free survival were worse, and early progression and histological transformation were more common. Compared to standard therapy, patients who underwent HDCT\/auto-HSCT in the FL 1\u20133B (14;18)-positive group without a single missense mutation in the KAT domain had better survival rates and lower rates of transformation and early progression. In addition, among patients with FL 3A\u20133B (14;18)-negative, we found that there were no cases of a missense mutation in the KAT domain of the CREBBP gene. This suggests that a single missense mutation in the CREBBP gene may be a feature that discriminates 14;18-positive FL with a favorable prognosis from a high-risk disease. FL 3A\u20133B (14;18)-negative may represent a distinct variant with different biology and underlying mechanisms of development compared to classical FL.<\/jats:p>","DOI":"10.3390\/ijms26146913","type":"journal-article","created":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T13:33:27Z","timestamp":1752845607000},"page":"6913","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Missense Mutations in the KAT Domain of CREBBP Gene in Patients with Follicular Lymphoma: Implications for Differential Diagnosis and Prognosis"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0591-2589","authenticated-orcid":false,"given":"Anna","family":"Smolianinova","sequence":"first","affiliation":[{"name":"National Medical Research Center for Hematology, 125167 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivan","family":"Bolshakov","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Hematology, 125167 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1936-0084","authenticated-orcid":false,"given":"Yulia","family":"Sidorova","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Hematology, 125167 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1082-8659","authenticated-orcid":false,"given":"Alla","family":"Kovrigina","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Hematology, 125167 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1613-652X","authenticated-orcid":false,"given":"Tatiana","family":"Obukhova","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Hematology, 125167 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nelli","family":"Gabeeva","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Hematology, 125167 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8357-977X","authenticated-orcid":false,"given":"Eduard","family":"Gemdzhian","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Hematology, 125167 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Nikulina","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Hematology, 125167 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6253-3334","authenticated-orcid":false,"given":"Bella","family":"Biderman","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Hematology, 125167 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nataliya","family":"Severina","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Hematology, 125167 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2957-1619","authenticated-orcid":false,"given":"Nataliya","family":"Risinskaya","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Hematology, 125167 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9463-9187","authenticated-orcid":false,"given":"Andrey","family":"Sudarikov","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Hematology, 125167 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eugeniy","family":"Zvonkov","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Hematology, 125167 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Parovichnikova","sequence":"additional","affiliation":[{"name":"National Medical Research Center for Hematology, 125167 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,18]]},"reference":[{"key":"ref_1","unstructured":"Swerdlow, S.H., Campo, E., Harris, N.L., Jaffe, E.S., Pileri, S.A., Stein, H., Thiele, J., and Vardiman, J.W. (2008). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, WHO Press. [4th ed.]."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1182\/blood-2018-04-843540","article-title":"Definitive radiotherapy for localized follicular lymphoma staged by 18F-FDG PET-CT: A collaborative study by ILROG","volume":"133","author":"Brady","year":"2019","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1684","DOI":"10.1182\/blood.2020010263","article-title":"Validation of POD24 as a robust early clinical end point of poor survival in FL from 5225 patients on 13 clinical trials","volume":"139","author":"Casulo","year":"2022","journal-title":"Blood"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2516","DOI":"10.1200\/JCO.2014.59.7534","article-title":"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","volume":"33","author":"Casulo","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.clml.2022.09.003","article-title":"Risk Factors for and Outcomes of Follicular Lymphoma Histological Transformation at First Progression in the GALLIUM Study","volume":"23","author":"Casulo","year":"2023","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Magnoli, F., Tibiletti, M.G., and Uccella, S. (2019). Unraveling Tumor Heterogeneity in an Apparently Monolithic Disease: BCL2 and Other Players in the Genetic Landscape of Nodal Follicular Lymphoma. Front. Med., 6.","DOI":"10.3389\/fmed.2019.00044"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5258","DOI":"10.1182\/bloodadvances.2022009456","article-title":"The clinical and molecular taxonomy of t(14;18)-negative follicular lymphomas","volume":"7","author":"Salaverria","year":"2023","journal-title":"Blood Adv."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1097\/PAP.0000000000000481","article-title":"Diagnosis and Classification of Follicular Lymphoma and Related Entities","volume":"32","author":"Laurent","year":"2025","journal-title":"Adv. Anat. Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1182\/blood.2022018719","article-title":"Genetic subdivisions of follicular lymphoma defined by distinct coding and noncoding mutation patterns","volume":"142","author":"Dreval","year":"2023","journal-title":"Blood"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1604","DOI":"10.1182\/blood-2012-09-457283","article-title":"Hierarchy in somatic mutations arising during genomic evolution and progression of follicular lymphoma","volume":"121","author":"Green","year":"2013","journal-title":"Blood"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"E1116","DOI":"10.1073\/pnas.1501199112","article-title":"Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation","volume":"112","author":"Green","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5652","DOI":"10.1182\/bloodadvances.2020002944","article-title":"Follicular lymphoma t(14;18)-negative is genetically a heterogeneous disease","volume":"4","author":"Nann","year":"2020","journal-title":"Blood Adv."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"344","DOI":"10.35754\/0234-5730-2023-68-3-344-362","article-title":"High-dose chemotherapy with transplantation of autologous hematopoietic stem cells in the first line of follicular lymphoma therapy","volume":"68","author":"Smolyaninova","year":"2023","journal-title":"Russ. J. Hematol. Transfusiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"150","DOI":"10.35754\/0234-5730-2019-64-2-150-164","article-title":"Chemotherapy According to the R-mNHL-BFM-90 Protocol in Combination with Lenalidomide as the First Line Therapy in Patients with Mum1-Positive Diffusive Large B-Cell Lymphoma and Follicular Lymphoma Grade 3B","volume":"64","author":"Gabeeva","year":"2019","journal-title":"Russ. J. Hematol. Transfusiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.1158\/2159-8290.CD-23-0111","article-title":"Tracing Founder Mutations in Circulating and Tissue-Resident Follicular Lymphoma Precursors","volume":"13","author":"Soo","year":"2023","journal-title":"Cancer Discov."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2908","DOI":"10.3109\/10428194.2016.1165816","article-title":"Rubinstein\u2013Taybi syndrome\u2014A window into follicular lymphoma biology","volume":"57","author":"Mar","year":"2016","journal-title":"Leuk. Lymphoma"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"25562","DOI":"10.1074\/jbc.M201196200","article-title":"Acetylation of \u03b2-Catenin by CREB-binding Protein (CBP)","volume":"277","author":"Wolf","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1182\/blood.2024026664","article-title":"Blunted CD40-responsive enhancer activation in CREBBP-mutant lymphomas can be restored by enforced CD4 T-cell engagement","volume":"146","author":"Yang","year":"2025","journal-title":"Blood J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1182\/blood-2024-208876","article-title":"Differential Role of Crebbp Missense and Truncating Mutations in the Malignant Transformation of Germinal Center B Cells","volume":"144","author":"Yu","year":"2024","journal-title":"Blood."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2645","DOI":"10.1182\/blood-2016-08-733469","article-title":"Crebbp loss cooperates with Bcl2 overexpression to promote lymphoma in mice","volume":"129","author":"Tadros","year":"2017","journal-title":"Blood"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Yang, H., Zhang, W., Ravanmehr, V., Mechaly, A., Regad, L., Haouz, A., Chen, R., Henderson, J.M., Rojas, E., and Wilson, A. (2023). CREBBP lysine acetyltransferase domain mutations create zombie enzymes that alter chromatin loading dynamics and prevent EP300 redundancy. bioRxiv.","DOI":"10.1101\/2023.09.05.556242"},{"key":"ref_22","first-page":"30","article-title":"Recurrent Crebbp Mutations in Follicular Lymphoma Appear Localized to the Committed B-Cell Lineage","volume":"136","author":"Soo","year":"2020","journal-title":"Blood"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1182\/blood-2021-144803","article-title":"CHOP but Not Bendamustine Reverses EZH2 Y641 Mutation Induced MHC-I\/II Loss in Human Lymphoma Models","volume":"138","author":"Adolph","year":"2021","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1038\/s41375-025-02603-9","article-title":"Molecular landscape of distinct follicular lymphoma histologic grades: Insights from genomic and transcriptome analyses","volume":"39","author":"Sun","year":"2025","journal-title":"Leukemia"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1111\/j.1600-0625.2011.01375.x","article-title":"A simple and efficient method for DNA extraction from skin and paraffin-embedded tissues applicable to T-cell clonality assays","volume":"21","author":"Sidorova","year":"2012","journal-title":"Exp. Dermatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2257","DOI":"10.1038\/sj.leu.2403202","article-title":"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","volume":"17","author":"Langerak","year":"2003","journal-title":"Leukemia"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic: A flexible trimmer for Illumina sequence data","volume":"30","author":"Bolger","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1093\/bioinformatics\/btp698","article-title":"Fast and accurate long-read alignment with Burrows-Wheeler transform","volume":"26","author":"Li","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e108","DOI":"10.1093\/nar\/gkw227","article-title":"VarDict: A novel and versatile variant caller for next-generation sequencing in cancer research","volume":"44","author":"Lai","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e164","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: Functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The Sequence Alignment\/Map format and SAMtools","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1101\/gr.9.8.677","article-title":"dbSNP\u2014database for single nucleotide polymorphisms and other classes of minor genetic variation","volume":"9","author":"Sherry","year":"1999","journal-title":"Genome Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"D941","DOI":"10.1093\/nar\/gky1015","article-title":"COSMIC: The Catalogue Of Somatic Mutations In Cancer","volume":"47","author":"Tate","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"D1062","DOI":"10.1093\/nar\/gkx1153","article-title":"ClinVar: Improving access to variant interpretations and supporting evidence","volume":"46","author":"Landrum","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Petrackova, A., Vasinek, M., Sedlarikova, L., Dyskova, T., Schneiderova, P., Novosad, T., Papajik, T., and Kriegova, E. (2019). Standardization of Sequencing Coverage Depth in NGS: Recommendation for Detection of Clonal and Subclonal Mutations in Cancer Diagnostics. Front. Oncol., 9.","DOI":"10.3389\/fonc.2019.00851"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1016\/j.gim.2022.01.001","article-title":"Standards for the classification of pathogenicity of somatic variants in cancer (oncogenicity): Joint recommendations of Clinical Genome Resource (ClinGen), Cancer Genomics Consortium (CGC), and Variant Interpretation for Cancer Consortium (VICC)","volume":"24","author":"Horak","year":"2022","journal-title":"Genet. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"297","DOI":"10.35754\/0234-5730-2024-69-3-297-318","article-title":"Analysis of microsatellite instability in primary mediastinal large B-cell lymphoma: Focus on PD-L1\/PD-L2 and CIITA","volume":"69","author":"Abdurashidova","year":"2024","journal-title":"Russ. J. Hematol. Transfusiol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/14\/6913\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:12:12Z","timestamp":1760033532000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/14\/6913"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,18]]},"references-count":37,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["ijms26146913"],"URL":"https:\/\/doi.org\/10.3390\/ijms26146913","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2025,7,18]]}}}