{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T22:26:43Z","timestamp":1773872803038,"version":"3.50.1"},"reference-count":38,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T00:00:00Z","timestamp":1744588800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Johnson &amp; Johnson","award":["Protocol 54179060CLL4020"],"award-info":[{"award-number":["Protocol 54179060CLL4020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Chronic lymphocytic leukemia (CLL) exhibits a heterogeneous clinical course influenced by genetic factors, such as the mutational status of immunoglobulin variable regions (IGHV). Recently, B-cell receptor (BcR) stereotypes have shown promising prognostic value, potentially surpassing IGHV status. The PAIS study analyzed BcR stereotypes and IGHV mutations in newly diagnosed Portuguese CLL patients to assess prognostic characteristics and disease progression. Methods: This cross-sectional study included 463 adult patients from 15 Portuguese centers, recruited between November 2020 and September 2023. The median age at diagnosis was 70.4 years. The most common clinical stages were 0 (54%) and 1 (32.83%). Results: A total of 15 different BcR stereotypes were identified in the cohort studied. Subtype #1, associated with a poorer prognosis, was the most prevalent, observed in 3.90% of newly diagnosed Portuguese CLL patients. Considering the 19 major stereotypes that could be assigned by the ARResT subsets tool, most patients exhibited a heterogeneous BcR profile (90.14%). A total of 57.24% of patients had mutated IGHV. The concentration of \u03b22-microglobulin was significantly lower in patients with mutated IGHV (2.6 mg\/L vs. 3.6 mg\/L, p &lt; 0.001). Clinical stage, assessed by the RAI staging system, differed between subgroups, with a higher frequency of stage 0 in patients with mutated IGHV and stage 2 in unmutated patients (p = 0.009). Conclusions: The PAIS study highlighted the predominance of a heterogeneous BcR profile in Portuguese CLL patients. The higher percentage of patients with mutated IGHV at diagnosis supports prior findings. This study improves the characterization of the 10% of Portuguese CLL patients with major BcR stereotypes, offering healthcare providers better predictive power for disease progression and potentially impacting clinical decision making.<\/jats:p>","DOI":"10.3390\/cancers17081316","type":"journal-article","created":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T06:18:36Z","timestamp":1744611516000},"page":"1316","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Analysis of Stereotyped B-Cell Receptor Frequencies Among Portuguese De Novo-Diagnosed Chronic Lymphocytic Leukemia Patients (PAIS Study)"],"prefix":"10.3390","volume":"17","author":[{"given":"Daniela","family":"Alves","sequence":"first","affiliation":[{"name":"Unidade Local de Sa\u00fade Santa Maria, E.P.E, 1649-035 Lisboa, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gisela","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Unidade Local de Sa\u00fade de Aveiro, 3810-501 Aveiro, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joana","family":"Caldas","sequence":"additional","affiliation":[{"name":"Hospital Santo Ant\u00f3nio dos Capuchos, Unidade Local de Sa\u00fade de S\u00e3o Jos\u00e9, 1169-050 Lisboa, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariana","family":"Fernandes","sequence":"additional","affiliation":[{"name":"Hospital Santo Ant\u00f3nio dos Capuchos, Unidade Local de Sa\u00fade de S\u00e3o Jos\u00e9, 1169-050 Lisboa, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C\u00e1tia","family":"Gaspar","sequence":"additional","affiliation":[{"name":"CUF Descobertas, 1998-018 Lisboa, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mafalda","family":"Alpoim","sequence":"additional","affiliation":[{"name":"Unidade Local de Sa\u00fade de Gaia\/Espinho, E.P.E, 4434-502 Vila Nova de Gaia, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"In\u00eas","family":"Carvalhais","sequence":"additional","affiliation":[{"name":"Centro Hospitalar Universit\u00e1rio de S\u00e3o Jo\u00e3o, Unidade Local de Sa\u00fade de S\u00e3o Jo\u00e3o, E.P.E, 4200-319 Porto, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7641-175X","authenticated-orcid":false,"given":"Sara","family":"Duarte","sequence":"additional","affiliation":[{"name":"Centro Hospitalar e Universit\u00e1rio de Coimbra, Unidade Local de Sa\u00fade de Coimbra, E.P.E, 3004-561 Coimbra, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helena","family":"Silva","sequence":"additional","affiliation":[{"name":"Hospital S\u00e3o Teot\u00f3nio de Viseu, Unidade Local de Sa\u00fade de Viseu D\u00e3o-Laf\u00f5es, E.P.E, 3504-509 Viseu, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana","family":"Montalv\u00e3o","sequence":"additional","affiliation":[{"name":"Unidade Local de Sa\u00fade do Baixo Alentejo, E.P.E, 7801-849 Beja, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernanda","family":"Vargas","sequence":"additional","affiliation":[{"name":"Hospital Garcia de Orta, Unidade Local Sa\u00fade de Almada-Seixal, E.P.E, 2805-267 Almada, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Hospital de Braga, Unidade Local de Sa\u00fade de Braga, E.P.E, 4710-243 Braga, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana","family":"Ant\u00f3nio","sequence":"additional","affiliation":[{"name":"Hospital de S\u00e3o Bernardo, Unidade Local de Sa\u00fade da Arr\u00e1bida, E.P.E, 4400-346 Vila Nova de Gaia, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rita","family":"Coutinho","sequence":"additional","affiliation":[{"name":"Hospital de Santo Ant\u00f3nio, Unidade Local de Sa\u00fade de Santo Ant\u00f3nio, E.P.E, 4050-342 Porto, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francisca","family":"Miranda","sequence":"additional","affiliation":[{"name":"Hospital de S\u00e3o Francisco Xavier, Unidade Local de Sa\u00fade de Lisboa Ocidental, E.P.E, 1449-005 Lisboa, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T\u00e2nia","family":"Maia","sequence":"additional","affiliation":[{"name":"Hospital Pedro Hispano, Unidade Local de Sa\u00fade de Matosinhos, E.P.E, 4464-513 Matosinhos, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1690-1292","authenticated-orcid":false,"given":"Marta","family":"Gomes","sequence":"additional","affiliation":[{"name":"Hospital Pedro Hispano, Unidade Local de Sa\u00fade de Matosinhos, E.P.E, 4464-513 Matosinhos, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9","family":"Carda","sequence":"additional","affiliation":[{"name":"Hospital da Luz de Lisboa, 1500-650 Lisboa, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S\u00f3nia","family":"Matos","sequence":"additional","affiliation":[{"name":"GenoMed, Diagn\u00f3sticos de Medicina Molecular, SA, 1649-028 Lisboa, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rita","family":"Jaime","sequence":"additional","affiliation":[{"name":"Johnson & Johnson Innovative Medicine, 2740-262 Porto Salvo, 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(2014). 102\u2014Chronic Lymphocytic Leukemia. Abeloff\u2019s Clinical Oncology, Churchill Livingstone. [5th ed.]."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Ou, Y., Long, Y., Ji, L., Zhan, Y., Qiao, T., Wang, X., Chen, H., and Cheng, Y. (2022). Trends in Disease Burden of Chronic Lymphocytic Leukemia at the Global, Regional, and National Levels from 1990 to 2019, and Projections Until 2030: A Population-Based Epidemiologic Study. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.840616"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Cardoso Borges, F., Ramos, A., Louren\u00e7o, A., Gomes da Silva, M., and Miranda, A. (2021). Detailing the epidemiological and clinical characteristics of chronic lymphocytic leukaemia in Portugal-Results from a population-based cancer registry cohort study. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0258423"},{"key":"ref_4","unstructured":"(2025, January 10). The Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute. Cancer Stat Facts: Leukemia\u2014Chronic Lymphocytic Leukemia (CLL), Available online: https:\/\/seer.cancer.gov\/statfacts\/html\/clyl.html."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21590","article-title":"Cancer statistics, 2020","volume":"70","author":"Siegel","year":"2020","journal-title":"CA Cancer J. Clin."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1038\/s41375-022-01620-2","article-title":"The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms","volume":"36","author":"Alaggio","year":"2022","journal-title":"Leukemia"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1002\/cyto.b.21595","article-title":"Reproducible diagnosis of chronic lymphocytic leukemia by flow cytometry: An European Research Initiative on CLL (ERIC) & European Society for Clinical Cell Analysis (ESCCA) Harmonisation project","volume":"94","author":"Rawstron","year":"2018","journal-title":"Cytom. B Clin. Cytom."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1908","DOI":"10.1038\/leu.2012.120","article-title":"EuroFlow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes","volume":"26","author":"Lhermitte","year":"2012","journal-title":"Leukemia"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1182\/blood.V46.2.219.219","article-title":"Clinical staging of chronic lymphocytic leukemia","volume":"46","author":"Rai","year":"1975","journal-title":"Blood"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1002\/1097-0142(19810701)48:1<198::AID-CNCR2820480131>3.0.CO;2-V","article-title":"A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis","volume":"48","author":"Binet","year":"1981","journal-title":"Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.jbi.2016.02.017","article-title":"Analysis of clinical prognostic variables for Chronic Lymphocytic Leukemia decision-making problems","volume":"60","author":"Luaces","year":"2016","journal-title":"J. Biomed. Inform."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1038\/s41408-022-00756-9","article-title":"Chronic lymphocytic leukemia treatment algorithm 2022","volume":"12","author":"Hampel","year":"2022","journal-title":"Blood Cancer J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2745","DOI":"10.1182\/blood-2017-09-806398","article-title":"iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL","volume":"131","author":"Hallek","year":"2018","journal-title":"Blood"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1038\/s41375-018-0303-x","article-title":"The importance of B cell receptor isotypes and stereotypes in chronic lymphocytic leukemia","volume":"33","author":"Gounari","year":"2019","journal-title":"Leukemia"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.1182\/blood.V94.6.1848","article-title":"Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia","volume":"94","author":"Hamblin","year":"1999","journal-title":"Blood"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2183","DOI":"10.1084\/jem.20120833","article-title":"Cellular origin and pathophysiology of chronic lymphocytic leukemia","volume":"209","author":"Seifert","year":"2012","journal-title":"J. Exp. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1182\/blood.2020007039","article-title":"Higher-order connections between stereotyped subsets: Implications for improved patient classification in CLL","volume":"137","author":"Agathangelidis","year":"2021","journal-title":"Blood"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Iyer, P., and Wang, L. (2023). Emerging Therapies in CLL in the Era of Precision Medicine. Cancers, 15.","DOI":"10.3390\/cancers15051583"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1961","DOI":"10.1038\/s41375-022-01604-2","article-title":"Immunoglobulin gene sequence analysis in chronic lymphocytic leukemia: The 2022 update of the recommendations by ERIC, the European Research Initiative on CLL","volume":"36","author":"Agathangelidis","year":"2022","journal-title":"Leukemia"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"107541","DOI":"10.1016\/j.leukres.2024.107541","article-title":"Unmutated IGHV at diagnosis in patients with early stage CLL independently predicts for shorter follow-up time to first treatment (TTFT)","volume":"143","author":"Galieni","year":"2024","journal-title":"Leuk. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.15252\/emmm.201707732","article-title":"Pathogen-specific B-cell receptors drive chronic lymphocytic leukemia by light-chain-dependent cross-reaction with autoantigens","volume":"9","author":"Fioravanti","year":"2017","journal-title":"EMBO Mol. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1002\/ajh.23591","article-title":"Stereotyped subset #1 chronic lymphocytic leukemia: A direct link between B-cell receptor structure, function, and patients\u2019 prognosis","volume":"89","author":"Chiaretti","year":"2014","journal-title":"Am. J. Hematol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1053\/j.seminhematol.2023.12.005","article-title":"B-cell receptor immunoglobulin stereotypy in chronic lymphocytic leukemia: Key to understanding disease biology and stratifying patients","volume":"61","author":"Agathangelidis","year":"2024","journal-title":"Semin. Hematol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1002\/ajh.25595","article-title":"Chronic lymphocytic leukemia: 2020 update on diagnosis, risk stratification and treatment","volume":"94","author":"Hallek","year":"2019","journal-title":"Am. J. Hematol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4467","DOI":"10.1182\/blood-2011-11-393694","article-title":"Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: A molecular classification with implications for targeted therapies","volume":"119","author":"Agathangelidis","year":"2012","journal-title":"Blood"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1182\/blood-2006-03-012948","article-title":"Over 20% of patients with chronic lymphocytic leukemia carry stereotyped receptors: Pathogenetic implications and clinical correlations","volume":"109","author":"Stamatopoulos","year":"2007","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1136\/bmj.39335.541782.AD","article-title":"Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: Guidelines for reporting observational studies","volume":"335","author":"Altman","year":"2007","journal-title":"BMJ"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"20520","DOI":"10.18632\/oncotarget.7819","article-title":"Immunoglobulin gene rearrangements in Chinese and Italian patients with chronic lymphocytic leukemia","volume":"7","author":"Marinelli","year":"2016","journal-title":"Oncotarget"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e803","DOI":"10.1097\/HS9.0000000000000803","article-title":"Distinct Immunogenetic Profiles of Chronic Lymphocytic Leukemia in Asia: A Taiwan Cooperative Oncology Group Registry Study","volume":"6","author":"Yao","year":"2022","journal-title":"Hemasphere"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.3324\/haematol.2016.157552","article-title":"Distinct molecular genetics of chronic lymphocytic leukemia in Taiwan: Clinical and pathogenetic implications","volume":"102","author":"Wu","year":"2017","journal-title":"Haematologica"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1111\/bjh.16051","article-title":"Distinct immunoglobulin heavy chain variable region gene repertoire and lower frequency of del(11q) in Taiwanese patients with chronic lymphocytic leukaemia","volume":"187","author":"Huang","year":"2019","journal-title":"Br. J. Haematol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e74","DOI":"10.1016\/S2352-3026(14)00005-2","article-title":"Clinical effect of stereotyped B-cell receptor immunoglobulins in chronic lymphocytic leukaemia: A retrospective multicentre study","volume":"1","author":"Baliakas","year":"2014","journal-title":"Lancet Haematol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1111\/j.1365-2141.2008.07469.x","article-title":"Molecular and clinical features of chronic lymphocytic leukaemia with stereotyped B cell receptors: Results from an Italian multicentre study","volume":"144","author":"Bomben","year":"2009","journal-title":"Br. J. Haematol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4410","DOI":"10.4049\/jimmunol.1502297","article-title":"B Cell Anergy Modulated by TLR1\/2 and the miR-17\u223c92 Cluster Underlies the Indolent Clinical Course of Chronic Lymphocytic Leukemia Stereotyped Subset #4","volume":"196","author":"Ntoufa","year":"2016","journal-title":"J. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1524","DOI":"10.1182\/blood-2007-07-099564","article-title":"Stereotyped patterns of somatic hypermutation in subsets of patients with chronic lymphocytic leukemia: Implications for the role of antigen selection in leukemogenesis","volume":"111","author":"Murray","year":"2008","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1182\/asheducation-2017.1.329","article-title":"The mutational landscape of chronic lymphocytic leukemia and its impact on prognosis and treatment","volume":"2017","author":"Gaidano","year":"2017","journal-title":"Hematol. Am. Soc. Hematol. Educ. Program"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"5018","DOI":"10.1182\/blood.V106.11.5018.5018","article-title":"Serum Beta-2 Microglobulin: The Universal Independent Prognostic Factor for Patients with CLL","volume":"106","author":"Wierda","year":"2005","journal-title":"Blood"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"White, A.M., Best, O.G., Hotinski, A.K., Kuss, B.J., and Thurgood, L.A. (2023). The Role of Cholesterol in Chronic Lymphocytic Leukemia Development and Pathogenesis. Metabolites, 13.","DOI":"10.3390\/metabo13070799"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/8\/1316\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:14:07Z","timestamp":1760030047000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/8\/1316"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,14]]},"references-count":38,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["cancers17081316"],"URL":"https:\/\/doi.org\/10.3390\/cancers17081316","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,14]]}}}