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- Baliakas, Panagiotis, et al.
(författare)
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Recurrent mutations refine prognosis in chronic lymphocytic leukemia
- 2015
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 29, s. 329-336
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Tidskriftsartikel (refereegranskat)abstract
- Through the European Research Initiative on chronic lymphocytic leukemia (CLL) (ERIC), we screened 3490 patients with CLL for mutations within the NOTCH1 (n=3334), SF3B1 (n=2322), TP53 (n=2309), MYD88 (n=1080) and BIRC3 (n=919) genes, mainly at diagnosis (75%) and before treatment (>90%). BIRC3 mutations (2.5%) were associated with unmutated IGHV genes (U-CLL), del(11q) and trisomy 12, whereas MYD88 mutations (2.2%) were exclusively found among M-CLL. NOTCH1, SF3B1 and TP53 exhibited variable frequencies and were mostly enriched within clinically aggressive cases. Interestingly, as the timespan between diagnosis and mutational screening increased, so too did the incidence of SF3B1 mutations; no such increase was observed for NOTCH1 mutations. Regarding the clinical impact, NOTCH1 mutations, SF3B1 mutations and TP53 aberrations (deletion/mutation, TP53ab) correlated with shorter time-to-first-treatment (P<0.0001) in 889 treatment-naive Binet stage A cases. In multivariate analysis (n=774), SF3B1 mutations and TP53ab along with del(11q) and U-CLL, but not NOTCH1 mutations, retained independent significance. Importantly, TP53ab and SF3B1 mutations had an adverse impact even in U-CLL. In conclusion, we support the clinical relevance of novel recurrent mutations in CLL, highlighting the adverse impact of SF3B1 and TP53 mutations, even independent of IGHV mutational status, thus underscoring the need for urgent standardization/harmonization of the detection methods.
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- Galigalidou, C, et al.
(författare)
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Understanding Monoclonal B Cell Lymphocytosis: An Interplay of Genetic and Microenvironmental Factors
- 2021
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Ingår i: Frontiers in oncology. - : Frontiers Media SA. - 2234-943X. ; 11, s. 769612-
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Tidskriftsartikel (refereegranskat)abstract
- The term monoclonal B-cell lymphocytosis (MBL) describes the presence of a clonal B cell population with a count of less than 5 × 109/L and no symptoms or signs of disease. Based on the B cell count, MBL is further classified into 2 distinct subtypes: ‘low-count’ and ‘high-count’ MBL. High-count MBL shares a series of biological and clinical features with chronic lymphocytic leukemia (CLL), at least of the indolent type, and evolves to CLL requiring treatment at a rate of 1-2% per year, whereas ‘low-count’ MBL seems to be distinct, likely representing an immunological rather than a pre-malignant condition. That notwithstanding, both subtypes of MBL can carry ‘CLL-specific’ genomic aberrations such as cytogenetic abnormalities and gene mutations, yet to a much lesser extent compared to CLL. These findings suggest that such aberrations are mostly relevant for disease progression rather than disease onset, indirectly pointing to microenvironmental drive as a key contributor to the emergence of MBL. Understanding microenvironmental interactions is therefore anticipated to elucidate MBL ontogeny and, most importantly, the relationship between MBL and CLL.
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- Gkoliou, G, et al.
(författare)
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Differences in the immunoglobulin gene repertoires of IgG versus IgA multiple myeloma allude to distinct immunopathogenetic trajectories
- 2023
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Ingår i: Frontiers in oncology. - : Frontiers Media SA. - 2234-943X. ; 13, s. 1123029-
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Tidskriftsartikel (refereegranskat)abstract
- The analysis of the immunogenetic background of multiple myeloma (MM) has proven key to understanding disease ontogeny. However, limited information is available regarding the immunoglobulin (IG) gene repertoire in MM cases carrying different heavy chain isotypes. Here, we studied the IG gene repertoire in a series of 523 MM patients, of whom 165 and 358 belonged to the IgA and IgG MM groups, respectively. IGHV3 subgroup genes predominated in both groups. However, at the individual gene level, significant (p<0.05) differences were identified regarding IGHV3-21 (frequent in IgG MM) and IGHV5-51 (frequent in IgA MM). Moreover, biased pairings were identified between certain IGHV genes and IGHD genes in IgA versus IgG MM. Turning to the imprints of somatic hypermutation (SHM), the bulk of rearrangements (IgA: 90.9%, IgG: 87.4%) were heavily mutated [exhibiting an IGHV germline identity (GI) <95%]. SHM topology analysis disclosed distinct patterns in IgA MM versus IgG MM cases expressing B cell receptor IG encoded by the same IGHV gene: the most pronounced examples concerned the IGHV3-23, IGHV3-30 and IGHV3-9 genes. Furthermore, differential SHM targeting was also identified between IgA MM versus IgG MM, particularly in cases utilizing certain IGHV genes, alluding to functional selection. Altogether, our detailed immunogenetic evaluation in the largest to-date series of IgA and IgG MM patients reveals certain distinct features in the IGH gene repertoires and SHM. These findings suggest distinct immune trajectories for IgA versus IgG MM, further underlining the role of external drive in the natural history of MM.
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- Agathangelidis, A, et al.
(författare)
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Immunoglobulin gene sequence analysis in chronic lymphocytic leukemia: the 2022 update of the recommendations by ERIC, the European Research Initiative on CLL
- 2022
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 36:8, s. 1961-1968
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Tidskriftsartikel (refereegranskat)abstract
- The somatic hypermutation (SHM) status of the clonotypic immunoglobulin heavy variable (IGHV) gene is a critical biomarker for assessing the prognosis of patients with chronic lymphocytic leukemia (CLL). Importantly, independent studies have documented that IGHV SHM status is also a predictor of responses to therapy, including both chemoimmunotherapy (CIT) and novel, targeted agents. Moreover, immunogenetic analysis in CLL has revealed that different patients may express (quasi)identical, stereotyped B cell receptor immunoglobulin (BcR IG) and are classified into subsets based on this common feature. Patients in certain stereotyped subsets display consistent biology, clinical presentation, and outcome that are distinct from other patients, even with concordant IGHV gene SHM status. All of the above highlights the relevance of immunogenetic analysis in CLL, which is considered a cornerstone for accurate risk stratification and clinical decision making. Recommendations for robust immunogenetic analysis exist thanks to dedicated efforts by ERIC, the European Research Initiative on CLL, covering all test phases, from the pre-analytical and analytical to the post-analytical, pertaining to the analysis, interpretation, and reporting of the findings. That said, these recommendations apply to Sanger sequencing, which is increasingly being superseded by next generation sequencing (NGS), further underscoring the need for an update. Here, we present an overview of the clinical utility of immunogenetics in CLL and update our analytical recommendations with the aim to assist in the refined management of patients with CLL.
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- Galigalidou, C, et al.
(författare)
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Purpose-Built Immunoinformatics for BcR IG/TR Repertoire Data Analysis
- 2022
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Ingår i: Methods in molecular biology (Clifton, N.J.). - New York, NY : Springer US. - 1940-6029. ; 2453, s. 585-603
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Tidskriftsartikel (refereegranskat)abstract
- The study of antigen receptor gene repertoires using next-generation sequencing (NGS) technologies has disclosed an unprecedented depth of complexity, requiring novel computational and analytical solutions. Several bioinformatics workflows have been developed to this end, including the T-cell receptor/immunoglobulin profiler (TRIP), a web application implemented in R shiny, specifically designed for the purposes of comprehensive repertoire analysis, which is the focus of this chapter. TRIP has the potential to perform robust immunoprofiling analysis through the extraction and processing of the IMGT/HighV-Quest output, via a series of functions, ensuring the analysis of high-quality, biologically relevant data through a multilevel process of data filtering. Subsequently, it provides in-depth analysis of antigen receptor gene rearrangements, including (a) clonality assessment; (b) extraction of variable (V), diversity (D), and joining (J) gene repertoires; (c) CDR3 characterization at both the nucleotide and amino acid level; and (d) somatic hypermutation analysis, in the case of immunoglobulin gene rearrangements. Relevant to mention, TRIP enables a high level of customization through the integration of various options in key aspects of the analysis, such as clonotype definition and computation, hence allowing for flexibility without compromising on accuracy.
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