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1. Clonotype definitions for immunogenetic studies: proposals from the EuroClonality NGS Working Group.

Author

Sofou, E., Vlachonikola, E., Zaragoza-Infante, L., Brüggemann, M., Darzentas, N., Groenen, P.J.T.A., Hummel, M., Macintyre, E.A., Psomopoulos, F., Davi, F., Langerak, A.W., Stamatopoulos, K., Sofou, E., Vlachonikola, E., Zaragoza-Infante, L., Brüggemann, M., Darzentas, N., Groenen, P.J.T.A., Hummel, M., Macintyre, E.A., Psomopoulos, F., Davi, F., Langerak, A.W., and Stamatopoulos, K.

Abstract

01 augustus 2023, Item does not contain fulltext

Published
2023

2. EuroClonality-NGS Recommendations for Evaluation of B-Cell Clonality Analysis by Next-Generation Sequencing: A Structured Approach with the DEPART Algorithm.

Author

Brand, M. van den, Möbs, M., Otto, F., Kroeze, L.I., Gonzalez de Castro, D., Stamatopoulos, K., Davi, F., Bravetti, C., Kolijn, P.M., Vlachonikola, E., Stewart, J.P., Pott, C., Hummel, M., Darzentas, N., Langerak, A.W., Fend, F., Groenen, P.J.T.A., Brand, M. van den, Möbs, M., Otto, F., Kroeze, L.I., Gonzalez de Castro, D., Stamatopoulos, K., Davi, F., Bravetti, C., Kolijn, P.M., Vlachonikola, E., Stewart, J.P., Pott, C., Hummel, M., Darzentas, N., Langerak, A.W., Fend, F., and Groenen, P.J.T.A.

Abstract

Contains fulltext : 296673.pdf (Publisher’s version ) (Open Access), Next-generation sequencing (NGS)-based clonality analysis allows in-depth assessment of the clonal composition of a sample with high sensitivity for detecting small clones. Within the EuroClonality-NGS Working Group, a protocol for NGS Ig clonality analysis was developed and validated previously. This NGS-based approach was designed to generate small amplicons, making it suitable for samples with suboptimal DNA quality, especially material derived from formalin-fixed, paraffin-embedded tissue. Using expert assessment of NGS Ig clonality results as a reference, a structured algorithmic approach to the assessment of NGS-amplicon-based B-cell clonality analysis was developed. A structured approach with the Detection of clonality through Evaluation of sample quality and assessment of Pattern, Abundance and RaTio (DEPART) algorithm was proposed, which consecutively evaluates sample quality, the pattern of the clonotypes present, the abundance of the most dominant clonotypes, and the ratio between the dominant clonotypes and the background to evaluate the different Ig gene targets. Specific issues with respect to evaluation of the various Ig targets as well as the integration of results of individual targets into a molecular clonality conclusion are discussed and illustrated with case examples. Finally, the importance of interpretation of NGS-based clonality results in clinical and histopathologic contexts is discussed. It is expected that these recommendations will have clinical utility to facilitate proper evaluation of clonality assessment.

Published
2023

4. Validation of the EuroClonality-NGS DNA capture panel as an integrated genomic tool for lymphoproliferative disorders

Author

Stewart, J, Gazdova, J, Darzentas, N, Wren, D, Proszek, P, Fazio, G, Songia, S, Alcoceba, M, Sarasquete, M, Villarese, P, Van Der Klift, M, Heezen, K, Mccafferty, N, Pal, K, Catherwood, M, Kim, C, Srivastava, S, Kroeze, L, Hodges, E, Stamatopoulos, K, Klapper, W, Genuardi, E, Ferrero, S, Van Den Brand, M, Cazzaniga, G, Davi, F, Sutton, L, Garcia-Sanz, R, Groenen, P, Macintyre, E, Bruggemann, M, Pott, C, Langerak, A, Gonzalez, D, Stewart J. P., Gazdova J., Darzentas N., Wren D., Proszek P., Fazio G., Songia S., Alcoceba M., Sarasquete M. E., Villarese P., Van Der Klift M. Y., Heezen K. C., McCafferty N., Pal K., Catherwood M., Kim C. S., Srivastava S., Kroeze L. I., Hodges E., Stamatopoulos K., Klapper W., Genuardi E., Ferrero S., Van Den Brand M., Cazzaniga G., Davi F., Sutton L. -A., Garcia-Sanz R., Groenen P. J. T. A., Macintyre E. A., Bruggemann M., Pott C., Langerak A. W., Gonzalez D., Stewart, J, Gazdova, J, Darzentas, N, Wren, D, Proszek, P, Fazio, G, Songia, S, Alcoceba, M, Sarasquete, M, Villarese, P, Van Der Klift, M, Heezen, K, Mccafferty, N, Pal, K, Catherwood, M, Kim, C, Srivastava, S, Kroeze, L, Hodges, E, Stamatopoulos, K, Klapper, W, Genuardi, E, Ferrero, S, Van Den Brand, M, Cazzaniga, G, Davi, F, Sutton, L, Garcia-Sanz, R, Groenen, P, Macintyre, E, Bruggemann, M, Pott, C, Langerak, A, Gonzalez, D, Stewart J. P., Gazdova J., Darzentas N., Wren D., Proszek P., Fazio G., Songia S., Alcoceba M., Sarasquete M. E., Villarese P., Van Der Klift M. Y., Heezen K. C., McCafferty N., Pal K., Catherwood M., Kim C. S., Srivastava S., Kroeze L. I., Hodges E., Stamatopoulos K., Klapper W., Genuardi E., Ferrero S., Van Den Brand M., Cazzaniga G., Davi F., Sutton L. -A., Garcia-Sanz R., Groenen P. J. T. A., Macintyre E. A., Bruggemann M., Pott C., Langerak A. W., and Gonzalez D.

Abstract

Current diagnostic standards for lymphoproliferative disorders include multiple tests for detection of clonal immunoglobulin (IG) and/or T-cell receptor (TCR) rearrangements, translocations, copy-number alterations (CNAs), and somatic mutations. The EuroClonality-NGS DNA Capture (EuroClonality-NDC) assay was designed as an integrated tool to characterize these alterations by capturing IGH switch regions along with variable, diversity, and joining genes of all IG and TCR loci in addition to clinically relevant genes for CNA and mutation analysis. Diagnostic performance against standard-of-care clinical testing was assessed in a cohort of 280 B-and T-cell malignancies from 10 European laboratories, including 88 formalin-fixed paraffin-embedded samples and 21 reactive lesions. DNA samples were subjected to the EuroClonality-NDC protocol in 7 EuroClonality-NGS laboratories and analyzed using a bespoke bioinformatic pipeline. The EuroClonality-NDC assay detected B-cell clonality in 191 (97%) of 197 B-cell malignancies and T-cell clonality in 71 (97%) of 73 T-cell malignancies. Limit of detection (LOD) for IG/TCR rearrangements was established at 5% using cell line blends. Chromosomal translocations were detected in 145 (95%) of 152 cases known to be positive. CNAs were validated for immunogenetic and oncogenetic regions, highlighting their novel role in confirming clonality in somatically hypermutated cases. Single-nucleotide variant LOD was determined as 4% allele frequency, and an orthogonal validation using 32 samples resulted in 98% concordance. The EuroClonality-NDC assay is a robust tool providing a single end-To-end workflow for simultaneous detection of B-and T-cell clonality, translocations, CNAs, and sequence variants.

Published
2021

5. Potential and pitfalls of whole transcriptome-based immunogenetic marker identification in acute lymphoblastic leukemia; a EuroMRD and EuroClonality-NGS Working Group study

Author

van der Velden, V, Bruggemann, M, Cazzaniga, G, Scheijen, B, Tops, B, Trka, J, Pal, K, Hanzelmann, S, Fazio, G, Songia, S, Langerak, A, Darzentas, N, van der Velden V. H. J., Bruggemann M., Cazzaniga G., Scheijen B., Tops B., Trka J., Pal K., Hanzelmann S., Fazio G., Songia S., Langerak A. W., Darzentas N., van der Velden, V, Bruggemann, M, Cazzaniga, G, Scheijen, B, Tops, B, Trka, J, Pal, K, Hanzelmann, S, Fazio, G, Songia, S, Langerak, A, Darzentas, N, van der Velden V. H. J., Bruggemann M., Cazzaniga G., Scheijen B., Tops B., Trka J., Pal K., Hanzelmann S., Fazio G., Songia S., Langerak A. W., and Darzentas N.

Published
2021

6. Immunoglobulin/T-Cell Receptor Gene Rearrangement Analysis Using RNA-Seq

Author

van der Velden, V. H. J., Bastian, L., Brüggemann, M., Hartmann, A. M., Darzentas, N., van der Velden, V. H. J., Bastian, L., Brüggemann, M., Hartmann, A. M., and Darzentas, N.

Abstract

Identification of immunoglobulin (IG) and T-cell receptor (TR) gene rearrangements in acute lymphoblastic leukemia (ALL) patients at initial presentation are crucial for monitoring of minimal residual disease (MRD) during subsequent follow-up and thereby for appropriate risk-group stratification. Here we describe how RNA-Seq data can be generated and subsequently analyzed with ARResT/Interrogate to identify possible MRD markers. In addition to the procedures, possible pitfalls will be discussed. Similar strategies can be employed for other lymphoid malignancies, such as lymphoma and myeloma.

Published
2022

8. Quality control and quantification in IG/TR next-generation sequencing marker identification: protocols and bioinformatic functionalities by EuroClonality-NGS

Author

Knecht, H, Reigl, T, Kotrova, M, Appelt, F, Stewart, P, Bystry, V, Krejci, A, Grioni, A, Pal, K, Stranska, K, Plevova, K, Rijntjes, J, Songia, S, Svaton, M, Fronkova, E, Bartram, J, Scheijen, B, Herrmann, D, Garcia-Sanz, R, Hancock, J, Moppett, J, van Dongen, J, Cazzaniga, G, Davi, F, Groenen, P, Hummel, M, Macintyre, E, Stamatopoulos, K, Trka, J, Langerak, A, Gonzalez, D, Pott, C, Bruggemann, M, Darzentas, N, Knecht H., Reigl T., Kotrova M., Appelt F., Stewart P., Bystry V., Krejci A., Grioni A., Pal K., Stranska K., Plevova K., Rijntjes J., Songia S., Svaton M., Fronkova E., Bartram J., Scheijen B., Herrmann D., Garcia-Sanz R., Hancock J., Moppett J., van Dongen J. J. M., Cazzaniga G., Davi F., Groenen P. J. T. A., Hummel M., Macintyre E. A., Stamatopoulos K., Trka J., Langerak A. W., Gonzalez D., Pott C., Bruggemann M., Darzentas N., Knecht, H, Reigl, T, Kotrova, M, Appelt, F, Stewart, P, Bystry, V, Krejci, A, Grioni, A, Pal, K, Stranska, K, Plevova, K, Rijntjes, J, Songia, S, Svaton, M, Fronkova, E, Bartram, J, Scheijen, B, Herrmann, D, Garcia-Sanz, R, Hancock, J, Moppett, J, van Dongen, J, Cazzaniga, G, Davi, F, Groenen, P, Hummel, M, Macintyre, E, Stamatopoulos, K, Trka, J, Langerak, A, Gonzalez, D, Pott, C, Bruggemann, M, Darzentas, N, Knecht H., Reigl T., Kotrova M., Appelt F., Stewart P., Bystry V., Krejci A., Grioni A., Pal K., Stranska K., Plevova K., Rijntjes J., Songia S., Svaton M., Fronkova E., Bartram J., Scheijen B., Herrmann D., Garcia-Sanz R., Hancock J., Moppett J., van Dongen J. J. M., Cazzaniga G., Davi F., Groenen P. J. T. A., Hummel M., Macintyre E. A., Stamatopoulos K., Trka J., Langerak A. W., Gonzalez D., Pott C., Bruggemann M., and Darzentas N.

Abstract

Assessment of clonality, marker identification and measurement of minimal residual disease (MRD) of immunoglobulin (IG) and T cell receptor (TR) gene rearrangements in lymphoid neoplasms using next-generation sequencing (NGS) is currently under intensive development for use in clinical diagnostics. So far, however, there is a lack of suitable quality control (QC) options with regard to standardisation and quality metrics to ensure robust clinical application of such approaches. The EuroClonality-NGS Working Group has therefore established two types of QCs to accompany the NGS-based IG/TR assays. First, a central polytarget QC (cPT-QC) is used to monitor the primer performance of each of the EuroClonality multiplex NGS assays; second, a standardised human cell line-based DNA control is spiked into each patient DNA sample to work as a central in-tube QC and calibrator for MRD quantification (cIT-QC). Having integrated those two reference standards in the ARResT/Interrogate bioinformatic platform, EuroClonality-NGS provides a complete protocol for standardised IG/TR gene rearrangement analysis by NGS with high reproducibility, accuracy and precision for valid marker identification and quantification in diagnostics of lymphoid malignancies.

Published
2019

9. Standardized next-generation sequencing of immunoglobulin and T-cell receptor gene recombinations for MRD marker identification in acute lymphoblastic leukaemia; a EuroClonality-NGS validation study

Author

Bruggemann, M, Kotrova, M, Knecht, H, Bartram, J, Boudjogrha, M, Bystry, V, Fazio, G, Fronkova, E, Giraud, M, Grioni, A, Hancock, J, Herrmann, D, Jimenez, C, Krejci, A, Moppett, J, Reigl, T, Salson, M, Scheijen, B, Schwarz, M, Songia, S, Svaton, M, van Dongen, J, Villarese, P, Wakeman, S, Wright, G, Cazzaniga, G, Davi, F, Garcia-Sanz, R, Gonzalez, D, Groenen, P, Hummel, M, Macintyre, E, Stamatopoulos, K, Pott, C, Trka, J, Darzentas, N, Langerak, A, Bruggemann M., Kotrova M., Knecht H., Bartram J., Boudjogrha M., Bystry V., Fazio G., Fronkova E., Giraud M., Grioni A., Hancock J., Herrmann D., Jimenez C., Krejci A., Moppett J., Reigl T., Salson M., Scheijen B., Schwarz M., Songia S., Svaton M., van Dongen J. J. M., Villarese P., Wakeman S., Wright G., Cazzaniga G., Davi F., Garcia-Sanz R., Gonzalez D., Groenen P. J. T. A., Hummel M., Macintyre E. A., Stamatopoulos K., Pott C., Trka J., Darzentas N., Langerak A. W., Bruggemann, M, Kotrova, M, Knecht, H, Bartram, J, Boudjogrha, M, Bystry, V, Fazio, G, Fronkova, E, Giraud, M, Grioni, A, Hancock, J, Herrmann, D, Jimenez, C, Krejci, A, Moppett, J, Reigl, T, Salson, M, Scheijen, B, Schwarz, M, Songia, S, Svaton, M, van Dongen, J, Villarese, P, Wakeman, S, Wright, G, Cazzaniga, G, Davi, F, Garcia-Sanz, R, Gonzalez, D, Groenen, P, Hummel, M, Macintyre, E, Stamatopoulos, K, Pott, C, Trka, J, Darzentas, N, Langerak, A, Bruggemann M., Kotrova M., Knecht H., Bartram J., Boudjogrha M., Bystry V., Fazio G., Fronkova E., Giraud M., Grioni A., Hancock J., Herrmann D., Jimenez C., Krejci A., Moppett J., Reigl T., Salson M., Scheijen B., Schwarz M., Songia S., Svaton M., van Dongen J. J. M., Villarese P., Wakeman S., Wright G., Cazzaniga G., Davi F., Garcia-Sanz R., Gonzalez D., Groenen P. J. T. A., Hummel M., Macintyre E. A., Stamatopoulos K., Pott C., Trka J., Darzentas N., and Langerak A. W.

Abstract

Amplicon-based next-generation sequencing (NGS) of immunoglobulin (IG) and T-cell receptor (TR) gene rearrangements for clonality assessment, marker identification and quantification of minimal residual disease (MRD) in lymphoid neoplasms has been the focus of intense research, development and application. However, standardization and validation in a scientifically controlled multicentre setting is still lacking. Therefore, IG/TR assay development and design, including bioinformatics, was performed within the EuroClonality-NGS working group and validated for MRD marker identification in acute lymphoblastic leukaemia (ALL). Five EuroMRD ALL reference laboratories performed IG/TR NGS in 50 diagnostic ALL samples, and compared results with those generated through routine IG/TR Sanger sequencing. A central polytarget quality control (cPT-QC) was used to monitor primer performance, and a central in-tube quality control (cIT-QC) was spiked into each sample as a library-specific quality control and calibrator. NGS identified 259 (average 5.2/sample, range 0–14) clonal sequences vs. Sanger-sequencing 248 (average 5.0/sample, range 0–14). NGS primers covered possible IG/TR rearrangement types more completely compared with local multiplex PCR sets and enabled sequencing of bi-allelic rearrangements and weak PCR products. The cPT-QC showed high reproducibility across all laboratories. These validated and reproducible quality-controlled EuroClonality-NGS assays can be used for standardized NGS-based identification of IG/TR markers in lymphoid malignancies.

Published
2019

10. CELL‐FREE DNA KINETICS DECIPHER POTENTIAL MECHANISMS OF ACTION OF IBRUTINIB COMBINATION THERAPY IN MANTLE CELL LYMPHOMA (MCL).

Author

Khouja, M., Genuardi, E., Ferrero, S., Alessandria, B., Verhagen, O. J., Homburg, C., van der Velden, V. H., Gameiro, P., Sanz, R. García, Herrera, A. Medina, Fronkova, E., Brüggemann, M., Dreyling, M., Hoster, E., Ladetto, M., Langerak, A. W., Darzentas, N., Pal, K., Stewart, P. J., and Gonzalez de Castro, D.

Subjects
CELL-free DNA, CIRCULATING tumor DNA, TUMOR genetics, CELLULAR therapy, MANTLE cell lymphoma, SINGLE nucleotide polymorphisms
Abstract

Cell-free (cf)DNA captures tumor genetics and can be used to assess disease kinetics and minimal residual disease (MRD). B Introduction: b The European MCL Network trial TRIANGLE (NCT02858258) evaluated the addition of ibrutinib to standard treatment with autologous stem cell transplantation (ASCT) (arm A+I) in comparison to ASCT alone (arm A) and ibrutinib plus chemoimmunotherapy without ASCT (arm I) demonstrating significant and clinically relevant superiority of additional ibrutinib on outcome. CELL-FREE DNA KINETICS DECIPHER POTENTIAL MECHANISMS OF ACTION OF IBRUTINIB COMBINATION THERAPY IN MANTLE CELL LYMPHOMA (MCL). [Extracted from the article]

Published
2023
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11. PREDICTION OF RELAPSE BY STANDARDIZED IG‐BASED ALLEL‐SPECIFIC QPCR, DDPCR AND AMPLICON NGS FOR MRD MONITORING IN MANTLE CELL LYMPHOMA: A COMPARATIVE ANALYSIS BY THE EU‐MCL NETWORK

Author

Pott, C., primary, Macintyre, E., additional, Delfau, M.‐H., additional, Weiß, A., additional, Schilhabel, A., additional, Soehlbrand, A., additional, Kehden, B., additional, Darzentas, N., additional, Kotrova, M., additional, Schoen, F., additional, Ribrag, V., additional, Brueggemann, M., additional, Villarese, P., additional, Dreyling, M., additional, Hermine, O., additional, Kluin‐Nelemans, H., additional, Jiang, L., additional, and Hoster, E., additional

Published
2021
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12. Potential and pitfalls of whole transcriptome-based immunogenetic marker identification in acute lymphoblastic leukemia; a EuroMRD and EuroClonality-NGS Working Group study

Author

Velden, V.H. van der, Brüggemann, M., Cazzaniga, G., Scheijen, B., Tops, B., Trka, J., Pal, K., Hänzelmann, S., Fazio, G., Songia, S., Langerak, A.W., Darzentas, N., Velden, V.H. van der, Brüggemann, M., Cazzaniga, G., Scheijen, B., Tops, B., Trka, J., Pal, K., Hänzelmann, S., Fazio, G., Songia, S., Langerak, A.W., and Darzentas, N.

Abstract

Contains fulltext : 232927.pdf (Publisher’s version ) (Open Access)

Published
2021

13. Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications

Author

Bikos, V, Darzentas, N, Hadzidimitriou, A, Davis, Z, Hockley, S, Traverse-Glehen, A, Algara, P, Santoro, A, Gonzalez, D, Mollejo, M, Dagklis, A, Gangemi, F, Bosler, D S, Bourikas, G, Anagnostopoulos, A, Tsaftaris, A, Iannitto, E, Ponzoni, M, Felman, P, Berger, F, Belessi, C, Ghia, P, Papadaki, T, Dogan, A, Degano, M, Matutes, E, Piris, M A, Oscier, D, and Stamatopoulos, K

Published
2012
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14. Antigen receptor stereotypy across B-cell lymphoproliferations: the case of IGHV4-59/IGKV3-20 receptors with rheumatoid factor activity

Author

Kostareli, E, Gounari, M, Janus, A, Murray, F, Brochet, X, Giudicelli, V, Pospisilova, S, Oscier, D, Foroni, L, di Celle, P F, Tichy, B, Pedersen, L B, Jurlander, J, Ponzoni, M, Kouvatsi, A, Anagnostopoulos, A, Thompson, K, Darzentas, N, Lefranc, M-P, Belessi, C, Rosenquist, R, Davi, F, Ghia, P, and Stamatopoulos, K

Published
2012
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24. Encyclopedia of CLL Subsets - a Unique Bioinformatics Tool and Database for Analysis of Subsets of Stereotypical B-Cell Receptors in CLL

Author

Reigl T, Stránská K, Bystrý V, Krejčí A, Grioni A, Š, Pospíšilová, Darzentas N, and Karla Plevova

Subjects
Databases, Factual, Biomarkers, Tumor, Computational Biology, Humans, Immunoglobulins, Receptors, Antigen, B-Cell, Leukemia, Lymphocytic, Chronic, B-Cell
Abstract

Chronic lymphocytic leukemia (CLL) is clinically and biologically highly variable disease which is closely related with multiple cellular and molecular markers, including sequence motifs of B-cell receptors. These motifs are highly similar (stereotyped) within one third of CLL patients and create homogeneous groups called stereotyped CLL subsets. The homogeneity is reflected also in clinical and biological characteristics of the disease. To facilitate access to the information about individual subsets, we have created a publicly available web-based tool Encyclopedia of CLL Subsets.The Encyclopedia of CLL subsets belongs to our bioinformatics platform Antigen Receptor Research Tool (ARResT) developed for analysis, clustering, and annotation of immunoglobulin sequences. To gather primary knowledge about the subsets, we have analyzed a dataset of 7,500 CLL patients published by Agathangelidis et al in 2012 [1]. We have created an overview of major stereotyped subsets and their characteristics. Additional clinical and cytogenomic information about individual subsets has been obtained by machine text processing of available literature from server PubMed and is regularly updated.We have created a unique web-based application Encyclopedia of CLL Subsets available from http: //arrest.tools/subsets for an interactive access to the information about stereotyped CLL subsets. A user can obtain and compare basic information about the major subsets including their clinical and cytogenomic characteristics. These have been manually curated from machine processed results from PubMed database by experts in CLL research. Through the Encyclopedias user interface, user can also directly use our published tool ARResT/AssignSubsets to assign new immunoglobulin sequences to the major subsets.The Encyclopedia of CLL Subsets is a publicly available online tool facilitating access to the most recent research knowledge about stereotyped CLL subsets and enabling analysis of own data and interpretation of the results. This gives the Encyclopedia a great potential for its use in clinical routine. This work was supported by Czech Ministry of Health grant No. 34272A. All rights reserved. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 1. 3. 2019 Accepted: 4. 3. 2019.

Published
2019

25. Quality control and quantification in IG/TR next-generation sequencing marker identification: protocols and bioinformatic functionalities by EuroClonality-NGS

Author

Knecht, H., Reigl, T., Kotrova, M, Appelt, F., Stewart, P., Bystry, V., Krejčí, A. (Alena), Grioni, A., Pal, K. (Karin) van der, Stranska, K., Plevova, K. (K.), Rijntjes, J., Songia, S., Svaton, M., Fronkova, E., Bartram, J., Scheijen, B. (Blanca), Herrmann, D., Garcia-Sanz, R. (Ramon), Hancock, J., Moppett, J. (John), van Dongen, JJM, Cazzaniga, G. (Gianni), Davi, F. (Frédéric), Groenen, P., Hummel, M. (Michael), Macintyre, E.A. (Elizabeth), Stamatopoulos, K. (Kostas), Trka, J. (Jan), Langerak, A.W. (Anton), Gonzalez, D., Pott, C. (Christiane), Bruggemann, M, Darzentas, N. (Nikos), Knecht, H., Reigl, T., Kotrova, M, Appelt, F., Stewart, P., Bystry, V., Krejčí, A. (Alena), Grioni, A., Pal, K. (Karin) van der, Stranska, K., Plevova, K. (K.), Rijntjes, J., Songia, S., Svaton, M., Fronkova, E., Bartram, J., Scheijen, B. (Blanca), Herrmann, D., Garcia-Sanz, R. (Ramon), Hancock, J., Moppett, J. (John), van Dongen, JJM, Cazzaniga, G. (Gianni), Davi, F. (Frédéric), Groenen, P., Hummel, M. (Michael), Macintyre, E.A. (Elizabeth), Stamatopoulos, K. (Kostas), Trka, J. (Jan), Langerak, A.W. (Anton), Gonzalez, D., Pott, C. (Christiane), Bruggemann, M, and Darzentas, N. (Nikos)

Abstract

Assessment of clonality, marker identification and measurement of minimal residual disease (MRD) of immunoglobulin (IG) and T cell receptor (TR) gene rearrangements in lymphoid neoplasms using next-generation sequencing (NGS) is currently under intensive development for use in clinical diagnostics. So far, however, there is a lack of suitable quality control (QC) options with regard to standardisation and quality metrics to ensure robust clinical application of such approaches. The EuroClonality-NGS Working Group has therefore established two types of QCs to accompany the NGS-based IG/TR assays. First, a central polytarget QC (cPT-QC) is used to monitor the primer performance of each of the EuroClonality multiplex NGS assays; second, a standardised human cell line-based DNA control is spiked into each patient DNA sample to work as a central in-tube QC and calibrator for MRD quantification (cIT-QC). Having integrated those two reference standards in the ARResT/Interrogate bioinformatic platform, EuroClonality-NGS provides a complete protocol for standardised IG/TR gene rearrangement analysis by NGS with high reproducibility, accuracy and precision for valid marker identification and quantification in diagnostics of lymphoid malignancies.

Published
2019
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26. The presence of CLL-associated stereotypic B cell receptors in the normal BCR repertoire from healthy individuals increases with age

Author

Muggen, A.F. (Alice), Jong, M. (Marion) de, Wolvers-Tettero, I.L.M. (I. L M), Kallemeijn, M.J. (Martine), Teodosio, C. (Cristina), Darzentas, N. (Nikos), Stadhouders, R. (Ralph), IJspeert, H. (Hanna), Burg, M. (Mirjam) van der, IJcken, W.F.J. (Wilfred) van, Verhaar, J.A.N. (Jan), Abdulahad, W.H., Brouwer, E. (Eric), Boots, A.M.H. (Anne Mieke), Hendriks, R.W. (Rudi), Dongen, J.J.M. (Jacques) van, Langerak, A.W. (Anton), Muggen, A.F. (Alice), Jong, M. (Marion) de, Wolvers-Tettero, I.L.M. (I. L M), Kallemeijn, M.J. (Martine), Teodosio, C. (Cristina), Darzentas, N. (Nikos), Stadhouders, R. (Ralph), IJspeert, H. (Hanna), Burg, M. (Mirjam) van der, IJcken, W.F.J. (Wilfred) van, Verhaar, J.A.N. (Jan), Abdulahad, W.H., Brouwer, E. (Eric), Boots, A.M.H. (Anne Mieke), Hendriks, R.W. (Rudi), Dongen, J.J.M. (Jacques) van, and Langerak, A.W. (Anton)

Abstract

__Background:__ Aging is known to induce immunosenescence, resulting in alterations in both the innate and adaptive immune system. Here we evaluated the effects of aging on B cell subsets in peripheral blood of 155 immunologically healthy individuals in four age categories (range 20-95y) via multi-parameter flow cytometry. Furthermore, we studied the naive and antigen-experienced B cell receptor (BCR) repertoire of different age groups and compared it to the clonal BCR repertoire of chronic lymphocytic leukemia (CLL), a disease typically presenting in elderly individuals. __Results:__ Total numb

Published
2019
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27. A simple RNA target capture NGS strategy for fusion genes assessment in the diagnostics of pediatric B-cell acute lymphoblastic leukemia

Author

Grioni, A, Fazio, G, Rigamonti, S, Bystry, V, Daniele, G, Dostalova, Z, Quadri, M, Saitta, C, Silvestri, D, Songia, S, Storlazzi, C, Biondi, A, Darzentas, N, Cazzaniga, G, Grioni, Andrea, Fazio, Grazia, Rigamonti, Silvia, Bystry, Vojtech, Daniele, Giulia, Dostalova, Zuzana, Quadri, Manuel, Saitta, Claudia, Silvestri, Daniela, Songia, Simona, Storlazzi, Clelia T., Biondi, Andrea, Darzentas, Nikos, Cazzaniga, Giovanni, Grioni, A, Fazio, G, Rigamonti, S, Bystry, V, Daniele, G, Dostalova, Z, Quadri, M, Saitta, C, Silvestri, D, Songia, S, Storlazzi, C, Biondi, A, Darzentas, N, Cazzaniga, G, Grioni, Andrea, Fazio, Grazia, Rigamonti, Silvia, Bystry, Vojtech, Daniele, Giulia, Dostalova, Zuzana, Quadri, Manuel, Saitta, Claudia, Silvestri, Daniela, Songia, Simona, Storlazzi, Clelia T., Biondi, Andrea, Darzentas, Nikos, and Cazzaniga, Giovanni

Abstract

Acute lymphoblastic leukemia (ALL) is the most frequent pediatric cancer. Fusion genes are hallmarks of ALL, and they are used as biomarkers for risk stratification as well as targets for precision medicine. Hence, clinical diagnostics pursues broad and comprehensive strategies for accurate discovery of fusion genes. Currently, the gold standard methodologies for fusion gene detection are fluorescence in situ hybridization and polymerase chain reaction; these, however, lack sensitivity for the identification of new fusion genes and breakpoints. In this study, we implemented a simple operating procedure (OP) for detecting fusion genes. The OP employs RNA CaptureSeq, a versatile and effortless next-generation sequencing assay, and an in-house as well as a purpose-built bioinformatics pipeline for the subsequent data analysis. The OP was evaluated on a cohort of 89 B-cell precursor ALL (BCP-ALL) pediatric samples annotated as negative for fusion genes by the standard techniques. The OP confirmed 51 samples as negative for fusion genes, and, more importantly, it identified known (KMT2A rearrangements) as well as new fusion events (JAK2 rearrangements) in the remaining 38 investigated samples, of which 16 fusion genes had prognostic significance. Herein, we describe the OP and its deployment into routine ALL diagnostics, which will allow substantial improvements in both patient risk stratification and precision medicine.

Published
2019

28. The presence of CLL-associated stereotypic B cell receptors in the normal BCR repertoire from healthy individuals increases with age

Author

Muggen, Alice, Jong, Madelon, Tettero, Ingrid, Kallemeijn, Martine, Goncalves Grunho Teodosio, Cristina, Darzentas, N, Stadhouders, Ralph, Ijspeert, Hanna, van der Burg, Mirjam, van Ijcken, Wilfred, Verhaar, Jan, Abdulahad, WH, Brouwer, E, Boots, AMH, Hendriks, Rudi, Dongen, Jacques, Langerak, Ton, Muggen, Alice, Jong, Madelon, Tettero, Ingrid, Kallemeijn, Martine, Goncalves Grunho Teodosio, Cristina, Darzentas, N, Stadhouders, Ralph, Ijspeert, Hanna, van der Burg, Mirjam, van Ijcken, Wilfred, Verhaar, Jan, Abdulahad, WH, Brouwer, E, Boots, AMH, Hendriks, Rudi, Dongen, Jacques, and Langerak, Ton

Published
2019

29. Next-generation sequencing of immunoglobulin gene rearrangements for clonality assessment: a technical feasibility study by EuroClonality-NGS

Author

Scheijen, B, Meijers, Ruud, Rijntjes, J, Klift, Michele, Mobs, M, Steinhilber, J, Reigl, T, Brand, M, Kotrova, M, Ritter, JM, Catherwood, MA, Stamatopoulos, K, Bruggemann, M, Davi, F, Darzentas, N, Pott, C, Fend, F, Hummel, M, Langerak, Ton, Groenen, P, Scheijen, B, Meijers, Ruud, Rijntjes, J, Klift, Michele, Mobs, M, Steinhilber, J, Reigl, T, Brand, M, Kotrova, M, Ritter, JM, Catherwood, MA, Stamatopoulos, K, Bruggemann, M, Davi, F, Darzentas, N, Pott, C, Fend, F, Hummel, M, Langerak, Ton, and Groenen, P

Published
2019

30. No improvement in long-term survival over time for chronic lymphocytic leukemia patients in stereotyped subsets #1 and #2 treated with chemo(Immuno)therapy

Author

Baliakas, P. Mattsson, M. Hadzidimitriou, A. Minga, E. Agathangelidis, A. Sutton, L.-A. Scarfo, L. Davis, Z. Yan, X.-J. Plevova, K. Sandberg, Y. Vojdeman, F.J. Tzenou, T. Chu, C.C. Veronese, S. Mansouri, L. Smedby, K.E. Giudicelli, V. Nguyen-Khac, F. Panagiotidis, P. Juliusson, G. Anagnostopoulos, A. Lefranc, M.-P. Trentin, L. Catherwood, M. Montillo, M. Niemann, C.U. Langerak, A.W. Pospisilova, S. Stavroyianni, N. Chiorazzi, N. Oscier, D. Jelinek, D.F. Shanafelt, T. Darzentas, N. Belessi, C. Davi, F. Ghia, P. Rosenquist, R. Stamatopoulos, K.

Published
2018

31. S129 TP53 SOMATIC MUTATIONS AS PRE-LEUKEMIC EVENTS IN ACUTE LYMPHOBLASTIC LEUKEMIA

Author

Chitadze, G., primary, Stengel, A., additional, John-Klaua, C., additional, Trautmann, H., additional, knecht, H., additional, Schwarz, M., additional, Kotrova, M., additional, Hollmann, J., additional, Hermann, D., additional, Appelt, F., additional, Theocharis, T., additional, Pal, K., additional, Darzentas, N., additional, Oberg, H.-H., additional, Kabelitz, D., additional, Gökbuget, N., additional, Baldus, C., additional, Haferlach, C., additional, and Brüggemann, M., additional

Published
2019
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32. PF237 THE PROGNOSTIC IMPACT OF LYMPHOCYTE REPERTOIRE RECOVERY AFTER INDUCTION TREATMENT OF CHILDHOOD AML

Author

Svaton, M., primary, Novakova, M., additional, Reznickova, L., additional, Darzentas, N., additional, Stuchly, J., additional, Svenkrtova, A., additional, Zaliova, M., additional, Zuna, J., additional, Mejstrikova, E., additional, Kotrova, M., additional, Reigl, T., additional, Hrusak, O., additional, Stary, J., additional, Trka, J., additional, and Fronkova, E., additional

Published
2019
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33. NEXT-GENERATION SEQUENCING-BASED CLONALITY ASSESSMENT OF IMMUNOGLOBULIN GENE REARRANGEMENTS DISTINGUISHES RELAPSE FROM SECOND PRIMARY CLASSICAL HODGKIN LYMPHOMA

Author

van Bladel, D., primary, van den Brand, M., additional, Rijntjes, J., additional, Brinkman, A., additional, Reigl, T., additional, Darzentas, N., additional, Hess, C., additional, Hebeda, K., additional, Groenen, P., additional, van Krieken, H., additional, and Scheijen, B., additional

Published
2019
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34. PF175 MULTICENTRE STANDARDIZATION OF MINIMAL RESIDUAL DISEASE DETECTION AND QUANTITATION USING THE EUROCLONALITY-NGS ASSAY

Author

Svaton, M., primary, Fronkova, E., additional, Kotrova, M., additional, Reigl, T., additional, Caye, A., additional, de Bie, M., additional, Genuardi, E., additional, Jelinkova, H., additional, Lim, E.H., additional, Nishijima, D., additional, Pal, K., additional, Salemi, D., additional, Sarasquete, M.E., additional, Songia, S., additional, Tosi, M., additional, Villarese, P., additional, Wakeman, S., additional, Cave, H., additional, Cazzaniga, G., additional, Ferrero, S., additional, Garcia Sanz, R., additional, Hancock, J., additional, Macintyre, E., additional, Plevova, K., additional, Sanada, M., additional, Santoro, A., additional, Spinelli, O., additional, van der Velden, V.H., additional, Yeoh, A.E. J., additional, Langerak, A.W., additional, Darzentas, N., additional, Brüggemann, M., additional, and Trka, J., additional

Published
2019
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36. PF512 NEXT-GENERATION SEQUENCING-BASED CLONALITY ASSESSMENT OF IMMUNOGLOBULIN GENE REARRANGEMENTS DISTINGUISHES RELAPSE FROM SECOND PRIMARY CLASSICAL HODGKIN LYMPHOMA

Author

van Bladel, D., primary, van den Brand, M., additional, Rijntjes, J., additional, Brinkman, A., additional, Reigl, T., additional, Darzentas, N., additional, Hess, C., additional, Hebeda, K., additional, Groenen, P., additional, van Krieken, H., additional, and Scheijen, B., additional

Published
2019
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38. No improvement in long-term survival over time for chronic lymphocytic leukemia patients in stereotyped subsets #1 and #2 treated with chemo(Immuno)therapy

Author

Baliakas, P. (P.), Mattsson, M. (Mattias), Hadzidimitriou, A. (A.), Minga, E. (Evangelia), Agathangelidis, A. (Andreas), Sutton, L.-A. (L.), Scarfó, L. (L.), Davis, Z. (Zadie), Yan, X.-J. (Xiao-Jie), Plevova, K. (K.), Sandberg, Y. (Yorick), Vojdeman, F.J. (Fie Juhl), Tzenou, T. (T.), Chu, C.C. (Charles C.), Veronese, S. (Silvio), Mansouri, A. (Ahmed), Smedby, O., Giudicelli, V. (Veronique), Nguyen-Khac, F. (Florence), Panagiotidis, P. (P.), Juliusson, G. (Gunnar), Anagnostopoulos, C. (Constantinos), Lefranc, M.-P. (Marie-Paule), Trentin, L. (Livio), Catherwood, M. (M.), Montillo, M. (Marco), Niemann, C.U. (Carsten U.), Langerak, A.W. (Anton), Pospisilova, S. (Sarka), Stavroyianni, N. (Niki), Chiorazzi, N. (Nicholas), Oscier, D.G. (David Graham), Jelinek, D.F. (Diane F.), Shanafelt, T. (Tait), Darzentas, N. (Nikos), Belessi, C. (C.), Davi, F. (Frédéric), Ghia, P. (Paolo), Rosenquist, R. (R.), Stamatopoulos, K. (Kostas), Baliakas, P. (P.), Mattsson, M. (Mattias), Hadzidimitriou, A. (A.), Minga, E. (Evangelia), Agathangelidis, A. (Andreas), Sutton, L.-A. (L.), Scarfó, L. (L.), Davis, Z. (Zadie), Yan, X.-J. (Xiao-Jie), Plevova, K. (K.), Sandberg, Y. (Yorick), Vojdeman, F.J. (Fie Juhl), Tzenou, T. (T.), Chu, C.C. (Charles C.), Veronese, S. (Silvio), Mansouri, A. (Ahmed), Smedby, O., Giudicelli, V. (Veronique), Nguyen-Khac, F. (Florence), Panagiotidis, P. (P.), Juliusson, G. (Gunnar), Anagnostopoulos, C. (Constantinos), Lefranc, M.-P. (Marie-Paule), Trentin, L. (Livio), Catherwood, M. (M.), Montillo, M. (Marco), Niemann, C.U. (Carsten U.), Langerak, A.W. (Anton), Pospisilova, S. (Sarka), Stavroyianni, N. (Niki), Chiorazzi, N. (Nicholas), Oscier, D.G. (David Graham), Jelinek, D.F. (Diane F.), Shanafelt, T. (Tait), Darzentas, N. (Nikos), Belessi, C. (C.), Davi, F. (Frédéric), Ghia, P. (Paolo), Rosenquist, R. (R.), and Stamatopoulos, K. (Kostas)

Published
2018
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39. No improvement in long-term survival over time for chronic lymphocytic leukemia patients in stereotyped subsets #1 and #2 treated with chemo(immuno)therapy

Author

Baliakas, P, Mattsson, M, Hadzidimitriou, A, Minga, E, Agathangelidis, A, Sutton, LA, Scarfo, L, Davis, Z, Yan, XJ, Plevova, K, Sandberg, Yorick, Vojdeman, FJ, Tzenou, T, Chu, CC, Veronese, S, Mansouri, L, Smedby, KE, Giudicelli, V, Nguyen-Khac, F, Panagiotidis, P, Juliusson, G, Anagnostopoulos, A, Lefranc, MP, Trentin, L, Catherwood, M, Montillo, M, Niemann, CU, Langerak, Ton, Pospisilova, S, Stavroyianni, N, Chiorazzi, N, Oscier, D, Jelinek, DF, Shanafelt, T, Darzentas, N, Belessi, C, Davi, F, Ghia, P, Rosenquist, R, Stamatopoulos, K, Baliakas, P, Mattsson, M, Hadzidimitriou, A, Minga, E, Agathangelidis, A, Sutton, LA, Scarfo, L, Davis, Z, Yan, XJ, Plevova, K, Sandberg, Yorick, Vojdeman, FJ, Tzenou, T, Chu, CC, Veronese, S, Mansouri, L, Smedby, KE, Giudicelli, V, Nguyen-Khac, F, Panagiotidis, P, Juliusson, G, Anagnostopoulos, A, Lefranc, MP, Trentin, L, Catherwood, M, Montillo, M, Niemann, CU, Langerak, Ton, Pospisilova, S, Stavroyianni, N, Chiorazzi, N, Oscier, D, Jelinek, DF, Shanafelt, T, Darzentas, N, Belessi, C, Davi, F, Ghia, P, Rosenquist, R, and Stamatopoulos, K

Published
2018

40. MULTI-CENTER VALIDATION OF STANDARDIZED NGS ASSAYS FOR REARRANGED IG / TR MARKER DETECTION IN ACUTE LYMPHOBLASTIC LEUKEMIA - A REPORT OF THE EUROCLONALITY-NGS CONSORTIUM

Author

Bruggemann, M., Knecht, H., Kotrova, M., Bartram, J., Bystry, V., Darzentas, N., Davi, F., Fazio, G., Fronkova, E., Garcia-Sanz, R., Giraud, M., Grioni, A., Groenen, P.J., Hancock, J., Herrmann, D., Hummel, M., Jimenez, C., Krejci, A., Pott, C., Riegl, T., Salson, M., Schwarz, M., Songia, S., Svenkrtova, A., Villarese, P., Cazzaniga, G., Dongen, J.J. van, Macintyre, E.A., Mopett, J., Trka, J., and Langerak, A.W.

Published
2017

41. High resolution IgH repertoire analysis reveals fetal liver as the likely origin of life-long, innate B lymphopoiesis in humans

Author

Roy, A, Bystry, V, Bohn, G, Goudevenou, K, Reigl, T, Papaioannou, M, Krejci, A, O'Byrne, S, Chaidos, A, Grioni, A, Darzentas, N, Roberts, IAG, and Karadimitris, A

Subjects
B-Lymphocytes, Lymphopoiesis, Immunology, High-Throughput Nucleotide Sequencing, Receptors, Antigen, B-Cell, Sequence Analysis, DNA, Leukemia, Lymphocytic, Chronic, B-Cell, Article, Fetal, Fetus, Immunoglobulin M, Liver, Bone Marrow, 1107 Immunology, IgH repertoire, Humans, Immunoglobulin Heavy Chains, Human
Abstract

The ontogeny of the natural, public IgM repertoire remains incompletely explored. Here, high-resolution immunogenetic analysis of B cells from (unrelated) fetal, child, and adult samples, shows that although fetal liver (FL) and bone marrow (FBM) IgM repertoires are equally diversified, FL is the main source of IgM natural immunity during the 2nd trimester. Strikingly, 0.25% of all prenatal clonotypes, comprising 18.7% of the expressed repertoire, are shared with the postnatal samples, consistent with persisting fetal IgM + B cells being a source of natural IgM repertoire in adult life. Further, the origins of specific stereotypic IgM + B cell receptors associated with chronic lymphocytic leukemia, can be traced back to fetal B cell lymphopoiesis, suggesting that persisting fetal B cells can be subject to malignant transformation late in life. Overall, these novel data provide unique insights into the ontogeny of physiological and malignant B lymphopoiesis that spans the human lifetime., Graphical abstract Image 1, Highlights • Second trimester human fetal liver and fetal bone marrow B-cells have IgM repertoires that are equally diversified • Human fetal liver B-cells are the main source of innate, natural IgM responses • CLL-associated, stereotypic B cell receptors are detected in fetal IgM repertoire

Published
2017

42. Immunoglobulin gene sequence analysis in chronic lymphocytic leukemia : updated ERIC recommendations

Author

Rosenquist, Richard, Ghia, P., Hadzidimitriou, A., Sutton, Lesley Ann, Agathangelidis, A., Baliakas, Panagiotis, Darzentas, N., Giudicelli, V., Lefranc, M-P, Langerak, A. W., Belessi, C., Davi, F., Stamatopoulos, Kostas, Rosenquist, Richard, Ghia, P., Hadzidimitriou, A., Sutton, Lesley Ann, Agathangelidis, A., Baliakas, Panagiotis, Darzentas, N., Giudicelli, V., Lefranc, M-P, Langerak, A. W., Belessi, C., Davi, F., and Stamatopoulos, Kostas

Published
2017
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43. ARResT/Interrogate: an interactive immunoprofiler for IG/TR NGS data

Author

Bystry, V., Reigl, T., Krejci, A., Demko, M., Hanakova, B., Grioni, A., Knecht, H., Schlitt, M., Dreger, P., Sellner, L., Herrmann, D., Pingeon, M., Boudjoghra, M., Rijntjes, J., Pott, C., Langerak, A.W., Groenen, P.J.T.A., Davi, F., Bruggemann, M., Darzentas, N., Bystry, V., Reigl, T., Krejci, A., Demko, M., Hanakova, B., Grioni, A., Knecht, H., Schlitt, M., Dreger, P., Sellner, L., Herrmann, D., Pingeon, M., Boudjoghra, M., Rijntjes, J., Pott, C., Langerak, A.W., Groenen, P.J.T.A., Davi, F., Bruggemann, M., and Darzentas, N.

Abstract

Item does not contain fulltext

Published
2017

44. High-Throughput Immunogenetics for Clinical and Research Applications in Immunohematology: Potential and Challenges

Author

Langerak, A.W., Bruggemann, M., Davi, F., Darzentas, N., Dongen, J.J. van, Gonzalez, D., Cazzaniga, G., Giudicelli, V., Lefranc, M.P., Giraud, M., Macintyre, E.A., Hummel, M., Pott, C., Groenen, P.J.T.A., Stamatopoulos, K., Langerak, A.W., Bruggemann, M., Davi, F., Darzentas, N., Dongen, J.J. van, Gonzalez, D., Cazzaniga, G., Giudicelli, V., Lefranc, M.P., Giraud, M., Macintyre, E.A., Hummel, M., Pott, C., Groenen, P.J.T.A., and Stamatopoulos, K.

Abstract

Item does not contain fulltext, Analysis and interpretation of Ig and TCR gene rearrangements in the conventional, low-throughput way have their limitations in terms of resolution, coverage, and biases. With the advent of high-throughput, next-generation sequencing (NGS) technologies, a deeper analysis of Ig and/or TCR (IG/TR) gene rearrangements is now within reach, which impacts on all main applications of IG/TR immunogenetic analysis. To bridge the generation gap from low- to high-throughput analysis, the EuroClonality-NGS Consortium has been formed, with the main objectives to develop, standardize, and validate the entire workflow of IG/TR NGS assays for 1) clonality assessment, 2) minimal residual disease detection, and 3) repertoire analysis. This concerns the preanalytical (sample preparation, target choice), analytical (amplification, NGS), and postanalytical (immunoinformatics) phases. Here we critically discuss pitfalls and challenges of IG/TR NGS methodology and its applications in hemato-oncology and immunology.

Published
2017

45. High-throughput immunogenetics for clinical and research applications in immunohematology: Potential and challenges

Author

Langerak, A, Brüggemann, M, Davi, F, Darzentas, N, Van Dongen, J, Gonzalez, D, Cazzaniga, G, Giudicelli, V, Lefranc, M, Giraud, M, Macintyre, E, Hummel, M, Pott, C, Groenen, P, Stamatopoulos, K, Langerak, AW, Van Dongen, JM, Lefranc, MP, Macintyre, EA, Groenen, PJTA, Langerak, A, Brüggemann, M, Davi, F, Darzentas, N, Van Dongen, J, Gonzalez, D, Cazzaniga, G, Giudicelli, V, Lefranc, M, Giraud, M, Macintyre, E, Hummel, M, Pott, C, Groenen, P, Stamatopoulos, K, Langerak, AW, Van Dongen, JM, Lefranc, MP, Macintyre, EA, and Groenen, PJTA

Abstract

Analysis and interpretation of Ig and TCR gene rearrangements in the conventional, low-throughput way have their limitations in terms of resolution, coverage, and biases. With the advent of high-throughput, nextgeneration sequencing (NGS) technologies, a deeper analysis of Ig and/or TCR (IG/TR) gene rearrangements is now within reach, which impacts on all main applications of IG/TR immunogenetic analysis. To bridge the generation gap from low- to high-throughput analysis, the EuroClonality-NGS Consortium has been formed, with the main objectives to develop, standardize, and validate the entire workflow of IG/TR NGS assays for 1) clonality assessment, 2) minimal residual disease detection, and 3) repertoire analysis. This concerns the preanalytical (sample preparation, target choice), analytical (amplification, NGS), and postanalytical (immunoinformatics) phases. Here we critically discuss pitfalls and challenges of IG/TR NGS methodology and its applications in hemato-oncology and immunology.

Published
2017

46. Immunoglobulin gene sequence analysis in chronic lymphocytic leukemia: updated ERIC recommendations

Author

Rosenquist, R, Ghia, P, Hadzidimitriou, A, Sutton, LA, Agathangelidis, A, Baliakas, P, Darzentas, N, Giudicelli, V, Lefranc, MP, Langerak, Ton, Belessi, C, Davi, F, Stamatopoulos, K, Rosenquist, R, Ghia, P, Hadzidimitriou, A, Sutton, LA, Agathangelidis, A, Baliakas, P, Darzentas, N, Giudicelli, V, Lefranc, MP, Langerak, Ton, Belessi, C, Davi, F, and Stamatopoulos, K

Published
2017

47. Clinical effect of stereotyped B-cell receptor immunoglobulins in chronic lymphocytic leukaemia: a retrospective multicentre study

Author

Baliakas P, Hadzidimitriou A, Sutton LA, Minga E, Agathangelidis A, Nichelatti M, Tsanousa A, Scarfò L, Davis Z, Yan XJ, Shanafelt T, Plevova K, Sandberg Y, Vojdeman FJ, Boudjogra M, Tzenou T, Chatzouli M, Chu CC, Veronese S, Gardiner A, Mansouri L, Smedby KE, Bredo Pedersen L, van Lom K, Giudicelli V, Skuhrova Francova H, Nguyen Khac F, Panagiotidis P, Juliusson G, Angelis L, Anagnostopoulos A, Lefranc MP, Facco M, Trentin L, Catherwood M, Montillo M, Geisler CH, Langerak AW, Pospisilova S, Chiorazzi N, Oscier D, Jelinek DF, Darzentas N, Belessi C, Davi F, Rosenquist R, GHIA , PAOLO PROSPERO, Stamatopoulos K. Ghia P. is Co senior author, corresponding author, Baliakas, P, Hadzidimitriou, A, Sutton, La, Minga, E, Agathangelidis, A, Nichelatti, M, Tsanousa, A, Scarfò, L, Davis, Z, Yan, Xj, Shanafelt, T, Plevova, K, Sandberg, Y, Vojdeman, Fj, Boudjogra, M, Tzenou, T, Chatzouli, M, Chu, Cc, Veronese, S, Gardiner, A, Mansouri, L, Smedby, Ke, Bredo Pedersen, L, van Lom, K, Giudicelli, V, Skuhrova Francova, H, Nguyen Khac, F, Panagiotidis, P, Juliusson, G, Angelis, L, Anagnostopoulos, A, Lefranc, Mp, Facco, M, Trentin, L, Catherwood, M, Montillo, M, Geisler, Ch, Langerak, Aw, Pospisilova, S, Chiorazzi, N, Oscier, D, Jelinek, Df, Darzentas, N, Belessi, C, Davi, F, Rosenquist, R, Ghia, PAOLO PROSPERO, Stamatopoulos K. Ghia P., is Co senior author, and Corresponding, Author

Abstract

Background About 30% of cases of chronic lymphocytic leukaemia (CLL) carry quasi-identical B-cell receptorimmunoglobulins and can be assigned to distinct stereotyped subsets. Although preliminary evidence suggeststhat B-cell receptor immunoglobulin stereotypy is relevant from a clinical viewpoint, this aspect has never beenexplored in a systematic manner or in a cohort of adequate size that would enable clinical conclusions to be drawn.Methods For this retrospective, multicentre study, we analysed 8593 patients with CLL for whom immunogeneticdata were available. These patients were followed up in 15 academic institutions throughout Europe (in CzechRepublic, Denmark, France, Greece, Italy, Netherlands, Sweden, and the UK) and the USA, and data were collectedbetween June 1, 2012, and June 7, 2013. We retrospectively assessed the clinical implications of CLL B-cell receptorimmunoglobulin stereotypy, with a particular focus on 14 major stereotyped subsets comprising cases expressingunmutated (U-CLL) or mutated (M-CLL) immunoglobulin heavy chain variable genes. The primary outcome ofour analysis was time to fi rst treatment, defi ned as the time between diagnosis and date of fi rst treatment.Findings 2878 patients were assigned to a stereotyped subset, of which 1122 patients belonged to one of 14 majorsubsets. Stereotyped subsets showed signifi cant diff erences in terms of age, sex, disease burden at diagnosis,CD38 expression, and cytogenetic aberrations of prognostic signifi cance. Patients within a specifi c subset generallyfollowed the same clinical course, whereas patients in diff erent stereotyped subsets—despite having the sameimmunoglobulin heavy variable gene and displaying similar immunoglobulin mutational status—showedsubstantially diff erent times to fi rst treatment. By integrating B-cell receptor immunoglobulin stereotypy (forsubsets 1, 2, and 4) into the well established Döhner cytogenetic prognostic model, we showed these, whichcollectively account for around 7% of all cases of CLL and represent both U-CLL and M-CLL, constituted separateclinical entities, ranging from very indolent (subset 4) to aggressive disease (subsets 1 and 2).Interpretation The molecular classifi cation of chronic lymphocytic leukaemia based on B-cell receptorimmunoglobulin stereotypy improves the Döhner hierarchical model and refi nes prognostication beyondimmunoglobulin mutational status, with potential implications for clinical decision making, especially withinprospective clinical trials.Funding European Union; General Secretariat for Research and Technology of Greece; AIRC; Italian Ministry ofHealth; AIRC Regional Project with Fondazione CARIPARO and CARIVERONA; Regione Veneto on ChronicLymphocytic Leukemia; Nordic Cancer Union; Swedish Cancer Society; Swedish Research Council; and NationalCancer Institute (NIH).

Published
2014

48. GvL effects in T-prolymphocytic leukemia: evidence from MRD kinetics and TCR repertoire analyses

Author

Sellner, L, primary, Brüggemann, M, additional, Schlitt, M, additional, Knecht, H, additional, Herrmann, D, additional, Reigl, T, additional, Krejci, A, additional, Bystry, V, additional, Darzentas, N, additional, Rieger, M, additional, Dietrich, S, additional, Luft, T, additional, Ho, A D, additional, Kneba, M, additional, and Dreger, P, additional

Published
2016
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49. Not all IGHV3-21 chronic lymphocytic leukemias are equal: Prognostic considerations

Author

Baliakas, P. Agathangelidis, A. Hadzidimitriou, A. Sutton, L.-A. Minga, E. Tsanousa, A. Scarfò, L. Davis, Z. Yan, X.-J. Shanafelt, T. Plevova, K. Sandberg, Y. Vojdeman, F.J. Boudjogra, M. Tzenou, T. Chatzouli, M. Chu, C.C. Veronese, S. Gardiner, A. Mansouri, L. Smedby, K.E. Pedersen, L.B. Moreno, D. Van Lom, K. Giudicelli, V. Francova, H.S. Nguyen-Khac, F. Panagiotidis, P. Juliusson, G. Angelis, L. Anagnostopoulos, A. Lefranc, M.-P. Facco, M. Trentin, L. Catherwood, M. Montillo, M. Geisler, C.H. Langerak, A.W. Pospisilova, S. Chiorazzi, N. Oscier, D. Jelinek, D.F. Darzentas, N. Belessi, C. Davi, F. Ghia, P. Rosenquist, R. Stamatopoulos, K.

Abstract

An unresolved issue in chronic lymphocytic leukemia (CLL) is whether IGHV3-21 gene usage, in general, or the expression of stereotyped B-cell receptor immunoglobulin defining subset #2 (IGHV3-21/IGLV3-21), in particular, determines outcome for IGHV3-21-utilizing cases. We reappraised this issue in 8593 CLL patients of whom 437 (5%) used the IGHV3-21 gene with 254/437 (58%) classified as subset #2.Within subset #2, immunoglobulin heavy variable (IGHV)-mutated cases predominated, whereas non-subset #2/IGHV3-21 was enriched for IGHV-unmutated cases (P = .002). Subset #2 exhibited significantly shorter time-to-first-treatment (TTFT) compared with non-subset #2/IGHV3-21 (22 vs 60 months, P = .001). No such difference was observed between non-subset #2/IGHV3-21 vs the remaining CLL with similar IGHV mutational status. In conclusion, IGHV3-21 CLL should not be axiomatically considered a homogeneous entity with adverse prognosis, given that only subset #2 emerges as uniformly aggressive, contrasting non-subset #2/IGVH3-21 patients whose prognosis depends on IGHV mutational status as the remaining CLL. © 2015 by The American Society of Hematology 10.1182/blood-2014-09-600874.

Published
2015

50. EuroClonality-NGS: aims and core projects

Author

Langerak, Ton, Bruggemann, M, Cazzaniga, G, Darzentas, N, Davi, F, Dongen, Jacques, Gonzalez, D, Groenen, PJTA, Hummel, M, Macintyre, EA, Pott, C, Stamatopoulos, K, van Dongen, J.J.M., and Immunology

Published
2015

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