scholarly journals InterTADs: integration of multi-omics data on topologically associated domains, application to chronic lymphocytic leukemia

2022 ◽  
Vol 4 (1) ◽  
Author(s):  
Maria Tsagiopoulou ◽  
Nikolaos Pechlivanis ◽  
Maria Christina Maniou ◽  
Fotis Psomopoulos
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Somatic Hypermutation ◽  
Enrichment Analysis ◽  
Lymphocytic Leukemia ◽  
Omics Data ◽  
Topologically Associated Domains ◽  
Chromatin Configuration ◽  
New Perspective ◽  
New Interactions ◽  
Omics Data Integration

ABSTRACT The integration of multi-omics data can greatly facilitate the advancement of research in Life Sciences by highlighting new interactions. However, there is currently no widespread procedure for meaningful multi-omics data integration. Here, we present a robust framework, called InterTADs, for integrating multi-omics data derived from the same sample, and considering the chromatin configuration of the genome, i.e. the topologically associating domains (TADs). Following the integration process, statistical analysis highlights the differences between the groups of interest (normal versus cancer cells) relating to (i) independent and (ii) integrated events through TADs. Finally, enrichment analysis using KEGG database, Gene Ontology and transcription factor binding sites and visualization approaches are available. We applied InterTADs to multi-omics datasets from 135 patients with chronic lymphocytic leukemia (CLL) and found that the integration through TADs resulted in a dramatic reduction of heterogeneity compared to individual events. Significant differences for individual events and on TADs level were identified between patients differing in the somatic hypermutation status of the clonotypic immunoglobulin genes, the core biological stratifier in CLL, attesting to the biomedical relevance of InterTADs. In conclusion, our approach suggests a new perspective towards analyzing multi-omics data, by offering reasonable execution time, biological benchmarking and potentially contributing to pattern discovery through TADs.

Stereotyped patterns of somatic hypermutation in subsets of patients with chronic lymphocytic leukemia: implications for the role of antigen selection in leukemogenesis

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1524-1533 ◽  
Author(s):  
Fiona Murray ◽  
Nikos Darzentas ◽  
Anastasia Hadzidimitriou ◽  
Gerard Tobin ◽  
Myriam Boudjogra ◽  
...  
Keyword(s):  
Amino Acid ◽  
Chronic Lymphocytic Leukemia ◽  
Heavy Chain ◽  
Germ Line ◽  
Somatic Hypermutation ◽  
Lymphocytic Leukemia ◽  
Chain Gene ◽  
Distinctive Features ◽  
Ighv Gene ◽  
Gene Usage

Abstract Somatic hypermutation (SHM) features in a series of 1967 immunoglobulin heavy chain gene (IGH) rearrangements obtained from patients with chronic lymphocytic leukemia (CLL) were examined and compared with IGH sequences from non-CLL B cells available in public databases. SHM analysis was performed for all 1290 CLL sequences in this cohort with less than 100% identity to germ line. At the cohort level, SHM patterns were typical of a canonical SHM process. However, important differences emerged from the analysis of certain subgroups of CLL sequences defined by: (1) IGHV gene usage, (2) presence of stereotyped heavy chain complementarity-determining region 3 (HCDR3) sequences, and (3) mutational load. Recurrent, “stereotyped” amino acid changes occurred across the entire IGHV region in CLL subsets carrying stereotyped HCDR3 sequences, especially those expressing the IGHV3-21 and IGHV4-34 genes. These mutations are underrepresented among non-CLL sequences and thus can be considered as CLL-biased. Furthermore, it was shown that even a low level of mutations may be functionally relevant, given that stereotyped amino acid changes can be found in subsets of minimally mutated cases. The precise targeting and distinctive features of somatic hypermutation (SHM) in selected subgroups of CLL patients provide further evidence for selection by specific antigenic element(s).

Chronic Lymphocytic Leukemia Patient Clustering Based on Somatic Hypermutation (SHM) Analysis

2017 ◽  
pp. 127-138 ◽  
Author(s):  
Eleftheria Polychronidou ◽  
Aliki Xochelli ◽  
Panagiotis Moschonas ◽  
Stavros Papadopoulos ◽  
Anastasia Hatzidimitriou ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Somatic Hypermutation ◽  
Chronic Lymphocytic Leukemia Patient ◽  
Lymphocytic Leukemia ◽  
Leukemia Patient

scholarly journals Immunoglobulin gene analysis in chronic lymphocytic leukemia in the era of next generation sequencing

Leukemia ◽  
2020 ◽  
Vol 34 (10) ◽  
pp. 2545-2551 ◽  
Author(s):  
Frédéric Davi ◽  
◽  
Anton W. Langerak ◽  
Anne Langlois de Septenville ◽  
P. Martijn Kolijn ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Somatic Hypermutation ◽  
Technological Development ◽  
Data Interpretation ◽  
Medical Diagnostics ◽  
Lymphocytic Leukemia ◽  
Immunoglobulin Gene ◽  
New Era ◽  
Ighv Gene ◽  
Therapeutic Decision Making

Abstract Twenty years after landmark publications, there is a consensus that the somatic hypermutation (SHM) status of the clonotypic immunoglobulin heavy variable (IGHV) gene is an important cornerstone for accurate risk stratification and therapeutic decision-making in patients with chronic lymphocytic leukemia (CLL). The IGHV SHM status has traditionally been determined by conventional Sanger sequencing. However, NGS has heralded a new era in medical diagnostics and immunogenetic analysis is following this trend. There is indeed a growing demand for shifting practice and using NGS for IGHV gene SHM assessment, although it is debatable whether it is always justifiable, at least taking into account financial considerations for laboratories with limited resources. Nevertheless, as this analysis impacts on treatment decisions, standardization of both technical aspects, and data interpretation becomes essential. Also, the need for establishing new recommendations and providing dedicated education and training on NGS-based immunogenetics is greater than ever before. Here we address potential and challenges of NGS-based immunogenetics in CLL. We are convinced that this perspective helps the hematological community to better understand the pros and cons of this new technological development for CLL patient management.

scholarly journals Chronic Lymphocytic Leukemia B Cells Can Undergo Somatic Hypermutation and Intraclonal Immunoglobulin VHDJH Gene Diversification

2002 ◽  
Vol 196 (5) ◽  
pp. 629-639 ◽  
Author(s):  
Carmela Gurrieri ◽  
Peter McGuire ◽  
Hong Zan ◽  
Xiao-Jie Yan ◽  
Andrea Cerutti ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Lymphocyte ◽  
Somatic Hypermutation ◽  
Point Mutations ◽  
Single Strand Conformation Polymorphism ◽  
Lymphocytic Leukemia ◽  
Gene Diversification

Chronic lymphocytic leukemia (CLL) arises from the clonal expansion of a CD5+ B lymphocyte that is thought not to undergo intraclonal diversification. Using VHDJH cDNA single strand conformation polymorphism analyses, we detected intraclonal mobility variants in 11 of 18 CLL cases. cDNA sequence analyses indicated that these variants represented unique point-mutations (1–35/patient). In nine cases, these mutations were unique to individual submembers of the CLL clone, although in two cases they occurred in a large percentage of the clonal submembers and genealogical trees could be identified. The diversification process responsible for these changes led to single nucleotide changes that favored transitions over transversions, but did not target A nucleotides and did not have the replacement/silent nucleotide change characteristics of antigen-selected B cells. Intraclonal diversification did not correlate with the original mutational load of an individual CLL case in that diversification was as frequent in CLL cells with little or no somatic mutations as in those with considerable mutations. Finally, CLL B cells that did not exhibit intraclonal diversification in vivo could be induced to mutate their VHDJH genes in vitro after stimulation. These data indicate that a somatic mutation mechanism remains functional in CLL cells and could play a role in the evolution of the clone.

The pattern and distribution of immunoglobulin VH gene mutations in chronic lymphocytic leukemia B cells are consistent with the canonical somatic hypermutation process

Blood ◽  
2004 ◽  
Vol 103 (9) ◽  
pp. 3490-3495 ◽  
Author(s):  
Bradley T. Messmer ◽  
Emilia Albesiano ◽  
Davorka Messmer ◽  
Nicholas Chiorazzi
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Germ Line ◽  
Somatic Hypermutation ◽  
Gene Mutations ◽  
Lymphocytic Leukemia ◽  
Antigen Receptors ◽  
Region Gene ◽  
Wobble Position ◽  
Gene Usage ◽  
Vh Gene

Abstract The overexpanded clone in most B-cell-type chronic lymphocytic leukemia (BCLL) patients expresses an immunoglobulin (Ig) heavy chain variable (VH) region gene with some level of mutation. While it is presumed that these mutations were introduced in the progenitor cell of the leukemic clone by the canonical somatic hypermutation (SHM) process, direct evidence of such is lacking. Nucleotide sequences of the Ig VH genes from 172 B-CLL patients were analyzed. Previously described VH gene usage biases were noted. As with canonical SHM, mutations found in B-CLL were more frequent in RGYW hot spots (mutations in an RGYW motif = 44.1%; germ line frequency of RGYW motifs = 25.6%) and favored transitions over transversions (transition-transversion ratio = 1.29). Significantly, transition preference was also noted when only mutations in the wobble position of degenerate codons were considered. Wobble positions are inherently unselected since regardless of change an identical amino acid is encoded; therefore, they represent a window into the nucleotide bias of the mutational mechanism. B-CLL VH mutations concentrated in complementarity-determining region 1 (CDR1) and CDR2, which exhibited higher replacement-to-silent ratios (CDR R/S, 4.60; framework region [FR] R/S, 1.72). These results are consistent with the notion that VH mutations in B-CLL cells result from canonical SHM and select for altered, structurally sound antigen receptors. (Blood. 2004;103:3490-3495)

scholarly journals 98% IGHV Gene Identity Is Still the Optimal Cutoff to Predict the Prognosis of Chronic Lymphocytic Leukemia Patients in China

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5545-5545
Author(s):  
Yi Xia ◽  
Ke Shi ◽  
Qian Sun ◽  
Chun Qiao ◽  
Huayuan Zhu ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Chronic Lymphocytic Leukemia ◽  
Conflicts Of Interest ◽  
Somatic Hypermutation ◽  
Lymphocytic Leukemia ◽  
Study Cohort ◽  
Optimal Cutoff ◽  
Entire Cohort ◽  
Mutational Status ◽  
Significant Difference

Abstract Background: Immunoglobulin heavy chain variable region (IGHV) has been an important prognostic factor for chronic lymphocytic leukemia (CLL) for decades. 98% being a cut-off value for IGHV is a mathematical choice and researches on the best cut-off value have never been stopped. Chinese CLL patients are known to differ from Caucasian CLL patients on both clinical and genetical features. However, the optimal cutoff for IGHV mutational status has not yet been studied in this particular ethnic group. Method: We carried out a study on 595 Chinese CLL patients in order to find out whether 98% is the best cut-off value for IGHV in Chinese CLL patients. Genomic DNA from peripheral blood or bone marrow was subjected to PCR amplification following the IGH Somatic Hypermutation Assay v2.0 protocol (InVivoScribe). Sequences were aligned to ImMunoGeneTics/V-QUEry and Standardization (IMGT/-VQUEST) database. Result: 600 sequences were received after IGHV rearrangement sequencing. IGHV3-23, IGHV4-34, IGHV3-7, IGHV4-39 and IGHV1-69 were the most frequently used IGHV genes. 352 (58.7%) cases were IGHV-mutated while 248 (41.3%) cases were IGHV-unmutated if the classical 98% classification by ERIC was used. In order to determine the optimal cut-off value, we used 1% as the interval to divide the entire cohort into 7 groups according to the mutational rate, which were <95%, 95%-95.99%, 96%-96.99%, 97%-97.99%, 98%-98.99%, 99%-99.99% and 100% respectively. Binet A patients had a relatively indolent course of disease and cases with different IGHV mutational rates had no significant differences in time to first treatment (TTFT) apart from truly unmutated (100%) cases. For the whole study cohort, significant difference appeared at 98% interval (P<0.001 and P=0.005 for TTFT and OS respectively) while intervals less than 98% had no significant difference compared with the <95% group. Similarly, there was no clear dissimilarities among 98%, 99% and 100% intervals (Table 1a and b). All the other prognostic factors including del(17p), del(11q), TP53 mutation, MYD88 mutation, NOTCH1 mutation, SF3B1 mutation, CD38, ZAP-70, Binet staging, gender, β2-microglobulin and EBV-DNA were differently distributed between group <98% and group ³98%, but not among subgroups in ³98%. In multivariate analysis, the 98% IGHV was also an independent prognostic factor for TTFT and OS. Conclusion: 98% is the optimal cutoff value for IGHV mutational status to predict the prognosis of CLL patients in China. Table 1. Table 1. Disclosures No relevant conflicts of interest to declare.

Analysis of Non-Expressed IGK Locus Rearrangements in Chronic Lymphocytic Leukemia Indicates a Role for Secondary Rearrangements in Shaping the Expressed Immunoglobulin Repertoire.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 972-972 ◽  
Author(s):  
Chrysoula Belessi ◽  
Kostas Stamatopoulos ◽  
Katerina Hatzi ◽  
Anastasia Hadzidimitriou ◽  
Fotini Marantidou ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Light Chain ◽  
Somatic Hypermutation ◽  
Lymphocytic Leukemia ◽  
Receptor Editing ◽  
Rt Pcr ◽  
Stop Codons ◽  
Immunoglobulin Kappa ◽  
Immunoglobulin Repertoire ◽  
Dna Pcr

Abstract Immunoglobulin kappa (IGK) locus rearrangements were analyzed in 164 κ-light chain (LC) expressing chronic lymphocytic leukemia (CLL) cases and 95 λ-LC expressing CLL cases. In κ-CLL, 151 IGKV-J transcripts were successfully amplified by RT-PCR; 147/151 were in frame; four out-of-frame IGKV-J transcripts were heavily mutated and contained one or more stop codons, presumably introduced by somatic hypermutation; in all four cases the corresponding expressed transcript was also mutated. DNA-PCR identified 24/164 κ-CLL cases (15%) with double IGKV-J rearrangements; 9/24 non-expressed IGKV-J rearrangements were in-frame; 3/9 were mutated. The most frequently used IGKV genes in expressed IGKV-J rearrangements were: 3–20, 1-39/1D-39, 1–5 and 4-1; the IGKV4-1 gene was by far the most frequent in non-expressed IGKV-J rearrangements (9/24 cases, 33%). In λ-CLL, a total of 65 IGKV-J rearrangements were amplified in 59/95 cases (62.0%); six cases had two different rearrangements. IGVK4-1 was the most frequently used gene (14/65 sequences, 21.5%), followed by IGKV1-16 (8 cases,12.3%), 1-33/1D-33 and 2-30 (7 cases each, 10.8%). IGKV-J transcripts were detected by RT-PCR in 10/59 λ-CLL cases with IGKV-J rearrangements, of which four were in-frame and six out-of-frame. Seven IGKV-J rearrangements in λ-CLL had less than 100% homology to germline; 3/7 were in-frame; 6/7 patients had mutated IGHV and 5/7 had mutated IGLV genes. In κ-CLL, biased usage of the IGKJ1/IGKJ2 genes was observed both in expressed (69%) and non-expressed rearrangements (78%); in contrast, in λ-CLL, downstream IGKJ (IGKJ3-5) usage was observed in 32/59 sequences (53%). Nonproductive rearrangements involving the kappa deleting element (KDE) that render the IGK locus inactive were also analyzed. In κ-CLL, 22/147 cases (15%) carried IGKV to KDE rearrangements, while 24/147 cases (16.5%) carried IGKJ-C- INTRON (JKI) to KDE rearrangements. In λ-CLL, IGKV-KDE rearrangements were amplified in 55/94 cases (59%); JKI-KDE rearrangements were amplified in 52/94 cases (56%). IGKV1D-43 was the most frequent gene in IGKV-KDE joints in κ-CLL (4/22 cases); in contrast, the most frequent genes in IGKV-KDE joints in λ-CLL were IGKV3-20 and IGKV2-30 (9/55 and 7/55 cases, respectively). In conclusion, the present study confirms IGK locus rearrangements in the vast majority of λ-LC expressing CLL cases. Differential usage of IGKJ genes along with significant IGKV repertoire differences in both IGKV-J and IGKV-KDE rearrangements between κ- and λ-CLL allude to prolonged IGK locus recombination before CLL clonogenic cells became λ-producers. The inactivation of productive and potentially functional IGKV-J joints by secondary rearrangements indicates a role for receptor editing in shaping the expressed IG repertoire in CLL. Finally, the identification of mutated, non-expressed IGKV-J rearrangements both in κ- and λ-CLL might be considered as evidence for secondary rearrangements occurring after the onset of somatic hypermutation, at least in a proportion of cases.

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