| 1. |
- Cahill, Nicola, 1983-, et al.
(författare)
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IGHV3-21 Gene Frequency in a Swedish Cohort of Patients With Newly Diagnosed Chronic Lymphocytic Leukemia
- 2012
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Ingår i: Clinical Lymphoma, Myeloma & Leukemia. - : Elsevier BV. - 2152-2650 .- 2152-2669. ; 12:3, s. 201-206
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Tidskriftsartikel (refereegranskat)abstract
- The IGHV3-21 gene has been shown to be overrepresented in Scandinavian patients with chronic lymphocytic leukemia (CLL). By investigating a population-based cohort of 337 Swedish patients with CLL, a lower (6.5%) IGHV3-21 frequency was determined relative to our previous hospital-based studies (10.1%-12.7%), yet this frequency remained higher compared to other Western CLL cohorts (2.6%-4.1%). Furthermore, we confirmed the poor outcome for patients with IGHV3-21 to be independent of mutational and stereotypy status. Background: Scandinavian patients with CLL have shown an overrepresentation of the poor-prognostic IGHV3-21 gene. Furthermore, approximately 50% of patients with IGHV3-21 carry stereotyped B-cell receptors, which implicate antigen selection in leukemogenesis. These patients have also been reported to have shorter time to progression than patients with nonstereotyped IGHV3-21. Materials and Methods: To investigate the IGHV3-21 frequency and the clinical impact of IGHV3-21 stereotypy, 337 newly diagnosed Swedish CLL patients from a population-based cohort were analyzed. Results: Interestingly, the IGHV3-21 frequency was indeed lower (6.5%) in this indolent patient cohort than in our previous hospital-based cohort studies (10.1%-12.7%). Hence, a selection bias of more-aggressive cases rendered a higher proportion of IGHV3-21 cases in our original studies. Nevertheless, the Swedish IGHV3-21 frequency still remained higher when compared with other larger European or American studies (2.6%-4.1%). Finally, we confirmed the poor outcome for IGHV3-21 patients to be independent of mutational status and found stereotypy to have no impact on survival or time to treatment. Conclusion: The Swedish geographic bias in IGHV3-21 gene frequency was validated albeit at a lower frequency than previously reported. Moreover, no prognostic value could be attributed to IGHV3-21 stereotype status.
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| 2. |
- Gunnarsson, Rebeqa
(författare)
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Array based genetic profiling of chronic lymphocytic leukemia
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Although no common genetic defect has been described in chronic lymphocytic leukemia (CLL), recurrent genomic aberrations (i.e. deletions of chromosome 11q, 13q, 17p and trisomy 12) are important for prognostication. Deletion of 13q as single aberration is associated with the best prognosis, whereas del(11q) and del(17p) predict a poor outcome. Recent development of high-resolution genomic techniques, i.e. microarrays, provides effective detection of the known recurrent aberrations and simultaneous exploration of the whole genome. Hence, this thesis aimed to map genomic aberrations in CLL through application of high-resolution microarrays. In paper I, we investigated the pros and cons of four differently designed microarray platforms. All platforms readily detected the known recurrent aberrations in CLL as well as other large copy-number aberrations (CNAs). The difference in technical performance and discrepancies in detection of small CNAs were influenced by differential platform density, different reference sets, and platform-specific analysis. In paper II and IV, 250K single nucleotide polymorphism (SNP)-array screening of 203 and 370 samples, respectively, detected CNAs in >90% and the known recurrent aberrations in >70% of patients. Moreover, novel recurrent gains of chromosome 2p in combination with 11q deletion and copy-number neutral loss of heterozygosity on chromosome 13q were revealed. Furthermore, a high genomic complexity was correlated to worse survival, but also closely linked to poor-prognostic markers. In addition, study IV also included follow-up samples (n=43) to investigate clonal evolution, which showed that patients with unmutated immunoglobulin heavy chain variable (IGHV) genes and treated patients with mutated IGHV genes often gained novel aberrations. In paper III, high-density screening revealed a different spectrum of genomic aberrations in CLL patients with ‘stereotyped’ IGHV3-21 (poor-prognostic) versus IGHV4-34 (good-prognostic) B-cell receptors. IGHV3-21 subset #2 (n=29) showed a high frequency of samples carrying genomic aberrations, and a particularly high prevalence of del(13q) and del(11q), which may correspond to the adverse survival reported for these patients. In contrast, IGHV4-34 subset #4 (n=17) showed a lower frequency and complexity of CNAs, which may reflect an inherent low-proliferative disease, preventing accumulation of genomic alterations. In summary, the studies included in this thesis provided a greater insight of genomic aberrations in newly diagnosed patients, at follow-up and in different subgroups of CLL.
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| 3. |
- Gunnarsson, Rebeqa, et al.
(författare)
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Array-based genomic screening at diagnosis and during follow-up in chronic lymphocytic leukemia
- 2011
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 1592-8721 .- 0390-6078. ; 96:8, s. 1161-1169
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Tidskriftsartikel (refereegranskat)abstract
- Background High-resolution genomic microarrays enable simultaneous detection of copy-number aberrations such as the known recurrent aberrations in chronic lymphocytic leukemia [del(11q), del(13q), del(17p) and trisomy 12], and copy-number neutral loss of heterozygosity. Moreover, comparison of genomic profiles from sequential patients' samples allows detection of clonal evolution. Design and Methods We screened samples from 369 patients with newly diagnosed chronic lymphocytic leukemia from a population-based cohort using 250K single nucleotide polymorphism-arrays. Clonal evolution was evaluated in 59 follow-up samples obtained after 5-9 years. Results At diagnosis, copy-number aberrations were identified in 90% of patients; 70% carried known recurrent alterations, including del(13q) (55%), trisomy 12 (10.5%), del(11q) (10%), and del(17p) (4%). Additional recurrent aberrations were detected on chromosomes 2 (1.9%), 4 (1.4%), 8 (1.6%) and 14 (1.6%). Thirteen patients (3.5%) displayed recurrent copy-number neutral loss of heterozygosity on 13q, of whom 11 had concurrent homozygous del(13q). Genomic complexity and large 13q deletions correlated with inferior outcome, while the former was linked to poor-prognostic aberrations. In the follow-up study, clonal evolution developed in 8/24 (33%) patients with unmutated IGHV, and in 4/25 (16%) IGHV-mutated and treated patients. In contrast, untreated patients with mutated IGHV (n=10) did not acquire additional aberrations. The most common secondary event, del(13q), was detected in 6/12 (50%) of all patients with acquired alterations. Interestingly, aberrations on, for example, chromosome 6q, 8p, 9p and 10q developed exclusively in patients with unmutated IGHV. Conclusions Whole-genome screening revealed a high frequency of genomic aberrations in newly diagnosed chronic lymphocytic leukemia. Clonal evolution was associated with other markers of aggressive disease and commonly included the known recurrent aberrations.
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| 4. |
- Gunnarsson, Rebeqa, et al.
(författare)
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Exploring the Genetic Landscape in Chronic Lymphocytic Leukemia Using High-Resolution Technologies
- 2013
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Ingår i: Leukemia and Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 54:8, s. 1583-1590
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Forskningsöversikt (refereegranskat)abstract
- During recent years, microarray-based technologies and next-generation sequencing (NGS) has have been applied in chronic lymphocytic leukemia (CLL) in order to identify novel genomic aberrations that may contribute to the pathogenesis of the disease. Even though high-resolution microarray studies have confirmed the importance of the known recurrent aberrations, i.e. del(11q), trisomy 12, del(13q) and del(17p), and have more precisely delineated the genomic borders of these aberrations, only a few novel aberrations, found at a low frequency, have been detected with these techniques. Contrary to this, the application of NGS technology of the coding genome (exome sequencing) or the entire genome (whole-genome sequencing) has unveiled a number of novel recurrent mutations in e.g. the NOTCH1, SF3B1 and BIRC3 genes. Importantly, mutations in these latter genes were reported to be associated with particularly poor outcome, similar to TP53 aberrations, and may play key roles in tumor development, treatment resistance and prognosis. In this review, we will not only summarize the latest achievements using array-based or NGS technologies, but also point to new directions for research aiming to unravel the complex genetic 'map' in CLL and its prognostic subsets.
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| 8. |
- Gunnarsson, Rebeqa, et al.
(författare)
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Mutation, methylation, and gene expression profiles in dup(1q)-positive pediatric B-cell precursor acute lymphoblastic leukemia
- 2018
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 32:10, s. 2117-2125
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Tidskriftsartikel (refereegranskat)abstract
- High-throughput sequencing was applied to investigate the mutation/methylation patterns on 1q and gene expression profiles in pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL) with/without (w/wo) dup(1q). Sequencing of the breakpoint regions and all exons on 1q in seven dup(1q)-positive cases revealed non-synonymous somatic single nucleotide variants (SNVs) in BLZF1, FMN2, KCNT2, LCE1C, NES, and PARP1. Deep sequencing of these in a validation cohort w (n = 17)/wo (n = 94) dup(1q) revealed similar SNV frequencies in the two groups (47% vs. 35%; P = 0.42). Only 0.6% of the 36,259 CpGs on 1q were differentially methylated between cases w (n = 14)/wo (n = 13) dup(1q). RNA sequencing of high hyperdiploid (HeH) and t(1;19)(q23;p13)-positive cases w (n = 14)/wo (n = 52) dup(1q) identified 252 and 424 differentially expressed genes, respectively; only seven overlapped. Of the overexpressed genes in the HeH and t(1;19) groups, 23 and 31%, respectively, mapped to 1q; 60-80% of these encode nucleic acid/protein binding factors or proteins with catalytic activity. We conclude that the pathogenetically important consequence of dup(1q) in BCP ALL is a gene-dosage effect, with the deregulated genes differing between genetic subtypes, but involving similar molecular functions, biological processes, and protein classes.
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| 9. |
- Gunnarsson, Rebeqa, et al.
(författare)
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New insights into the pathobiology of chronic lymphocytic leukemia
- 2011
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Ingår i: Journal of Hematopathology. - : Springer Science and Business Media LLC. - 1868-9256 .- 1865-5785. ; 4:3, s. 149-163
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Forskningsöversikt (refereegranskat)abstract
- Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a varying clinical outcome; however, the pathogenic mechanisms involved in disease development have remained largely unknown. In recent years, novel biomarkers, such as certain recurrent genomic alterations and the immunoglobulin heavy variable gene mutational status, have significantly improved the subdivision of the disease along with the prognostic assessment of individual patients. Advanced molecular studies have also revealed important genetic/epigenetic events and potential susceptibility loci for CLL, as well as implicating antigens in CLL development. Furthermore, the presence of monoclonal B cell lymphocytosis (MBL) has been demonstrated to precede CLL and appears to be a pre-leukemic condition. In this review, we will not only focus on recent developments made in the fields of genetics and immunogenetics in CLL, but also provide a brief overview of MBL, since we believe that advancements in these areas will have a major impact on our understanding of CLL pathobiology.
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| 10. |
- Gunnarsson, Rebeqa, et al.
(författare)
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Screening for copy-number alterations and loss of heterozygosity in chronic lymphocytic leukemia-A comparative study of four differently designed, high resolution microarray platforms
- 2008
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 93, s. 0536-0536
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Tidskriftsartikel (refereegranskat)abstract
- Screening for gene copy-number alterations (CNAs) has improved by applying genome-wide microarrays, where SNP arrays also allow analysis of loss of heterozygozity (LOH). We here analyzed 10 chronic lymphocytic leukemia (CLL) samples using four different high-resolution platforms: BAC arrays (32K), oligonucleotide arrays (185K, Agilent), and two SNP arrays (250K, Affymetrix and 317K, Illumina). Cross-platform comparison revealed 29 concordantly detected CNAs, including known recurrent alterations, which confirmed that all platforms are powerful tools when screening for large aberrations. However, detection of 32 additional regions present in 2-3 platforms illustrated a discrepancy in detection of small CNAs, which often involved reported copy-number variations. LOH analysis using dChip revealed concordance of mainly large regions, but showed numerous, small nonoverlapping regions and LOH escaping detection. Evaluation of baseline variation and copy-number ratio response showed the best performance for the Agilent platform and confirmed the robustness of BAC arrays. Accordingly, these platforms demonstrated a higher degree of platform-specific CNAs. The SNP arrays displayed higher technical variation, although this was compensated by high density of elements. Affymetrix detected a higher degree of CNAs compared to Illumina, while the latter showed a lower noise level and higher detection rate in the LOH analysis. Large-scale studies of genomic aberrations are now feasible, but new tools for LOH analysis are requested.
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