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Sökning: WFRF:(Cahill Nicola)

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1.
  • Agathangelidis, Andreas, et al. (författare)
  • Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia : a molecular classification with implications for targeted therapies
  • 2012
  • Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 119:19, s. 4467-4475
  • Tidskriftsartikel (refereegranskat)abstract
    • Mounting evidence indicates that grouping of chronic lymphocytic leukemia (CLL) into distinct subsets with stereotyped BCRs is functionally and prognostically relevant. However, several issues need revisiting, including the criteria for identification of BCR stereotypy and its actual frequency as well as the identification of "CLL-biased" features in BCR Ig stereotypes. To this end, we examined 7596 Ig VH (IGHV-IGHD-IGHJ) sequences from 7424 CLL patients, 3 times the size of the largest published series, with an updated version of our purpose-built clustering algorithm. We document that CLL may be subdivided into 2 distinct categories: one with stereotyped and the other with nonstereotyped BCRs, at an approximate ratio of 1: 2, and provide evidence suggesting a different ontogeny for these 2 categories. We also show that subset-defining sequence patterns in CLL differ from those underlying BCR stereotypy in other B-cell malignancies. Notably, 19 major subsets contained from 20 to 213 sequences each, collectively accounting for 943 sequences or one-eighth of the cohort. Hence, this compartmentalized examination of VH sequences may pave the way toward a molecular classification of CLL with implications for targeted therapeutic interventions, applicable to a significant number of patients assigned to the same subset.
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2.
  • Bessa, Agustina, et al. (författare)
  • Designing a Pragmatic Intervention to Help Improve the Bladder Cancer Patient Experience
  • 2021
  • Ingår i: Inquiry. - : Sage Publications. - 0046-9580 .- 1945-7243. ; 58
  • Tidskriftsartikel (refereegranskat)abstract
    • Bladder cancer (BC) is the 10th most common malignancy worldwide and the patient experience is found to be worse than that for patients diagnosed with other cancer types. We aimed to develop a wellbeing intervention to help improve the bladder cancer patient experience by ameliorating their health-related Quality of Life (HRQoL). We followed the 3 phases of the modified Medical Research Council (MRC) Framework for development of complex interventions. Following a systematic review of the literature on mental, sexual, and physical wellbeing, we conducted discussion groups with patients and healthcare professionals on these 3 themes. A consultation phase was then conducted with all relevant stakeholders to co-design a wellbeing intervention as part of a feasibility study. A pragmatic wellbeing feasibility trial was designed based on the hypothesis that a wellbeing program will increase patient awareness and attendance to services available to them and will better support their needs to improve HRQoL. The primary feasibility endpoints are patient attendance to the services offered and changes in HRQoL. The principle of patient centered care has strengthened the commitment to provide a holistic approach to support BC patients. In this study, we developed a wellbeing intervention in collaboration with patients and healthcare professionals to meet an unmet need in terms of the BC patient experience.
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3.
  • Cahill, Nicola, et al. (författare)
  • 450K-array analysis of chronic lymphocytic leukemia cells reveals global DNA methylation to be relatively stable over time and similar in resting and proliferative compartments
  • 2013
  • Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 27:1, s. 150-158
  • Tidskriftsartikel (refereegranskat)abstract
    • In chronic lymphocytic leukemia (CLL), the microenvironment influences gene expression patterns; however, knowledge is limited regarding the extent to which methylation changes with time and exposure to specific microenvironments. Using high-resolution 450K arrays, we provide the most comprehensive DNA methylation study of CLL to date, analyzing paired diagnostic/follow-up samples from IGHV-mutated/untreated and IGHV-unmutated/treated patients (n = 36) and patient-matched peripheral blood and lymph node samples (n = 20). On an unprecedented scale, we revealed 2239 differentially methylated CpG sites between IGHV-mutated and unmutated patients, with the majority of sites positioned outside annotated CpG islands. Intriguingly, CLL prognostic genes (for example, CLLU1, LPL, ZAP70 and NOTCH1), epigenetic regulator (for example, HDAC9, HDAC4 and DNMT3B), B-cell signaling (for example, IBTK) and numerous TGF-beta and NF-kappa B/TNF pathway genes were alternatively methylated between subgroups. Contrary, DNA methylation over time was deemed rather stable with few recurrent changes noted within subgroups. Although a larger number of non-recurrent changes were identified among IGHV-unmutated relative to mutated cases over time, these equated to a low global change. Similarly, few changes were identified between compartment cases. Altogether, we reveal CLL subgroups to display unique methylation profiles and unveil methylation as relatively stable over time and similar within different CLL compartments, implying aberrant methylation as an early leukemogenic event. Leukemia (2013) 27, 150-158; doi:10.1038/leu.2012.245
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6.
  • Cahill, Nicola, 1983-, et al. (författare)
  • IGHV3-21 Gene Frequency in a Swedish Cohort of Patients With Newly Diagnosed Chronic Lymphocytic Leukemia
  • 2012
  • Ingår i: Clinical Lymphoma, Myeloma & Leukemia. - : Elsevier BV. - 2152-2650 .- 2152-2669. ; 12:3, s. 201-206
  • 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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7.
  • Cahill, Nicola, 1983- (författare)
  • Molecular Genetic and DNA Methylation Profiling of Chronic Lymphocytic Leukaemia : A Focus on Divergent Prognostic Subgroups and Subsets
  • 2012
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Advancements in prognostication have improved the subdivision of chronic lymphocytic leukaemia (CLL) into diverse prognostic subgroups. In CLL, IGHV unmutated and IGHV3-21 genes are associated with a poor-prognosis, conversely, IGHV mutated genes with a favourable outcome. The finding of multiple CLL subsets expressing ‘stereotyped’ B-cell receptors (BCRs) has suggested a role for antigen(s) in leukemogenesis. Patients belonging to certain stereotyped subsets share clinical and biological characteristics, yet limited knowledge exists regarding the genetic and epigenetic events that may influence their clinical behaviour. This thesis aimed to, further investigate Swedish IGHV3-21-utilising patients, screen for genetic and DNA-methylation events in CLL subgroups/subsets and study DNA methylation over time and within different CLL compartments. In paper I, IGHV gene sequencing of 337 CLL patients from a Swedish population-based cohort revealed a lower (6.5%) IGHV3-21 frequency relative to previous Swedish hospital-based studies (10.1-12.7%). Interestingly, this frequency remained higher compared to other Western CLL (2.6-4.1%) hospital-based cohorts. Furthermore, we confirmed the poor-outcome for IGHV3-21 patients to be independent of mutational and stereotypy status. In paper II, genomic events in stereotyped IGHV3-21-subset #2, IGHV4-34-subset #4 and subset #16 and their non-stereotyped counterparts were investigated via SNP arrays (n=101). Subset #2 and non-subset #2 carried a higher frequency of events compared to subset #4. A high frequency of del(11q) was evident in IGHV3-21 patients particularly subset #2 cases, which may partially explain their poor-prognosis. In contrast, the lower prevalence of aberrations and absence of poor-prognostic alterations may reflect the inherent low-proliferative disease seen in subset #4 cases. In papers III and IV, differential methylation profiles in IGHV mutated and IGHV unmutated patients were identified using DNA-methylation microarrays. CLL prognostic genes (CLLU1, LPL), tumor-suppressor genes (TSGs) (ABI3, WISP3) and genes belonging to TGF-ß and NF-kB/TNFR1 pathways were differentially methylated between the subgroups. Additionally, the re-expression of methylated TSGs by use of methyl and deacetyl inhibitors was demonstrated. Interestingly, analysis of patient-paired diagnostic/follow-up samples and patient-matched lymph node (LN) and peripheral blood (PB) cases revealed global DNA methylation to be relatively stable over time and remarkably similar within the different compartments. Altogether, this thesis provides insight into the aberrant genomic and DNA methylation events in divergent CLL subgroups. Moreover this thesis helps distinguish the extent to which DNA methylation changes with respect to time and microenvironment in CLL.
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8.
  • Cahill, Nicola, et al. (författare)
  • Uncovering the DNA methylome in chronic lymphocytic leukemia
  • 2013
  • Ingår i: Epigenetics. - : Informa UK Limited. - 1559-2294 .- 1559-2308. ; 8:2, s. 138-148
  • Forskningsöversikt (refereegranskat)abstract
    • Over the past two decades, aberrant DNA methylation has emerged as a key player in the pathogenesis of chronic lymphocytic leukemia (CLL), and knowledge regarding its biological and clinical consequences in this disease has evolved rapidly. Since the initial studies relating DNA hypomethylation to genomic instability in CLL, a plethora of reports have followed showing the impact of DNA hypermethylation in silencing vital single gene promoters and the reversible nature of DNA methylation through inhibitor drugs. With the recognition that DNA hypermethylation events could potentially act as novel prognostic and treatment targets in CLL, the search for aberrantly methylated genes, gene families and pathways has ensued. Subsequently, the advent of microarray and next-generation sequencing technologies has supported the hunt for such targets, allowing exploration of the methylation landscape in CLL at an unprecedented scale. In light of these analyses, we now understand that different CLL prognostic subgroups are characterized by differential methylation profiles; we recognize DNA methylation of a number of signaling pathways genes to be altered in CLL, and acknowledge the role of DNA methylation outside of traditional CpG island promoters as fundamental players in the regulation of gene expression. Today, the significance and timing of altered DNA methylation within the complex epigenetic network of concomitant epigenetic messengers such as histones and miRNAs is an intensive area of research. In CLL, it appears that DNA methylation is a rather stable epigenetic mark occurring rather early in the disease pathogenesis. However, other consequences, such as how and why aberrant methylation marks occur, are less explored. In this review, we will not only provide a comprehensive summary of the current literature within the epigenetics field of CLL, but also highlight some of the novel findings relating to when, where, why and how altered DNA methylation materializes in CLL.
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9.
  • Cavelier, Lucia, et al. (författare)
  • Clonal distribution of BCR-ABL1 mutations and splice isoforms by single-molecule long-read RNA sequencing
  • 2015
  • Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407 .- 1471-2407. ; 15
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The evolution of mutations in the BCR-ABL1 fusion gene transcript renders CML patients resistant to tyrosine kinase inhibitor (TKI) based therapy. Thus screening for BCR-ABL1 mutations is recommended particularly in patients experiencing poor response to treatment. Herein we describe a novel approach for the detection and surveillance of BCR-ABL1 mutations in CML patients. Methods: To detect mutations in the BCR-ABL1 transcript we developed an assay based on the Pacific Biosciences (PacBio) sequencing technology, which allows for single-molecule long-read sequencing of BCR-ABL1 fusion transcript molecules. Samples from six patients with poor response to therapy were analyzed both at diagnosis and follow-up. cDNA was generated from total RNA and a 1,6 kb fragment encompassing the BCR-ABL1 transcript was amplified using long range PCR. To estimate the sensitivity of the assay, a serial dilution experiment was performed. Results: Over 10,000 full-length BCR-ABL1 sequences were obtained for all samples studied. Through the serial dilution analysis, mutations in CML patient samples could be detected down to a level of at least 1%. Notably, the assay was determined to be sufficiently sensitive even in patients harboring a low abundance of BCR-ABL1 levels. The PacBio sequencing successfully identified all mutations seen by standard methods. Importantly, we identified several mutations that escaped detection by the clinical routine analysis. Resistance mutations were found in all but one of the patients. Due to the long reads afforded by PacBio sequencing, compound mutations present in the same molecule were readily distinguished from independent alterations arising in different molecules. Moreover, several transcript isoforms of the BCR-ABL1 transcript were identified in two of the CML patients. Finally, our assay allowed for a quick turn around time allowing samples to be reported upon within 2 days. Conclusions: In summary the PacBio sequencing assay can be applied to detect BCR-ABL1 resistance mutations in both diagnostic and follow-up CML patient samples using a simple protocol applicable to routine diagnosis. The method besides its sensitivity, gives a complete view of the clonal distribution of mutations, which is of importance when making therapy decisions.
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