Mark A Catherwood

Belfast Healthy Cities, Béal Feirste, Northern Ireland, United Kingdom

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Publications (46)223.47 Total impact

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    ABSTRACT: Next-generation sequencing (NGS) technologies have begun to revolutionize the field of haematological malignancies through the assessment of a patient's genetic makeup with a minimal cost. Significant discoveries have already provided a unique insight into disease initiation, risk stratification and therapeutic intervention. Sequencing analysis will likely form part of the routine diagnostic testing in the future. However, a number of important issues need to be addressed for that to become a reality with regard to result interpretation, laboratory workflow, data storage and ethical issues. In this review we summarize the contribution that NGS has already made to the field of haematological malignancies. Finally, we discuss the challenges that NGS technologies will bring in relation to data storage, ethical and legal issues and laboratory validation. Despite these challenges, we predict that high-throughput DNA sequencing will redefine haematological malignancies based on individualized genomic analysis.
    06/2015; 431(1-2). DOI:10.1016/j.pathog.2015.05.004
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    ABSTRACT: Abstract Modern cancer research on prognostic and predictive biomarkers demands the integration of established and emerging high throughput technologies. However, these data are meaningless unless carefully integrated with patient clinical outcome and epidemiological information. Integrated datasets hold the key to discovering new biomarkers and therapeutic targets in cancer. We have developed a novel approach and set of methods for integrating and interrogating phenomic, genomic and clinical data sets to facilitate cancer biomarker discovery and patient stratification. Applied to a known paradigm, the biological and clinical relevance of TP53, PICan was able to recapitulate the known biomarker status and prognostic significance at a DNA, RNA and protein levels.
    Molecular Oncology 03/2015; DOI:10.1016/j.molonc.2015.02.002 · 5.94 Impact Factor
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    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.
    Blood 01/2015; 125(5):856-9. DOI:10.1182/blood-2014-09-600874 · 10.43 Impact Factor
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    ABSTRACT: - Copyright © 2014, Ferrata Storti Foundation.
    Haematologica 12/2014; DOI:10.3324/haematol.2014.116780 · 5.87 Impact Factor
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    ABSTRACT: Serial quantification of BCR-ABL1 mRNA is an important therapeutic indicator in chronic myeloid leukemia, but there is substantial variation in results reported by different laboratories. To improve comparability, an internationally accepted plasmid certified reference material (CRM) was developed according to ISO Guide 34:2009. Fragments of BCR-ABL1 (e14a2 mRNA fusion), BCR and GUSB transcripts were amplified and cloned into pUC18 to yield plasmid pIRMM0099. Six different linearised plasmid solutions were produced with the following copy number concentrations, assigned by digital PCR, and expanded uncertainties: 1.08±0.13 × 10(6), 1.08±0.11 × 10(5), 1.03±0.10 × 10(4), 1.02±0.09 × 10(3), 1.04±0.10 × 10(2) and 10.0±1.5 copies/μL. The certification of the material for the number of specific DNA fragments per plasmid, copy number concentration of the plasmid solutions and the assessment of inter-unit heterogeneity and stability were performed according to ISO Guide 35:2006. Two suitability studies performed by 63 BCR-ABL1 testing laboratories demonstrated that this set of 6 plasmid CRMs can help to standardise the numbers of measured transcripts of e14a2 BCR-ABL1 and three control genes; ABL1, BCR and GUSB. The set of 6 plasmid CRMs is distributed worldwide by the Institute for Reference Materials and Measurements (Belgium) and its authorised distributors (http://irmm.jrc.ec.europa.eu; CRM code ERM-AD623a-f).Leukemia accepted article preview online, 18 July 2014; doi:10.1038/leu.2014.217.
    Leukemia 07/2014; 29(2). DOI:10.1038/leu.2014.217 · 9.38 Impact Factor
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    ABSTRACT: Utility of p53 as a prognostic assay has been elusive. We describe a novel, reproducible scoring system and assess the relationship between differential p53 IHC expression patterns, TP53 mutation status and patient outcomes for breast cancer. Tissue microarrays were used to study p53 IHC expression patterns: expression was defined as extreme positive (EP), extreme negative (EN) and intermediate patterns as non-extreme (NE). Overall survival was used to define patient outcome. A representative subgroup (n=30) displaying the various p53 immunophenotypes was analysed for TP53 hotspot mutation status (exons 4-9). Extreme expression of any type occurred in 176/288 (61%) cases. EP p53 compared to NE p53 was significantly associated (p = 0.039) with poor OS. In addition, EN p53 compared to NE p53 was associated (p = 0.059) with poor OS. Combining cases displaying either EP/EN expression better predicted OS than either pattern alone (p = 0.028). This combination immunophenotype was significant in univariate but not multivariate analysis. In subgroup analysis six substitution exon mutations were detected, all corresponding to extreme IHC phenotypes. Five missense mutations corresponded to EP staining while the nonsense mutation corresponded to EN staining. None were detected in the NE group. Patients with extreme p53 IHC expression have a worse OS compared to those with NE expression. Accounting for EN as well as EP p53 improves its prognostic impact. Extreme expression positively correlates with nodal stage and histological grade and negatively with hormone receptor status. Extreme expression may relate to specific mutational status. This article is protected by copyright. All rights reserved.
    Histopathology 02/2014; 65(3). DOI:10.1111/his.12398 · 3.30 Impact Factor
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    ABSTRACT: Molecular medicine is transforming modern clinical practice, from diagnostics to therapeutics. Discoveries in research are being incorporated into the clinical setting with increasing rapidity. This transformation is also deeply changing the way we practise pathology. The great advances in cell and molecular biology which have accelerated our understanding of the pathogenesis of solid tumours have been embraced with variable degrees of enthusiasm by diverse medical professional specialties. While histopathologists have not been prompt to adopt molecular diagnostics to date, the need to incorporate molecular pathology into the training of future histopathologists is imperative. Our goal is to create, within an existing 5-year histopathology training curriculum, the structure for formal substantial teaching of molecular diagnostics. This specialist training has two main goals: (1) to equip future practising histopathologists with basic knowledge of molecular diagnostics and (2) to create the option for those interested in a subspecialty experience in tissue molecular diagnostics to pursue this training. It is our belief that this training will help to maintain in future the role of the pathologist at the centre of patient care as the integrator of clinical, morphological and molecular information.
    Journal of clinical pathology 02/2014; 67(7). DOI:10.1136/jclinpath-2014-202176 · 2.55 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):57-57. DOI:10.1158/1538-7445.AM2013-57 · 9.28 Impact Factor
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    ABSTRACT: Next Generation Sequencing (NGS) has the potential of becoming an important tool in clinical diagnosis and therapeutic decision-making in oncology owing to its enhanced sensitivity in DNA mutation detection, fast-turnaround of samples in comparison to current gold standard methods and the potential to sequence a large number of cancer-driving genes at the one time. We aim to test the diagnostic accuracy of current NGS technology in the analysis of mutations that represent current standard-of-care, and its reliability to generate concomitant information on other key genes in human oncogenesis. Thirteen clinical samples (8 lung adenocarcinomas, 3 colon carcinomas and 2 malignant melanomas) already genotyped for EGFR, KRAS and BRAF mutations by current standard-of-care methods (Sanger Sequencing and q-PCR), were analysed for detection of mutations in the same three genes using two NGS platforms and an additional 43 genes with one of these platforms. The results were analysed using closed platform-specific proprietary bioinformatics software as well as open third party applications. Our results indicate that the existing format of the NGS technology performed well in detecting the clinically relevant mutations stated above but may not be reliable for a broader unsupervised analysis of the wider genome in its current design. Our study represents a diagnostically lead validation of the major strengths and weaknesses of this technology before consideration for diagnostic use.
    PLoS ONE 07/2013; 8(7):e69604. DOI:10.1371/journal.pone.0069604 · 3.53 Impact Factor
  • M A Catherwood, F Schmitt, M Salto-Tellez
    Cytopathology 10/2012; 23(5):283-5. DOI:10.1111/cyt.12015 · 1.47 Impact Factor
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    ABSTRACT: PCR-based immunoglobulin (Ig)/T-cell receptor (TCR) clonality testing in suspected lymphoproliferations has largely been standardized and has consequently become technically feasible in a routine diagnostic setting. Standardization of the pre-analytical and post-analytical phases is now essential to prevent misinterpretation and incorrect conclusions derived from clonality data. As clonality testing is not a quantitative assay, but rather concerns recognition of molecular patterns, guidelines for reliable interpretation and reporting are mandatory. Here, the EuroClonality (BIOMED-2) consortium summarizes important pre- and post-analytical aspects of clonality testing, provides guidelines for interpretation of clonality testing results, and presents a uniform way to report the results of the Ig/TCR assays. Starting from an immunobiological concept, two levels to report Ig/TCR profiles are discerned: the technical description of individual (multiplex) PCR reactions and the overall molecular conclusion for B and T cells. Collectively, the EuroClonality (BIOMED-2) guidelines and consensus reporting system should help to improve the general performance level of clonality assessment and interpretation, which will directly impact on routine clinical management (standardized best-practice) in patients with suspected lymphoproliferations.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 08/2012; 26(10):2159-71. DOI:10.1038/leu.2012.246 · 9.38 Impact Factor
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    ABSTRACT: Multidrug resistance (MDR) mediated by P-glycoprotein (P-gp) can compromise the successful treatment of many malignancies including plasma cell myeloma (PCM). However, methods do not yet exist that can accurately determine P-gp activity in PCM patient samples. In this study, we have utilized new advances in flow cytometric methods to determine the activity of P-gp in PCM tumor cells. Furthermore, we have used several PCR-based approaches to perform a pilot study determining the functional impact of ABCB1 SNPs in patients with PCM. No associations were seen between P-gp activity or expression and subgroups of PCM. Similarly, no association was seen between P-gp expression and SNPs within ABCB1 although a nonsignificant reduction in activity was demonstrated for rs1045642 (P = 0.121). We have described a new method for the determination of P-gp and MRP activity suitable for use in clinical studies and have optimized this method to include a gating strategy, allowing routine use on PCM bone marrow aspirate samples. This is the first patient study to consider the full impact of SNPs within ABCB1 all the way from the genome to the proteome in PCM. The methods described here could also be utilized for future studies of "stem cell like" side populations in PCM that are considered to be drug resistant. Furthermore, minor amendments to these methods will facilitate studies of P-gp, MRP, and BCRP activity in other haematological malignancies.
    Cytometry Part B Clinical Cytometry 07/2012; 82(4):229-37. DOI:10.1002/cyto.b.21018 · 2.28 Impact Factor
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    British Journal of Haematology 07/2011; 156(1):133-6. DOI:10.1111/j.1365-2141.2011.08798.x · 4.96 Impact Factor
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    ABSTRACT: In chronic lymphocytic leukemia (CLL) the proliferation rate and resistance to drug-induced apoptosis are recognized as important factors in the outcome of treatment. In this study, we assess the activity and the mechanism of action of the prototype cell division cycle kinase 7 (Cdc7) inhibitor, PHA-767491, which inhibits the initiation of DNA replication but also has cyclin-dependent kinase 9 (Cdk9) inhibitory activity. We have studied the effects of this dual Cdc7/Cdk9 inhibitor in both quiescent CLL cells and CLL cells that have been induced to proliferate using a cellular coculture system that mimics the lymph node microenvironment. We find that this compound, originally developed as a DNA replication inhibitor, is particularly active in promoting mitochondrial dependent apoptosis in quiescent CLL cells purified from peripheral blood of patients regardless of recognized risk factors. In this setting, apoptosis is preceded by a decrease in the levels of Mcl-1 protein and transcript possibly due to inhibition of Cdk9. Following stimulation by CD154 and interleukin-4, CLL cells become highly chemoresistant, reenter into the cell cycle, reexpress Cdc7 kinase, a key molecular switch for the initiation of DNA replication, replicate their DNA, and undergo cell division. In this context, treatment with PHA-767491 abolished DNA synthesis by inhibiting Cdc7 but is less effective in triggering cell death, although Mcl-1 protein is no longer detectable. Thus, dual Cdc7/Cdk9 inhibition has the potential to target both the quiescent and actively proliferating CLL populations through two distinct mechanisms and may be a new therapeutic strategy in CLL.
    Molecular Cancer Therapeutics 07/2011; 10(9):1624-34. DOI:10.1158/1535-7163.MCT-10-1119 · 6.11 Impact Factor
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    ABSTRACT: Multi-drug resistance (MDR) leads to impaired treatment efficacy in all forms of malignancy. The main forms of MDR are thought to be mediated by the substrate transporting actions of certain adenosine triphosphate binding cassette (ABC) transport proteins. The genes ABCB1, ABCB4, ABCC1, ABCG2 and LRP1 have been identified as the most prominent contributors to clinically significant MDR. To date, no study has investigated the expression of these genes in plasma cell myeloma (PCM), or attempted to relate their expression to the incidence of relapse and/or stage at presentation. Here, we show that ABCB4 may be a prominent mediator of tumour cell MDR within PCM. Additionally, there are three SNPs (rs1045642, rs2032582 and rs1128503) within the most widely studied of these genes, ABCB1, which have been suggested to have a potential impact on OS in PCM and which may form a haplotype in ABCB1. rs1045642 in ABCB1 appears to be the only SNP affecting OS within the PCM patients studied, with minimal linkage disequilibrium demonstrated between it and rs2032582 and rs1128503.
    Leukemia research 06/2011; 35(11):1457-63. DOI:10.1016/j.leukres.2011.05.033 · 2.69 Impact Factor
  • EJC Supplements 11/2010; 8(7):161-161. DOI:10.1016/S1359-6349(10)72212-6 · 9.39 Impact Factor
  • Stephen Drain, Mark A Catherwood, H Denis Alexander
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    ABSTRACT: Multidrug resistance (MDR) is a phenomenon in malignancy whereby tumor cells generate mechanisms to resist cytotoxic treatments. Several such mechanisms have been identified. However, to date the most significant research on MDR has involved the adenosine triphosphate binding cassette (ABC) transporter proteins, including P-glycoprotein (P-gp) and multidrug resistance associated protein (MRP). These proteins have natural functions involving substrate transport in normal cells but are detrimental to treatment when expressed in the membrane of tumor cells. It remains unclear whether ABC mediated MDR functions primarily through protein up-regulation or via a relevant signaling mechanism, or is simply due to selective pressure on an already resistant tumor cell subpopulation. Here we present an overview of MDR in the chronic lymphoproliferative disorders (CLPDs), in particular that attributed to the ABC transporter protein family.
    Leukemia & lymphoma 10/2010; 51(10):1793-804. DOI:10.3109/10428194.2010.500434 · 2.89 Impact Factor
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    ABSTRACT: Pyrrolo-1,5-benzoxazepine-15 (PBOX-15) is a novel microtubule depolymerization agent that induces cell cycle arrest and subsequent apoptosis in a number of cancer cell lines. Chronic lymphocytic leukemia (CLL) is characterized by clonal expansion of predominately nonproliferating mature B cells. Here, we present data suggesting PBOX-15 is a potential therapeutic agent for CLL. We show activity of PBOX-15 in samples taken from a cohort of CLL patients (n = 55) representing both high-risk and low-risk disease. PBOX-15 exhibited cytotoxicity in CLL cells (n = 19) in a dose-dependent manner, with mean IC(50) of 0.55 micromol/L. PBOX-15 significantly induced apoptosis in CLL cells (n = 46) including cells with poor prognostic markers: unmutated IgV(H) genes, CD38 and zeta-associated protein 70 (ZAP-70) expression, and fludarabine-resistant cells with chromosomal deletions in 17p. In addition, PBOX-15 was more potent than fludarabine in inducing apoptosis in fludarabine-sensitive cells. Pharmacologic inhibition and small interfering RNA knockdown of caspase-8 significantly inhibited PBOX-15-induced apoptosis. Pharmacologic inhibition of c-jun NH(2)-terminal kinase inhibited PBOX-15-induced apoptosis in mutated IgV(H) and ZAP-70(-) CLL cells but not in unmutated IgV(H) and ZAP-70(+) cells. PBOX-15 exhibited selective cytotoxicity in CLL cells compared with normal hematopoietic cells. Our data suggest that PBOX-15 represents a novel class of agents that are toxic toward both high-risk and low-risk CLL cells. The need for novel treatments is acute in CLL, especially for the subgroup of patients with poor clinical outcome and drug-resistant disease. This study identifies a novel agent with significant clinical potential.
    Cancer Research 10/2009; 69(21):8366-75. DOI:10.1158/0008-5472.CAN-09-0131 · 9.28 Impact Factor
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    ABSTRACT: This report describes a case of aleukaemic myeloid sarcoma of the small intestine in a 50-year-old woman presenting with small bowel obstruction. Fluorescence in situ hybridisation analysis of interphase nuclei revealed a split CBFbeta signal, consistent with an underlying inversion of chromosome 16, inv(16)(p13q22). The resultant type A CBFbeta/MYH11 transcript was detected by reverse transcriptase PCR. Immunohistochemistry with the AH107 antibody to the CBFbeta-SMMHC chimeric protein showed strong nuclear staining of the tumour cell nuclei. This represents the first use of this antibody in the diagnosis of this subtype of myeloid sarcoma in the small intestine.
    Journal of clinical pathology 09/2009; 62(8):757-9. DOI:10.1136/jcp.2008.063669 · 2.55 Impact Factor
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    ABSTRACT: Multi-drug resistance (MDR) may compromise the successful management of haematological malignancies, impairing the effectiveness of chemotherapy. The P-glycoprotein (P-gp) drug efflux pump, encoded by the gene ABCB1 (MDR1), is the most widely studied component in MDR. A single nucleotide polymorphism (SNP) has been identified within ABCB1, rs1045642 (C3435T), which may alter P-gp substrate specificity and have an impact on the effectiveness of treatment, and hence overall survival (OS). We estimated the frequency of this SNP in the Northern Irish population and investigated its impact on the OS of patients with plasma cell myeloma (PCM). There was no significant difference in the frequency of rs1045642 between the PCM cohort and an age- and gender-matched control population. Findings within the PCM cohort suggest that rs1045642 genotype influences OS (p = 2 x 10(-2)). If confirmed in larger studies, these results suggest that genotyping rs1045642 may be a useful predictor of outcome in PCM and could indicate modified treatment modalities in certain individuals.
    Leukemia & lymphoma 05/2009; 50(4):566-70. DOI:10.1080/10428190902853144 · 2.89 Impact Factor

Publication Stats

739 Citations
223.47 Total Impact Points

Institutions

  • 2003–2015
    • Belfast Healthy Cities
      Béal Feirste, Northern Ireland, United Kingdom
  • 1998–2015
    • Queen's University Belfast
      • • Centre for Cancer Research and Cell Biology
      • • Institute of Clinical Sciences
      Béal Feirste, Northern Ireland, United Kingdom
  • 2009–2014
    • Belfast Health and Social Care Trust
      Béal Feirste, Northern Ireland, United Kingdom
  • 2007–2011
    • University of Ulster
      • • Biomedical Sciences Research Institute
      • • School of Biomedical Sciences
      Aontroim, Northern Ireland, United Kingdom