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  • Genomic copy number predicts esophageal cancer years before transformation

    Killcoyne, S.; Gregson, E.; Wedge, David C; Woodcock, D. J.; Eldridge, M. D.; de la Rue, R.; Miremadi, A.; Abbas, S.; Blasko, A.; Kosmidou, C.; et al. (2020)
    Recent studies show that aneuploidy and driver gene mutations precede cancer diagnosis by many years1-4. We assess whether these genomic signals can be used for early detection and pre-emptive cancer treatment using the neoplastic precursor lesion Barrett's esophagus as an exemplar5. Shallow whole-genome sequencing of 777 biopsies, sampled from 88 patients in Barrett's esophagus surveillance over a period of up to 15 years, shows that genomic signals can distinguish progressive from stable disease even 10 years before histopathological transformation. These findings are validated on two independent cohorts of 76 and 248 patients. These methods are low-cost and applicable to standard clinical biopsy samples. Compared with current management guidelines based on histopathology and clinical presentation, genomic classification enables earlier treatment for high-risk patients as well as reduction of unnecessary treatment and monitoring for patients who are unlikely to develop cancer.
  • Clinical and translational research challenges in neuroendocrine tumours

    Barriuso, Jorge; Lamarca, Angela; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom. (2020)
    Neuroendocrine tumours (NETs) represent a range of neoplasms that may arise from any (neuro)endocrine cell situated in any part of the human body. As any other rare diseases, NETs face several difficulties in relation to research. This review will describe some of the main challenges and proposed solutions faced by researchers with expertise in rare malignancies. Some of the most common challenges in clinical and translational research are enumerated in this review, covering aspects from clinical, translational and basic research. NETs being a heterogeneous group of diseases and a limited sample size of clinical and translational research projects are the main challenges. Challenges with NETs lay over the disparities between healthcare models to tackle rare diseases. NETs add an extra layer of complexity due to a numerous group of different entities. Prospective real-world data trials are an opportunity for rare cancers with the revolution of electronic health technologies. This review explores potential solutions to these challenges that could be useful not only to the NET community but also to other rare tumours researchers.
  • In vivo binding of recombination proteins to non-DSB DNA lesions and to replication forks

    González-Prieto, R.; Cabello-Lobato, Maria J; Prado, F.; Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands. (2021)
    Homologous recombination (HR) has been extensively studied in response to DNA double-strand breaks (DSBs). In contrast, much less is known about how HR deals with DNA lesions other than DSBs (e.g., at single-stranded DNA) and replication forks, despite the fact that these DNA structures are associated with most spontaneous recombination events. A major handicap for studying the role of HR at non-DSB DNA lesions and replication forks is the difficulty of discriminating whether a recombination protein is associated with the non-DSB lesion per se or rather with a DSB generated during their processing. Here, we describe a method to follow the in vivo binding of recombination proteins to non-DSB DNA lesions and replication forks. This approach is based on the cleavage and subsequent electrophoretic analysis of the target DNA by the recombination protein fused to the micrococcal nuclease.
  • When what you see is not always what you get: raising the bar of evidence for new diagnostic imaging modalities

    Sundahl, N.; Gillessen, Silke; Sweeney, C.; Ost, P.; Department of Radiation Oncology, Ghent University Hospital, Ghent, Belgium; Division of Radiotherapy and Imaging, Institute of Cancer Research, London, UK. Electronic address: nora.sundahl@ugent.be. (2020)
    Even though prostate-specific membrane antigen (PSMA)-positron emission tomography (PET)-computed tomography (CT) is more accurate than conventional imaging in prostate cancer patients, its impact on patient-relevant outcomes is unknown. We argue that more evidence is required before using PSMA-PET-CT as the standard of care for staging.
  • Multi-site clonality analysis uncovers pervasive heterogeneity across melanoma metastases

    Rabbie, R.; Ansari-Pour, N.; Cast, O.; Lau, D.; Scott, F.; Welsh, S. J.; Parkinson, C.; Khoja, L.; Moore, L.; Tullett, M.; et al. (2020)
    Metastatic melanoma carries a poor prognosis despite modern systemic therapies. Understanding the evolution of the disease could help inform patient management. Through whole-genome sequencing of 13 melanoma metastases sampled at autopsy from a treatment naïve patient and by leveraging the analytical power of multi-sample analyses, we reveal evidence of diversification among metastatic lineages. UV-induced mutations dominate the trunk, whereas APOBEC-associated mutations are found in the branches of the evolutionary tree. Multi-sample analyses from a further seven patients confirmed that lineage diversification was pervasive, representing an important mode of melanoma dissemination. Our analyses demonstrate that joint analysis of cancer cell fraction estimates across multiple metastases can uncover previously unrecognised levels of tumour heterogeneity and highlight the limitations of inferring heterogeneity from a single biopsy.
  • Dose-response relationships for radiation-related heart disease: Impact of uncertainties in cardiac dose reconstruction

    Ntentas, G.; Darby, S. C.; Aznar, Marianne Camille; Hodgson, D. C.; Howell, R. M.; Maraldo, M. V.; Ahmed, S.; Ng, A.; Aleman, B. M. P.; Cutter, D. J.; et al. (2020)
    Background and purpose: Radiation-related heart disease (RRHD) can occur many decades after thoracic radiotherapy for Hodgkin lymphoma (HL) or childhood cancer (CC). To quantify the likely risk of RRHD for patients treated today, dose-response relationships derived from patients treated in previous decades are used. Publications presenting these dose-response relationships usually include estimates of uncertainties in the risks but ignore the effect of uncertainties in the reconstructed cardiac doses. Materials/methods: We assessed the systematic and random uncertainties in the reconstructed doses for published dose-response relationships for RRHD risk in survivors of HL or CC. Using the same reconstruction methods as were used in the original publications, we reconstructed mean heart doses and, wherever possible, mean left-ventricular doses for an independent case-series of test patients. These patients had known, CT-based, cardiac doses which were compared with the reconstructed doses to estimate the magnitude of the uncertainties and their effect on the dose-response relationships. Results: For all five reconstruction methods the relationship between reconstructed and CT-based doses was linear. For all but the simplest reconstruction method, the dose uncertainties were moderate, the effect of the systematic uncertainty on the dose-response relationships was less than 10%, and the effects of random uncertainty were small except at the highest doses. Conclusions: These results increase confidence in the published dose-response relationships for the risk of RRHD in HL and CC survivors. This may encourage doctors to use these dose-response relationships when estimating individualised risks for patients-an important aspect of personalising radiotherapy treatments today.
  • Malignant transformation and genetic alterations are uncoupled in early colorectal cancer progression

    Mamlouk, S.; Simon, T.; Tomás, L.; Wedge, David C; Arnold, A.; Menne, A.; Horst, D.; Capper, D.; Morkel, M.; Posada, D.; et al. (2020)
    Background: Colorectal cancer (CRC) development is generally accepted as a sequential process, with genetic mutations determining phenotypic tumor progression. However, matching genetic profiles with histological transition requires the analyses of temporal samples from the same patient at key stages of progression. Results: Here, we compared the genetic profiles of 34 early carcinomas with their respective adenomatous precursors to assess timing and heterogeneity of driver alterations accompanying the switch from benign adenoma to malignant carcinoma. In almost half of the cases, driver mutations specific to the carcinoma stage were not observed. In samples where carcinoma-specific alterations were present, TP53 mutations and chromosome 20 copy gains commonly accompanied the switch from adenomatous tissue to carcinoma. Remarkably, 40% and 50% of high-grade adenomas shared TP53 mutations and chromosome 20 gains, respectively, with their matched carcinomas. In addition, multi-regional analyses revealed greater heterogeneity of driver mutations in adenomas compared to their matched carcinomas. Conclusion: Genetic alterations in TP53 and chromosome 20 occur at the earliest histological stage in colorectal carcinomas (pTis and pT1). However, high-grade adenomas can share these alterations despite their histological distinction. Based on the well-defined sequence of CRC development, we suggest that the timing of genetic changes during neoplastic progression is frequently uncoupled from histological progression.
  • Patterns of omega-3 and omega-6 fatty acid dietary intake and melanoma thickness at diagnosis

    Mahamat-Saleh, Y.; Hughes, M. C. B.; Miura, K.; Malt, M. K.; von Schuckmann, L.; Khosrotehrani, K.; Smithers, B. M.; Green, Adèle C; Centre for Research in Epidemiology and Population Health (CESP) School of Medicine, Universite Paris Sud School of Medicine, Universite Versailles Saint-Quentin-en-Yvelines (UVSQ); INSERM French National Institute for Health and Medical Research, Universite Paris Saclay, Villejuif, France. (2020)
    Background: Experimental evidence suggests that dietary intakes of omega-3 and omega-6 polyunsaturated fatty acids have divergent effects on melanoma growth, but epidemiologic evidence on their combined effect is lacking. Methods: In 634 Australian patients with primary melanoma, we assessed prediagnosis consumption of 39 food groups by food frequency questionnaires completed within 2 months of diagnosis. We derived, by reduced rank regression, dietary patterns that explained variability in selected omega-3 and omega-6 fatty acid intakes. Prevalence ratios (PR) and 95% confidence intervals (CI) for the association between tertiles of dietary patterns and melanoma thickness >2 mm versus ≤2 mm were estimated using Poisson regression. Results: Overall omega-3 fatty acid intakes were low. Two major fatty acid dietary patterns were identified: "meat, fish, and fat," positively correlated with intakes of all fatty acids; and "fish, low-meat, and low-fat," positively correlated with long-chain omega-3 fatty acid intake, and inversely with medium-chain omega-3 and omega-6 fatty acid intakes. Prevalence of thick melanomas was significantly higher in those in the highest compared with lowest tertile of the "meat, fish, and fat" pattern (PR, 1.40; 95% CI, 1.01-1.94), especially those with serious comorbidity (PR, 1.83; 95% CI, 1.15-2.92) or a family history (PR, 2.32; 95% CI, 1.00-5.35). The "fish, low-meat, and low-fat" pattern was not associated with melanoma thickness. Conclusions: People with high meat, fish, and fat intakes, who thus consumed relatively high levels of omega-3 and high omega-6 fatty acid intakes, are more likely to be diagnosed with thick than thin melanomas.
  • Regular application of sunscreen can prevent skin cancer

    Green, Adèle C; Population Studies Department, QIMR Berghofer Medical Research Institute, Brisbane, 4006 Australia, CRUK Manchester Institute and Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, M13 9PL United Kingdom (A.C.G.) (2020)
    This review summarizes the evidence on the protection against skin cancer afforded by sunscreen.Solid evidence can come only from randomized controlled trials, despite a multitude of case–control and cohort studies that have addressed the issue, because observational evidence is intractably confounded since those at highest risk of skin cancer are naturally the highest users of sunscreen. of the single human trial conducted in subtropical Australia during 1992–1996 with follow-up to 2014 showed that the application of a broad-spectrum, sun protection factor 16 sunscreen to exposed skin of the head and neck and upper limbs at least 3–4 days per week in adulthood can reduce the risk of developing cutaneous squamous cell carcinoma and melanoma but does not appear to reduce the risk of basal cell carcinoma (BCC) overall, although it may reduce the occurrence of multiple BCCs over time
  • A call to standardise the BCC:SCC ratio

    Jiyad, Z.; Marquart, L.; Green, Adèle C; Dermatology Unit, St George's University of London, London, UK. (2020)
    Basal cell carcinoma (BCC) followed by squamous cell carcinoma (SCC) are the two commonest cancers in white populations worldwide.1 While sharing some features, they are distinct clinically and pathologically and thus the ratio of BCC to SCC incidence rates serves as a useful composite that enables immediate comparisons of trends within and between populations. There is a widely held belief that the BCC:SCC ratio sits relatively constantly at around 4:1 in the general population, though this belief has little apparent basis.
  • Density compensated diodes for small field dosimetry: comprehensive testing and implications for design

    Georgiou, G.; Kumar, S.; Wurfel, J. U.; Underwood, Tracy; Thompson, J. M.; Hill, M. A.; Rowbottom, C. G.; Fenwick, J. D.; Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool,Liverpool L69 3BX (2020)
    Purpose: In small megavoltage photon fields, the accuracies of an unmodified PTW 60017-type diode dosimeter and six diodes modified by adding airgaps of thickness 0.6-1.6 mm and diameter 3.6 mm have been comprehensively characterized experimentally and computationally. The optimally thick airgap for density compensation was determined, and detectors were micro-CT imaged to investigate differences between experimentally measured radiation responses and those predicted computationally. Methods: Detectors were tested onand off-axis, at 5 and 15 cm depths in 6 and 15 MV fields ≥ 0.5 × 0.5 cm2. Computational studies were carried out using the EGSnrc/BEAMnrc Monte Carlo radiation transport code. Experimentally, radiation was delivered using a Varian TrueBeam linac and doses absorbed by water were measured using Gafchromic EBT3 film and ionization chambers, and compared with diode readings. Detector response was characterized via the [Formula: see text] formalism, choosing a 4 × 4 cm2 reference field. Results: For the unmodified 60017 diode, the maximum error in small field doses obtained from diode readings uncorrected by [Formula: see text] factors was determined as 11.9% computationally at +0.25 mm off-axis and 5 cm depth in a 15 MV 0.5 × 0.5 cm2 field, and 11.7% experimentally at -0.30 mm off-axis and 5 cm depth in the same field. A detector modified to include a 1.6 mm thick airgap performed best, with maximum computationally and experimentally determined errors of 2.2% and 4.1%. The 1.6 mm airgap deepened the modified dosimeter's effective point of measurement by 0.5 mm. For some detectors significant differences existed between responses in small fields determined computationally and experimentally, micro-CT imaging indicating that these differences were due to within-tolerance variations in the thickness of an epoxy resin layer. Conclusions: The dosimetric performance of a 60017 diode detector was comprehensively improved throughout 6 and 15 MV small photon fields via density compensation. For this approach to work well with good detector-to-detector reproducibility, tolerances on dense component dimensions should be reduced to limit associated variations of response in small fields, or these components should be modified to have more water-like densities.
  • Gene-specific linear trends constrain transcriptional variability of the toll-like receptor signaling

    Bagnall, J.; Rowe, W.; Alachkar, N.; Roberts, J.; England, H.; Clark, Christopher; Platt, M.; Jackson, D. A.; Muldoon, M.; Paszek, P.; et al. (2020)
    Single-cell gene expression is inherently variable, but how this variability is controlled in response to stimulation remains unclear. Here, we use single-cell RNA-seq and single-molecule mRNA counting (smFISH) to study inducible gene expression in the immune toll-like receptor system. We show that mRNA counts of tumor necrosis factor α conform to a standard stochastic switch model, while transcription of interleukin-1β involves an additional regulatory step resulting in increased heterogeneity. Despite different modes of regulation, systematic analysis of single-cell data for a range of genes demonstrates that the variability in transcript count is linearly constrained by the mean response over a range of conditions. Mathematical modeling of smFISH counts and experimental perturbation of chromatin state demonstrates that linear constraints emerge through modulation of transcriptional bursting along with gene-specific relationships. Overall, our analyses demonstrate that the variability of the inducible single-cell mRNA response is constrained by transcriptional bursting.
  • Omega-3 fatty acid intake and decreased risk of skin cancer in organ transplant recipients

    Miura, K.; Way, M.; Jiyad, Z.; Marquart, L.; Plasmeijer, E. I.; Campbell, S.; Isbel, N.; Fawcett, J.; Ferguson, L. E.; Davis, M.; et al. (2020)
    Purpose: Organ transplant recipients have over 100-fold higher risk of developing skin cancer than the general population and are in need of further preventive strategies. We assessed the possible preventive effects of omega-3 polyunsaturated fatty acid (PUFA) intake from food on the two main skin cancers, squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) in kidney and liver transplant recipients. Methods: Adult kidney or liver transplant recipients transplanted for at least 1 year and at high risk of skin cancer were recruited from the main transplant hospital in Queensland, 2012-2014 and followed until mid-2016. We estimated their dietary total long-chain omega-3 PUFAs and α-linolenic acid intakes at baseline using a food frequency questionnaire and ranked PUFA intakes as low, medium, or high. Relative risks (RRsadj) of skin cancer adjusted for confounding factors with 95% confidence intervals (CIs) were calculated. Results: There were 449 transplant recipients (mean age, 55 years; 286 (64%) male). During follow-up, 149 (33%) patients developed SCC (median 2/person; range 1-40) and 134 (30%), BCC. Transplant recipients with high total long-chain omega-3 PUFA compared with low intakes showed substantially reduced SCC tumour risk (RRadj 0.33, 95% CI 0.18-0.60), and those with high α-linolenic acid intakes experienced significantly fewer BCCs (RRadj 0.40, 95% CI 0.22-0.74). No other significant associations were seen. Conclusion: Among organ transplant recipients, relatively high intakes of long-chain omega-3 PUFAs and of α-linolenic acid may reduce risks of SCC and BCC, respectively.
  • Resolution of R-loops by INO80 promotes DNA replication and maintains cancer cell proliferation and viability

    Prendergast, Lisa; McClurg, U. L.; Hristova, R.; Berlinguer-Palmini, R.; Greener, S.; Veitch, K.; Hernandez, I.; Pasero, P.; Rico, D.; Higgins, J. M. G.; et al. (2020)
    Collisions between the DNA replication machinery and co-transcriptional R-loops can impede DNA synthesis and are a major source of genomic instability in cancer cells. How cancer cells deal with R-loops to proliferate is poorly understood. Here we show that the ATP-dependent chromatin remodelling INO80 complex promotes resolution of R-loops to prevent replication-associated DNA damage in cancer cells. Depletion of INO80 in prostate cancer PC3 cells leads to increased R-loops. Overexpression of the RNA:DNA endonuclease RNAse H1 rescues the DNA synthesis defects and suppresses DNA damage caused by INO80 depletion. R-loops co-localize with and promote recruitment of INO80 to chromatin. Artificial tethering of INO80 to a LacO locus enabled turnover of R-loops in cis. Finally, counteracting R-loops by INO80 promotes proliferation and averts DNA damage-induced death in cancer cells. Our work suggests that INO80-dependent resolution of R-loops promotes DNA replication in the presence of transcription, thus enabling unlimited proliferation in cancers.
  • Destructive and topical treatments of skin lesions in organ transplant recipients and relation to skin cancer

    Green, Adèle C; Way, M.; Oster, M.; Plasmeijer, E. I.; Jiyad, Z.; O'Rourke, P.; Miura, K.; Campbell, S.; Isbel, N.; Chambers, D. C.; et al. (2020)
    Various treatments of keratotic skin lesions and early skin cancers are performed in organ transplant recipients (OTRs) at high risk of skin malignancies but the frequency of their use is unknown. We prospectively assessed the frequency of use of cryotherapy, diathermy, and topical therapies and also investigated their associations with background incidence of histologically-confirmed squamous-cell carcinoma (SCC) and basal cell carcinoma (BCC) in a cohort of OTRs in Queensland, Australia. Median follow-up ranged from 1.7 to 3.2 years across organ transplant groups. Among 285 kidney, 125 lung and 203 liver transplant recipients [382 (62%) male, 380 (62%) immunosuppressed > 5 years, 394 (64%) previously diagnosed with skin cancer], 306 (50%) reported treatment of skin lesions with major types of non-excision therapies during follow-up: 278 (45%) cryotherapy or diathermy; 121 (20%) topical treatments. Of these 306, 150 (49%) developed SCC at double the incidence of those who did not receive these treatments, as assessed by incidence rate ratio (IRR) adjusted for age, sex, type of organ transplant, skin color and history of skin cancer at baseline, calculated by multivariable Poisson regression (IRRadj = 2.1, 95% confidence interval (CI) 1.4-3.1). BCC incidence was not associated with these therapies. Skin lesions in OTRs that are treated with cryotherapy, diathermy, or topical treatment warrant judicious selection and careful follow-up.
  • Chronic myelomonocytic leukaemia stem cell transcriptomes anticipate disease morphology and outcome

    Wiseman, Daniel H; Baker, S. M.; Dongre, Arundhati V|Gurashi, Kristian; Storer, Joanna A; Somervaille, Tim CP; Batta, Kiran; Epigenetics of Haematopoiesis Laboratory, Division of Cancer Sciences, The University of Manchester, Manchester M20 4GJ, UK. (2020)
    Background: Chronic myelomonocytic leukaemia (CMML) is a clinically heterogeneous stem cell malignancy with overlapping features of myelodysplasia and myeloproliferation. Over 90% of patients carry mutations in epigenetic and/or splicing genes, typically detectable in the Lin-CD34+CD38- immunophenotypic stem cell compartment in which the leukaemia-initiating cells reside. Transcriptional dysregulation at the stem cell level is likely fundamental to disease onset and progression. Methods: We performed single-cell RNA sequencing on 6826 Lin-CD34+CD38-stem cells from CMML patients and healthy controls using the droplet-based, ultra-high-throughput 10x platform. Findings: We found substantial inter- and intra-patient heterogeneity, with CMML stem cells displaying distinctive transcriptional programs. Compared with normal controls, CMML stem cells exhibited transcriptomes characterized by increased expression of myeloid-lineage and cell cycle genes, and lower expression of genes selectively expressed by normal haematopoietic stem cells. Neutrophil-primed progenitor genes and a MYC transcription factor regulome were prominent in stem cells from CMML-1 patients, whereas CMML-2 stem cells exhibited strong expression of interferon-regulatory factor regulomes, including those associated with IRF1, IRF7 and IRF8. CMML-1 and CMML-2 stem cells (stages distinguished by proportion of downstream blasts and promonocytes) differed substantially in both transcriptome and pseudotime, indicating fundamentally different biology underpinning these disease states. Gene expression and pathway analyses highlighted potentially tractable therapeutic vulnerabilities for downstream investigation. Importantly, CMML patients harboured variably-sized subpopulations of transcriptionally normal stem cells, indicating a potential reservoir to restore functional haematopoiesis. Interpretation: Our findings provide novel insights into the CMML stem cell compartment, revealing an unexpected degree of heterogeneity and demonstrating that CMML stem cell transcriptomes anticipate disease morphology, and therefore outcome. Funding: Project funding was supported by Oglesby Charitable Trust, Cancer Research UK, Blood Cancer UK, and UK Medical Research Council. Keywords: CMML; Leukaemia; Stem cells; sc-RNA Seq.
  • Investigating the importance of B cells and antibodies during Trichuris muris infection using the IgMi mouse

    Sahputra, R.; Murphy, E. A.; Forman, R.; Mair, I.; Fadlullah, Muhammad ZH; Waisman, A.; Muller, W.; Else, K. J.; Division of Infection, Immunity and Respiratory Medicine, Lydia Becker Institute for Immunology, The University of Manchester, Manchester, UK. (2020)
    The IgMi mouse has normal B cell development; its B cells express an IgM B cell receptor but cannot class switch or secrete antibody. Thus, the IgMi mouse offers a model system by which to dissect out antibody-dependent and antibody-independent B cell function. Here, we provide the first detailed characterisation of the IgMi mouse post-Trichuris muris (T. muris) infection, describing expulsion phenotype, cytokine production, gut pathology and changes in T regulatory cells, T follicular helper cells and germinal centre B cells, in addition to RNA sequencing (RNA seq) analyses of wild-type littermates (WT) and mutant B cells prior to and post infection. IgMi mice were susceptible to a high-dose infection, with reduced Th2 cytokines and elevated B cell-derived IL-10 in mesenteric lymph nodes (MLN) compared to controls. A low-dose infection regime revealed IgMi mice to have significantly more apoptotic cells in the gut compared to WT mice, but no change in intestinal inflammation. IL-10 levels were again elevated. Collectively, this study showcases the potential of the IgMi mouse as a tool for understanding B cell biology and suggests that the B cell plays both antibody-dependent and antibody-independent roles post high- and low-dose T. muris infection. KEY MESSAGES: During a high-dose T. muris infection, B cells are important in maintaining the Th1/Th2 balance in the MLN through an antibody-independent mechanism. High levels of IL-10 in the MLN early post-infection, and the presence of IL-10-producing B cells, correlates with susceptibility to T. muris infection. B cells maintain gut homeostasis during chronic T. muris infection via an antibody-dependent mechanism. Keywords: B cells; IgMi mouse; Interleukin-10; Intestinal pathology; Th1/Th2; Trichuris muris.
  • Prostate cancer heterogeneity assessment with multi-regional sampling and alignment-free methods

    Murphy, R. G.; Roddy, A. C.; Srivastava, S.; Baena, Esther; Waugh, D. J.; J, M. O. S.; McArt, D. G.; Jain, S.; LaBonte, M. J.; Movember FASTMAN Centre of Excellence, Patrick G Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast BT9 7AE, UK. (2020)
    Combining alignment-free methods for phylogenetic analysis with multi-regional sampling using next-generation sequencing can provide an assessment of intra-patient tumour heterogeneity. From multi-regional sampling divergent branching, we validated two different lesions within a patient's prostate. Where multi-regional sampling has not been used, a single sample from one of these areas could misguide as to which drugs or therapies would best benefit this patient, due to the fact these tumours appear to be genetically different. This application has the power to render, in a fraction of the time used by other approaches, intra-patient heterogeneity and decipher aberrant biomarkers. Another alignment-free method for calling single-nucleotide variants from raw next-generation sequencing samples has determined possible variants and genomic locations that may be able to characterize the differences between the two main branching patterns. Alignment-free approaches have been applied to relevant clinical multi-regional samples and may be considered as a valuable option for comparing and determining heterogeneity to help deliver personalized medicine through more robust efforts in identifying targetable pathways and therapeutic strategies. Our study highlights the application these tools could have on patient-aligned treatment indications.
  • Mechanisms of drug resistance mediated by long non-coding RNAs in non-small-cell lung cancer

    La Montagna, Manuela; Ginn, Lucy; Garofalo, Michela; Transcriptional Networks in Lung Cancer Group, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Manchester, SK10 4TG, UK. (2020)
    Non-small-cell lung cancer (NSCLC) is the most prevalent form of lung cancer and has a poor five-year survival rate of 15%. Chemotherapy and targeted therapies have significantly improved patients' prognosis. Nevertheless, after a successful initial response, some patients relapse when cancer cells become resistant to drug treatments, representing an important clinical limitation. Therefore, investigating the mechanisms of drug resistance is of significant importance. Recently, considerable attention has been given to long non-coding RNAs (lncRNAs), a heterogeneous class of regulatory molecules that play essential roles in tumorigenesis by modulating genes and signalling pathways involved in cell growth, metastasis and drug response. In this article, we review recent research findings on the role of lncRNAs in drug resistance in NSCLC, highlighting their mechanisms of action.
  • Alternative enhancer usage and targeted polycomb marking hallmark promoter choice during t cell differentiation

    Maqbool, M. A.; Pioger, L.; El Aabidine, A. Z.; Karasu, N.; Molitor, A. M.; Dao, L. T. M.; Charbonnier, G.; van Laethem, F.; Fenouil, R.; Koch, F.; et al. (2020)
    During thymic development and upon peripheral activation, T cells undergo extensive phenotypic and functional changes coordinated by lineage-specific developmental programs. To characterize the regulatory landscape controlling T cell identity, we perform a wide epigenomic and transcriptional analysis of mouse thymocytes and naive CD4 differentiated T helper cells. Our investigations reveal a dynamic putative enhancer landscape, and we could validate many of the enhancers using the high-throughput CapStarr sequencing (CapStarr-seq) approach. We find that genes using multiple promoters display increased enhancer usage, suggesting that apparent "enhancer redundancy" might relate to isoform selection. Furthermore, we can show that two Runx3 promoters display long-range interactions with specific enhancers. Finally, our analyses suggest a novel function for the PRC2 complex in the control of alternative promoter usage. Altogether, our study has allowed for the mapping of an exhaustive set of active enhancers and provides new insights into their function and that of PRC2 in controlling promoter choice during T cell differentiation. Keywords: CapSTARR-seq; T cell enhancerome; enhancer and promoter usage; enhancer redundancy; long-distance enhancer-promoter interactions.

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