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  • Tissue-resident FOLR2(+) macrophages associate with CD8(+) T cell infiltration in human breast cancer

    Nalio Ramos, R.; Missolo-Koussou, Y.; Gerber-Ferder, Y.; Bromley, C. P.; Bugatti, M.; Núñez, N. G.; Tosello Boari, J.; Richer, W.; Menger, L.; Denizeau, J.; et al. (2022)
    Macrophage infiltration is a hallmark of solid cancers, and overall macrophage infiltration correlates with lower patient survival and resistance to therapy. Tumor-associated macrophages, however, are phenotypically and functionally heterogeneous. Specific subsets of tumor-associated macrophage might be endowed with distinct roles on cancer progression and antitumor immunity. Here, we identify a discrete population of FOLR2+ tissue-resident macrophages in healthy mammary gland and breast cancer primary tumors. FOLR2+ macrophages localize in perivascular areas in the tumor stroma, where they interact with CD8+ T cells. FOLR2+ macrophages efficiently prime effector CD8+ T cells ex vivo. The density of FOLR2+ macrophages in tumors positively correlates with better patient survival. This study highlights specific roles for tumor-associated macrophage subsets and paves the way for subset-targeted therapeutic interventions in macrophages-based cancer therapies.
  • The economics of skin cancer prevention with implications for Australia and New Zealand: where are we now?

    Gordon, L. G.; Shih, S.; Watts, C.; Goldsbury, D.; Green, A. C. (2022)
    The incidence of skin cancer, including melanoma, continues to climb in white populations around the world, imposing a large and growing burden on health systems and individuals. Harmful exposure to ultraviolet (UV) radiation, mostly solar UV, is the most avoidable cause of skin cancer risk and mortality. Many economic evaluations attest to the favourable benefits for governments and citizens from skin cancer prevention programs. This overview presents the current ‘state of play’ of the economics of skin cancer prevention. More research is required to document contemporary costs of managing skin cancer in Australia and New Zealand to accurately assess the true savings from primary prevention. New directions are proposed for ways that economics could contribute to the investment case for prevention. The majority of skin cancers are avoidable and curable, yet cost the Australian health economy A$1.7 billion each year. Therefore primary prevention of skin cancers must remain high on the public health agenda.
  • Prevalence of cataract among Australian commercial airline pilots

    Miura, K.; Coroneo, M.; Dusingize, J. C.; Olsen, C. M.; Tinker, R.; Karipidis, K.; Hosegood, I.; Green, A. C. (2022)
    Because little is known about cataract in pilots, we estimated prevalence by anonymously ascertaining all commercial airline pilots diagnosed with cataract 2011–2016 using the electronic Medical Records System of the Australian Civil Aviation Safety Authority. Of 14,163 Australian male commercial pilots licensed in 2011, 1286 aged ≥60 had biennial eye examinations showing a cataract prevalence of 11.6%. Among 12,877 pilots aged <60, based on compulsory eye examinations only when first licensed, prevalence was 0.5%. There was no significant difference by ambient ultraviolet (UV) radiation levels in state of residence though lowest prevalence was seen in the low-UV state of Victoria. Most cataract in pilots ≥60 years was bilateral and of mild severity, while cataract in pilots <60 were more likely to be unilateral and of greater severity.
  • NMR Molecular Replacement Provides New Insights into Binding Modes to Bromodomains of BRD4 and TRIM24

    Torres, F.; Walser, R.; Kaderli, J.; Rossi, E.; Bobby, R.; Packer, M. J.; Sarda, S.; Walker, G.; Hitchin, J. R.; Milbradt, A. G.; et al. (2022)
    Structure-based drug discovery (SBDD) largely relies on structural information from X-ray crystallography because traditional NMR structure calculation methods are too time consuming to be aligned with typical drug discovery timelines. The recently developed NMR molecular replacement (NMR2) method dramatically reduces the time needed to generate ligand–protein complex structures using published structures (apo or holo) of the target protein and treating all observed NOEs as ambiguous restraints, bypassing the laborious process of obtaining sequence-specific resonance assignments for the protein target. We apply this method to two therapeutic targets, the bromodomain of TRIM24 and the second bromodomain of BRD4. We show that the NMR2 methodology can guide SBDD by rationalizing the observed SAR. We also demonstrate that new types of restraints and selective methyl labeling have the potential to dramatically reduce “time to structure” and extend the method to targets beyond the reach of traditional NMR structure elucidation.
  • Keratinocyte cancer incidence in Australia: a review of population-based incidence trends and estimates of lifetime risk

    Olsen, C. M.; Pandeya, N.; Green, A. C.; Ragaini, B. S.; Venn, A. J.; Whiteman, D. C. (2022)
    Objectives: To review the most recent population-based estimates of keratinocyte cancer incidence in Australia, to describe the trends over time and to calculate lifetime risk of developing these skin cancers. Methods: We conducted a literature search of PubMed/MEDLINE from 2001 to August 2021 to identify relevant literature. We defined eligible articles as those reporting population-based studies of adults and excluded studies that reported only on high-risk or paediatric populations, or on incidence of precursor or related lesions. We summarised identified studies qualitatively. We calculated lifetime risk of developing keratinocyte cancer using the methods of Cancer Research UK, adjusting for multiple primaries and the competing risk of death. Results: We identified six eligible studies. In the absence of compulsory notifications of keratinocyte cancer to state and territory cancer registries in Australia, all estimates of national incidence rates of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) have limitations. The most recent population-based estimates of people annually affected for the period 2011–2014 (BCC: 770/100 000 person years; SCC: 271/100 000 person years) represent the lower end of the possible range of incidence rates nationally. Because many people are affected by multiple lesions, the lesion-based incidence estimates are more than double the person-based rates (BCC: 1565/100 000 person years; SCC: 580/100 000 person years). Analyses of temporal trends in treatment rates (excisions, cryotherapy/curettage) show increases over time, most marked for people aged 55 years or older. We estimate that 69% of Australians will have at least one excision for histologically confirmed keratinocyte cancer in their lifetime (60% to age 79 years). Conclusion: The available evidence on national incidence rates is out of date and of moderate quality, but indicates very high rates of keratinocyte cancer in Australia. We recommend that population-based cancer registries work towards statutory notification and routine reporting of keratinocyte cancer in Australia.
  • Effectiveness, compliance and application of sunscreen for solar ultraviolet radiation protection in Australia

    Henderson, S. I.; King, K. L.; Karipidis, K. K.; Tinker, R. A.; Green, A. C. (2022)
    Objectives and importance of study: Sunscreens are widely used, not only to prevent acute sunburn, but also for skin cancer prevention and protection against photoaging and other skin conditions related to cumulative solar ultraviolet radiation (UVR) exposure. When correctly applied, sunscreens reduce the amount of UVR reaching the skin and therefore they can reduce harmful effects of such exposures. This paper examines the benefits and risks of sunscreens, compliance requirements and how sunscreen should be used for optimal effectiveness. Study type: Narrative review. Methods: We reviewed evidence relating to the benefits and risks of sunscreens, sunscreen manufacturing compliance, consumer usage of sunscreen and how sunscreen should be used to be most effective. Results: There is strong evidence that sunscreen is safe to use and, when applied correctly, reduces the risk of skin cancer. There is a need to address questions about the impact of sunscreen on vitamin D and its risk to the environment, as well as a need to develop sun protection factor (SPF) sunscreen testing methods that are more reproducible and ethically based. The amount of sunscreen and the way it is applied varies considerably between individuals, and this in turn markedly affects the degree and duration of protection received. Sunscreen should be used in combination with other sun protection measures that include clothing, hats, sunglasses and seeking shade. Conclusions: Regulation is essential to ensure high-quality, safe and effective sunscreen products are available to the Australian population. There is an important role for governments to put in place skin cancer prevention policies and long-term funding arrangements to build on our successful sunscreen programs so that future generations are afforded the highest level of topical protection against solar UVR.
  • Early detection of cancer

    Crosby, D.; Bhatia, S.; Brindle, K. M.; Coussens, L. M.; Dive, C.; Emberton, M.; Esener, S.; Fitzgerald, R. C.; Gambhir, S. S.; Kuhn, P.; et al. (2022)
    Survival improves when cancer is detected early. However, ~50% of cancers are at an advanced stage when diagnosed. Early detection of cancer or precancerous change allows early intervention to try to slow or prevent cancer development and lethality. To achieve early detection of all cancers, numerous challenges must be overcome. It is vital to better understand who is at greatest risk of developing cancer. We also need to elucidate the biology and trajectory of precancer and early cancer to identify consequential disease that requires intervention. Insights must be translated into sensitive and specific early detection technologies and be appropriately evaluated to support practical clinical implementation. Interdisciplinary collaboration is key; advances in technology and biological understanding highlight that it is time to accelerate early detection research and transform cancer survival.
  • Diagnosis and treatment of nail melanoma: a review of the clinicopathologic, dermoscopic, and genetic characteristics

    Darmawan, C. C.; Ohn, J.; Mun, J. H.; Kim, S.; Lim, Y.; Jo, S. J.; Kim, Y. G.; Kim, B.; Seong, M. W.; Kim, B. J.; et al. (2022)
    Nail melanoma (NM) is an important differential diagnosis in patients with longitudinal melanonychia. However, diagnosis is often challenging as it is difficult to differentiate from other pigmented nail disorders. The main challenge for diagnosis is obtaining adequate nail matrix biopsy specimens for histopathological assessment. Furthermore, the histopathological changes in the early stages of NM are subtle and contribute to a delay in diagnosis and care. Therefore, the integration of clinical and histopathological analyses is essential. Clinical and dermoscopic features, such as a broadened width of asymmetric bands in an irregular pattern, with multicolour pigmentation, periungual pigmentation, and continuous growth, are features that support the diagnosis of NM. The essential histological features that must be assessed are cellular morphology, architectural features, melanocyte density, and inflammatory changes. The reported mutations in NMs were BRAF (0–43%), NRAS (0–31%), KIT (0–50%), NF1 (0–50%), and GNAQ (0–25%). Surgery is the primary treatment for NM. The recommended treatment for in situ or minimally invasive NM is functional surgery, but cases with suspected bone invasion should be treated with amputation. Targeted therapy and immunotherapy are indicated for advanced stages of NM. This review summarizes the updated guidelines for the diagnosis and treatment of NM.
  • RNA sensing via the RIG-I-like receptor LGP2 is essential for the induction of a type I IFN response in ADAR1 deficiency

    Stok, J. E.; Oosenbrug, T.; Ter Haar, L. R.; Gravekamp, D.; Bromley, C. P.; Zelenay, S.; Reis, E. S. C.; van der Veen, A. G.; Department of Immunology, Leiden University Medical Centre, Leiden, The Netherlands. Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, UK. Immunobiology Laboratory, The Francis Crick Institute, London, UK. (2022)
    RNA editing by the adenosine deaminase ADAR1 prevents innate immune responses to endogenous RNAs. In ADAR1-deficient cells, unedited self RNAs form base-paired structures that resemble viral RNAs and inadvertently activate the cytosolic RIG-I-like receptor (RLR) MDA5, leading to an antiviral type I interferon (IFN) response. Mutations in ADAR1 cause Aicardi-Goutières Syndrome (AGS), an autoinflammatory syndrome characterized by chronic type I IFN production. Conversely, ADAR1 loss and the consequent type I IFN production restricts tumor growth and potentiates the activity of some chemotherapeutics. Here, we show that another RIG-I-like receptor, LGP2, also has an essential role in the induction of a type I IFN response in ADAR1-deficient human cells. This requires the canonical function of LGP2 as an RNA sensor and facilitator of MDA5-dependent signaling. Furthermore, we show that the sensitivity of tumor cells to ADAR1 loss requires LGP2 expression. Finally, type I IFN induction in tumor cells depleted of ADAR1 and treated with some chemotherapeutics fully depends on LGP2 expression. These findings highlight a central role for LGP2 in self RNA sensing with important clinical implications.
  • Chemoprevention of cutaneous squamous cell carcinoma and its precursors in solid organ transplant recipients using topical sirolimus: a randomized, double-blind, placebo-controlled pilot trial

    Chong, S.; Wong, H. Y.; Althabteh, A.; Cox, C.; Stevenson, P.; Brown, S.; Griffin, A.; Isbel, N.; Siller, G.; Soyer, H. P.; et al. (2022)
  • Conversations with LGBT+ scientists about visibility, leadership and climbing the career ladder

    Bristow, R. G.; Engel, J.; Jayasinghe, I.; Kampmann, M.; James Sansom, O.; Bryant, D. M.; CRUK Manchester Institute and Manchester Cancer Research Centre, University of Manchester, Manchester M20 4GJ, UK. Department of Medicine, and Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA. Division of Molecular & Cellular Biology, School of Biosciences, The University of Sheffield, Sheffield S10 2TN, UK. Institute for Neurodegenerative Diseases, Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA. Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK. Institute of Cancer Sciences, The University of Glasgow, Glasgow G61 1QH, UK. (2022)
    February is LGBT+ history month, and to celebrate, Journal of Cell Science Editorial Advisory Board member David Bryant organised a conversation with a selection of scientists to explore their experiences of being LGBT+ in academia.
  • Link Between Obesity and Early-Onset Colorectal Cancers (EOCRC): Importance of Accounting for BMI Trajectories in Early Life

    Hawwash, N.; Martin, G. P.; Sperrin, M.; Renehan, A. G.; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom. Cancer Research UK Manchester Cancer Research Centre, Manchester, United Kingdom. Centre for Health Informatics, Division of Informatics, Imaging and Data Sciences, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom. National Institute for Health Research (NIHR) Manchester Biomedical Research Centre, Manchester, United Kingdom. (2022)
  • Biomarker identification using dynamic time warping analysis: a longitudinal cohort study of patients with COVID-19 in a UK tertiary hospital

    Burke, H.; Freeman, A.; O'Regan, P.; Wysocki, O.; Freitas, A.; Dushianthan, A.; Celinski, M.; Batchelor, J.; Phan, H.; Borca, F.; et al. (2022)
    Objectives COVID-19 is a heterogeneous disease, and many reports have described variations in demographic, biochemical and clinical features at presentation influencing overall hospital mortality. However, there is little information regarding longitudinal changes in laboratory prognostic variables in relation to disease progression in hospitalised patients with COVID-19. Design and setting This retrospective observational report describes disease progression from symptom onset, to admission to hospital, clinical response and discharge/death among patients with COVID-19 at a tertiary centre in South East England. Participants Six hundred and fifty-one patients treated for SARS-CoV-2 between March and September 2020 were included in this analysis. Ethical approval was obtained from the HRA Specific Review Board (REC 20/HRA/2986) for waiver of informed consent. Results The majority of patients presented within 1 week of symptom onset. The lowest risk patients had low mortality (1/45, 2%), and most were discharged within 1 week after admission (30/45, 67%). The highest risk patients, as determined by the 4C mortality score predictor, had high mortality (27/29, 93%), with most dying within 1 week after admission (22/29, 76%). Consistent with previous reports, most patients presented with high levels of C reactive protein (CRP) (67% of patients >50 mg/L), D-dimer (98%>upper limit of normal (ULN)), ferritin (65%>ULN), lactate dehydrogenase (90%>ULN) and low lymphocyte counts (81%<lower limit of normal (LLN)). Increases in platelet counts and decreases in CRP, neutrophil:lymphocyte ratio (p<0.001), lactate dehydrogenase, neutrophil counts, urea and white cell counts (all p<0.01) were each associated with discharge. Conclusions Serial measurement of routine blood tests may be a useful prognostic tool for monitoring treatment response in hospitalised patients with COVID-19. Changes in other biochemical parameters often included in a ‘COVID-19 bundle’ did not show significant association with outcome, suggesting there may be limited clinical benefit of serial sampling. This may have direct clinical utility in the context of escalating healthcare costs of the pandemic.
  • Activating RAC1 variants in the switch II region cause a developmental syndrome and alter neuronal morphology

    Banka, S.; Bennington, A.; Baker, M. J.; Rijckmans, E.; Clemente, G. D.; Ansor, N. M.; Sito, H.; Prasad, P.; Anyane-Yeboa, K.; Badalato, L.; et al. (2022)
    RAC1 is a highly conserved Rho GTPase critical for several cellular and developmental processes. De novo missense RAC1 variants cause a highly variable neurodevelopmental disorder. Some of these variants have been previously shown to have a dominant negative effect. Most previously reported patients with this disorder have either severe microcephaly or severe macrocephaly. Here we describe eight patients with pathogenic missense RAC1 variants affecting residues between Q61 and R68 within the switch II region of RAC1. These patients display variable combinations of developmental delay, intellectual disability, brain anomalies such as polymicrogyria, and cardiovascular defects with normocephaly or relatively milder micro- or macrocephaly. Pulldown assays, NIH3T3 fibroblasts spreading assays and staining for activated PAK1/2/3 and WAVE2 suggest that these variants increase RAC1 activity and over-activate downstream signalling targets. Axons of neurons isolated from Drosophila embryos expressing the most common of the activating variants are significantly shorter, with an increased density of filopodial protrusions. In vivo, these embryos exhibit frequent defects in axonal organization. Class IV dendritic arborisation neurons expressing this variant exhibit a significant reduction in the total area of the dendritic arbour, increased branching and failure of self-avoidance. RNAi knock down of the WAVE regulatory complex component Cyfip significantly rescues these morphological defects. These results establish that activating substitutions affecting residues Q61-R68 within the switch II region of RAC1 cause developmental syndrome. Our findings reveal that these variants cause altered downstream signalling resulting in abnormal neuronal morphology and reveal the WAVE regulatory complex/Arp2/3 pathway as a possible therapeutic target for activating RAC1 variants. These insights also have the potential to inform the mechanism and therapy for other disorders caused by variants in genes encoding other Rho GTPases, their regulators and downstream effectors.
  • Radiation-induced neuroinflammation: a potential protective role for poly(ADP-ribose) polymerase inhibitors?

    Gutierrez-Quintana, R.; Walker, D. J.; Williams, K. J.; Forster, D. M.; Chalmers, A. J.; Institute of Cancer Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. Division of Pharmacy and Optometry, School of Health Sciences, Manchester Cancer Research Centre, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK. Division of Informatics, Imaging and Data Sciences, Manchester Molecular Imaging Centre, The University of Manchester, Manchester, UK. (2022)
    Radiotherapy (RT) plays a fundamental role in the treatment of glioblastoma (GBM). GBM are notoriously invasive and harbor a subpopulation of cells with stem-like features which exhibit upregulation of the DNA damage response (DDR) and are radioresistant. High radiation doses are therefore delivered to large brain volumes and are known to extend survival but also cause delayed toxicity with 50%–90% of patients developing neurocognitive dysfunction. Emerging evidence identifies neuroinflammation as a critical mediator of the adverse effects of RT on cognitive function. In addition to its well-established role in promoting repair of radiation-induced DNA damage, activation of poly(ADP-ribose) polymerase (PARP) can exacerbate neuroinflammation by promoting secretion of inflammatory mediators. Therefore, PARP represents an intriguing mechanistic link between radiation-induced activation of the DDR and subsequent neuroinflammation. PARP inhibitors (PARPi) have emerged as promising new agents for GBM when given in combination with RT, with multiple preclinical studies demonstrating radiosensitizing effects and at least 3 compounds being evaluated in clinical trials. We propose that concomitant use of PARPi could reduce radiation-induced neuroinflammation and reduce the severity of radiation-induced cognitive dysfunction while at the same time improving tumor control by enhancing radiosensitivity.
  • MiR-378a inhibits glucose metabolism by suppressing GLUT1 in prostate cancer

    Cannistraci, A.; Hascoet, P.; Ali, A.; Mundra, P.; Clarke, N. W.; Pavet, V.; Marais, R.; Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK. Genito-Urinary Cancer Research Group and the FASTMAN Prostate Cancer Centre for Excellence, Division of Cancer Sciences, Manchester Cancer Research Centre, The University of Manchester, 555 Wilmslow Road, Manchester, M20 4GJ, UK. The Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, UK. Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK. Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK. (2022)
    Prostate cancer (PCa) is the fifth leading cause of cancer related deaths worldwide, in part due to a lack of molecular stratification tools that can distinguish primary tumours that will remain indolent from those that will metastasise. Amongst potential molecular biomarkers, microRNAs (miRs) have attracted particular interest because of their high stability in body fluids and fixed tissues. These small non-coding RNAs modulate several physiological and pathological processes, including cancer progression. Herein we explore the prognostic potential and the functional role of miRs in localised PCa and their relation to nodal metastasis. We define a 7-miR signature that is associated with poor survival independently of age, Gleason score, pathological T state, N stage and surgical margin status and that is also prognostic for disease-free survival in patients with intermediate-risk localised disease. Within our 7-miR signature, we show that miR-378a-3p (hereafter miR-378a) levels are low in primary tumours compared to benign prostate tissue, and also lower in Gleason score 8–9 compared to Gleason 6–7 PCa. We demonstrate that miR-378a impairs glucose metabolism and reduces proliferation in PCa cells through independent mechanisms, and we identify glucose transporter 1 (GLUT1) messenger RNA as a direct target of miR-378a. We show that GLUT1 inhibition hampers glycolysis, leading to cell death. Our data provides a rational for a new PCa stratification strategy based on miR expression, and it reveals that miR-378a and GLUT1 are potential therapeutic targets in highly aggressive glycolytic PCa.
  • Dark Green Leafy Vegetable Intake, MTHFR Genotype, and Risk of Cutaneous Squamous Cell Carcinoma

    Hughes, M. C. B.; Antonsson, A.; Rodriguez-Acevedo, A. J.; Liyanage, U. E.; Green, A. C.; van der Pols, J. C.; QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia. University of Queensland Diamantina Institute, Woolloongabba, Queensland, Australia. CRUK Manchester Institute and Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom. Queensland University of Technology (QUT), Faculty of Health, School of Exercise and Nutrition Sciences, Brisbane, Queensland, Australia. (2022)
    Background: Evidence suggests that consumption of dark green leafy vegetables may influence the decrease in the risk of cutaneous squamous cell carcinoma (SCC). Dark green leafy vegetables contain folate as a main component among other nutrients; thus, we hypothesised that their possible observed protective effect on SCC, observed in previous studies, would be more evident in persons with specific genotypes related to folate metabolism. Methods: Genotyping of methylenetetrahydrofolate reductase (MTHFR) gene variants rs1801133 (C677T) and rs1801131 (A1298C) was carried out for 1,128 participants in an Australian community-based longitudinal study of skin cancer. Dietary intakes were assessed through repeated Food Frequency Questionnaires (1992–1996), and all incident skin cancers were recorded in 1992–2007 and histologically confirmed. We assessed associations between intake of dark green leafy vegetables and SCC development in strata defined by genotype, by calculating relative risks (RRs) with 95% confidence intervals (CIs) using generalised linear models with negative binomial distribution and person-years of follow-up as offset. Results: High versus low intake of dark green leafy vegetables was associated with a lower risk of SCC tumours in carriers of the C677T variant allele (RR = 0.42, 95% CI = 0.23–0.75), and within wild-type A1298C homozygotes (RR = 0.43, 95% CI = 0.22–0.85). Conclusion: The protective effect of dark green leafy vegetables on cutaneous SCC may be genotype-dependent. Folate metabolism-related gene polymorphisms should be considered when assessing the relation of green leafy vegetables to cancer risk.
  • Benchmarking small-variant genotyping in polyploids

    Cooke, D. P.; Wedge, D. C.; Lunter, G. (2022)
    Genotyping from sequencing is the basis of emerging strategies in the molecular breeding of polyploid plants. However, compared with the situation for diploids, in which genotyping accuracies are confidently determined with comprehensive benchmarks, polyploids have been neglected; there are no benchmarks measuring genotyping error rates for small variants using real sequencing reads. We previously introduced a variant calling method, Octopus, that accurately calls germline variants in diploids and somatic mutations in tumors. Here, we evaluate Octopus and other popular tools on whole-genome tetraploid and hexaploid data sets created using in silico mixtures of diploid Genome in a Bottle (GIAB) samples. We find that genotyping errors are abundant for typical sequencing depths but that Octopus makes 25% fewer errors than other methods on average. We supplement our benchmarks with concordance analysis in real autotriploid banana data sets.
  • Correction to: Nationwide randomised trial evaluating elective neck dissection for early stage oral cancer (SEND study) with meta-analysis and concurrent real-world cohort

    Hutchison, I. L.; Ridout, F.; Cheung, S. M. Y.; Shah, N.; Hardee, P.; Surwald, C.; Thiruchelvam, J.; Cheng, L.; Mellor, T. K.; Brennan, P. A.; et al. (2021)
  • Tracing Lung Cancer Risk Factors Through Mutational Signatures in Never-Smokers

    Landi, M. T.; Synnott, N. C.; Rosenbaum, J.; Zhang, T. W.; Zhu, B.; Shi, J. X.; Zhao, W.; Kebede, M.; Sang, J.; Choi, J.; et al. (2021)
    Epidemiologic studies often rely on questionnaire data, exposure measurement tools, and/or biomarkers to identify risk factors and the underlying carcinogenic processes. An emerging and promising complementary approach to investigate cancer etiology is the study of somatic “mutational signatures” that endogenous and exogenous processes imprint on the cellular genome. These signatures can be identified from a complex web of somatic mutations thanks to advances in DNA sequencing technology and analytical algorithms. This approach is at the core of the Sherlock-Lung study (2018–ongoing), a retrospective case-only study of over 2,000 lung cancers in never-smokers (LCINS), using different patterns of mutations observed within LCINS tumors to trace back possible exposures or endogenous processes. Whole genome and transcriptome sequencing, genome-wide methylation, microbiome, and other analyses are integrated with data from histological and radiological imaging, lifestyle, demographic characteristics, environmental and occupational exposures, and medical records to classify LCINS into subtypes that could reveal distinct risk factors. To date, we have received samples and data from 1,370 LCINS cases from 17 study sites worldwide and whole-genome sequencing has been completed on 1,257 samples. Here, we present the Sherlock-Lung study design and analytical strategy, also illustrating some empirical challenges and the potential for this approach in future epidemiologic studies.

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