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  • A polygenic two-hit hypothesis for prostate cancer

    Houlahan, K. E.; Livingstone, J.; Fox, N. S.; Kurganovs, N.; Zhu, H.; Sietsma Penington, J.; Jung, C. H.; Yamaguchi, T. N.; Heisler, L. E.; Jovelin, R.; et al. (2023)
    Prostate cancer is one of the most heritable cancers. Hundreds of germline polymorphisms have been linked to prostate cancer diagnosis and prognosis. Polygenic risk scores can predict genetic risk of a prostate cancer diagnosis. While these scores inform on the probability of developing a tumor, it remains unknown how germline risk influences the tumor molecular evolution. We cultivated a cohort of 1,250 localized European-descent patients with germline and somatic DNA profiling. Men of European descent with higher genetic risk were diagnosed earlier, had less genomic instability, and fewer driver genes mutated. Higher genetic risk was associated with better outcome. These data imply a polygenic "two-hit" model where germline risk reduces the number of somatic alterations required for tumorigenesis. These findings support further clinical studies of PRS as inexpensive and minimally invasive adjuncts to standard risk stratification. Further studies are required to interrogate generalizability to more ancestrally and clinically diverse populations.
  • Life-course trajectories of physical activity and melanoma risk in a large cohort of norwegian women

    Perrier, F.; Ghiasvand, R.; Lergenmuller, S.; Robsahm, T. E.; Green, Adèle C; Borch, K. B.; Sandanger, T. M.; Weiderpass, E.; Rueegg, C. S.; Veierød, M. B.; et al. (2022)
    Purpose: Physical activity (PA) is a cornerstone in disease prevention and varies throughout life. A pooled analysis of cohort studies and a meta-analysis of cohort studies found positive associations between PA and melanoma risk. However, previous studies focused on PA at specific ages and often lacked information on ultraviolet radiation (UVR) exposure. Using the population-based Norwegian Women and Cancer (NOWAC) cohort, including information on PA and UVR exposure, we estimated life-course PA trajectories from adolescence to adulthood and their associations with melanoma. Methods: Total PA across different domains (recreation, occupation, transport, household) was reported for ages 14 and 30 years, and when responding to the questionnaire (31-76 years) using a 10-point scale, validated to rank PA levels in Norwegian females. We estimated life-course PA trajectories using a latent class mixed model in 152,248 women divided into three subcohorts depending on age at questionnaire completion: 31-39 (n = 27,098), 40-49 (n = 52,515) and ≥50 years (n = 72,635). The unique 11-digit identity number of Norwegian citizens was used to link NOWAC to the Cancer Registry of Norway for information on cancer diagnoses, emigration and death. Associations between PA trajectories and melanoma risk were estimated in each subcohort using multivariable Cox regression. Results: Five classes of individual life-course PA trajectories were identified in subcohort 31-39 years (low, moderate, high, decreasing, increasing PA) and four in subcohorts 40-49 and ≥50 years (low, moderate, high, decreasing PA). No significant association was found between life-course PA trajectories and melanoma risk in any subcohort. Hazard ratios (95% confidence intervals) for the high versus moderate trajectory were 0.92 (0.66-1.29), 1.15 (0.97-1.37) and 0.90 (0.78-1.05) for subcohorts 31-39, 40-49 and ≥50 years, respectively. Conclusion: Our results do not support a positive association between PA and melanoma risk found in previous studies, which is important for public health guidelines promoting regular PA.
  • THOC5 complexes with DDX5, DDX17, and CDK12 to regulate R loop structures and transcription elongation rate

    Polenkowski, M.; Allister, A. B.; Burbano de Lara, S.; Pierce, A.; Geary, Bethany; El Bounkari, O.; Wiehlmann, L.; Hoffmann, A.; Whetton, A. D.; Tamura, T.; et al. (2023)
    THOC5, a member of the THO complex, is essential for the 3'processing of some inducible genes, the export of a subset of mRNAs and stem cell survival. Here we show that THOC5 depletion results in altered 3'cleavage of >50% of mRNAs and changes in RNA polymerase II binding across genes. THOC5 is recruited close to high-density polymerase II sites, suggesting that THOC5 is involved in transcriptional elongation. Indeed, measurement of elongation rates in vivo demonstrated decreased rates in THOC5-depleted cells. Furthermore, THOC5 is preferentially recruited to its target genes in slow polymerase II cells compared with fast polymerase II cells. Importantly chromatin-associated THOC5 interacts with CDK12 (a modulator of transcription elongation) and RNA helicases DDX5, DDX17, and THOC6 only in slow polymerase II cells. The CDK12/THOC5 interaction promotes CDK12 recruitment to R-loops in a THOC6-dependent manner. These data demonstrate a novel function of THOC5 in transcription elongation.
  • RAC1B function is essential for breast cancer stem cell maintenance and chemoresistance of breast tumor cells

    Chen, Fuhui; Gurler, Sevim B; Novo, D.; Selli, C.; Alferez, Denis G; Eroglu, Secil; Pavlou, Kyriaki; Zhang, Jingwei; Sims, A. H.; Humphreys, N. E.; et al. (2023)
    Breast cancer stem cells (BCSC) are presumed to be responsible for treatment resistance, tumor recurrence and metastasis of breast tumors. However, development of BCSC-targeting therapies has been held back by their heterogeneity and the lack of BCSC-selective molecular targets. Here, we demonstrate that RAC1B, the only known alternatively spliced variant of the small GTPase RAC1, is expressed in a subset of BCSCs in vivo and its function is required for the maintenance of BCSCs and their chemoresistance to doxorubicin. In human breast cancer cell line MCF7, RAC1B is required for BCSC plasticity and chemoresistance to doxorubicin in vitro and for tumor-initiating abilities in vivo. Unlike Rac1, Rac1b function is dispensable for normal mammary gland development and mammary epithelial stem cell (MaSC) activity. In contrast, loss of Rac1b function in a mouse model of breast cancer hampers the BCSC activity and increases their chemosensitivity to doxorubicin treatment. Collectively, our data suggest that RAC1B is a clinically relevant molecular target for the development of BCSC-targeting therapies that may improve the effectiveness of doxorubicin-mediated chemotherapy.
  • Delphi initiative for early-onset colorectal cancer (DIRECt). International Management Guidelines

    Cavestro Giulia, M.; Mannucci, A.; Balaguer, F.; Hampel, H.; Kupfer, S. S.; Repici, A.; Sartore-Bianchi, A.; Seppälä Toni, T.; Valentini, V.; Boland Clement, R.; et al. (2022)
    Background and aims: Patients with early-onset colorectal cancer (eoCRC) are managed according to guidelines that are not age-specific. A multidisciplinary international group (DIRECt), comprised of 69 experts, was convened to develop the first evidence-based consensus recommendations for eoCRC. Methods: After reviewing the published literature, a Delphi methodology was employed to draft and respond to clinically relevant questions. Each statement underwent 3 rounds of voting and reached a consensus level of agreement of ≥80%. Results: The DIRECt group produced 31 statements in 7 areas of interest: diagnosis, risk factors, genetics, pathology-oncology, endoscopy, therapy, and supportive care. There was strong consensus that all individuals younger than 50 should undergo CRC risk stratification and prompt symptom assessment. All newly diagnosed eoCRC patients should receive germline genetic testing, ideally before surgery. Based on current evidence, endoscopic, surgical, and oncologic treatment of eoCRC should not differ from later onset CRC, except for individuals with pathogenic or likely pathogenic germline variants. The evidence on chemotherapy is not sufficient to recommend changes to established therapeutic protocols. Fertility preservation and sexual health are important to address in eoCRC survivors.The DIRECt group highlighted areas with knowledge gaps that should be prioritized in future research efforts, including age at first screening for the general population, use of fecal immunochemical tests, chemotherapy, endoscopic therapy, and post-treatment surveillance for eoCRC patients. Conclusions: The DIRECt group produced the first consensus recommendations on eoCRC. All statements should be considered together with the accompanying comments and literature reviews. We highlighted areas where research should be prioritized. These guidelines represent a useful tool for clinicians caring for patients with eoCRC.
  • Cohort profile of the Sloane Project: methodology for a prospective UK cohort study of >15 000 women with screen-detected non-invasive breast neoplasia

    Clements, K.; Dodwell, D.; Hilton, B.; Stevens-Harris, I.; Pinder, S.; Wallis, M. G.; Maxwell, A. J.; Kearins, O.; Sibbering, M.; Shaaban, A. M.; et al. (2022)
    Purpose: The introduction of breast screening in the UK led to an increase in the detection of non-invasive breast neoplasia, predominantly ductal carcinoma in situ (DCIS), a non-obligatory precursor of invasive breast cancer. The Sloane Project, a UK prospective cohort study of screen-detected non-invasive breast neoplasia, commenced in 2003 to evaluate the radiological assessment, surgical management, pathology, adjuvant therapy and outcomes for non-invasive breast neoplasia. Long-term follow-up and accurate data collection are essential to examine the clinical impact. Here, we describe the establishment, development and analytical processes for this large UK cohort study. Participants: Women diagnosed with non-invasive breast neoplasia via the UK National Health Service Breast Screening Programme (NHSBSP) from 01 April 2003 are eligible, with a minimum age of 46 years. Diagnostic, therapeutic and follow-up data collected via proformas, complement date and cause of death from national data sources. Accrual for patients with DCIS ceased in 2012 but is ongoing for patients with epithelial atypia/in situ neoplasia, while follow-up for all continues long term. Findings to date: To date, patients within the Sloane cohort comprise one-third of those diagnosed with DCIS within the NHSBSP and are representative of UK practice. DCIS has a variable outcome and confirms the need for longer-term follow-up for screen-detected DCIS. However, the radiology and pathology features of DCIS can be used to inform patient management. We demonstrate validation of follow-up information collected from national datasets against traditional, manual methods. Future plans: Conclusions derived from the Sloane Project are generalisable to women in the UK with screen-detected DCIS. The follow-up methodology may be extended to other UK cohort studies and routine clinical follow-up. Data from English patients entered into the Sloane Project are available on request to researchers under data sharing agreement. Annual follow-up data collection will continue for a minimum of 20 years.
  • Pro-MAP: a robust pipeline for the pre-processing of single channel protein microarray data

    Mowoe, M. O.; Garnett, S.; Lennard, K.; Talbot, Jade; Townsend, P.; Jonas, E.; Blackburn, J. M.; Department of Integrated Biomedical Sciences, Division of Chemical and Systems Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa. (2022)
    Background: The central role of proteins in diseases has made them increasingly attractive as therapeutic targets and indicators of cellular processes. Protein microarrays are emerging as an important means of characterising protein activity. Their accurate downstream analysis to produce biologically significant conclusions is largely dependent on proper pre-processing of extracted signal intensities. However, existing computational tools are not specifically tailored to the nature of these data and lack unanimity. Results: Here, we present the single-channel Protein Microarray Analysis Pipeline, a tailored computational tool for analysis of single-channel protein microarrays enabling biomarker identification, implemented in R, and as an interactive web application. We compared four existing background correction and normalization methods as well as three array filtering techniques, applied to four real datasets with two microarray designs, extracted using two software programs. The normexp, cyclic loess, and array weighting methods were most effective for background correction, normalization, and filtering respectively. Conclusions: Thus, here we provided a versatile and effective pre-processing and differential analysis workflow for single-channel protein microarray data in form of an R script and web application ( .) for those not well versed in the R programming language.
  • Improved survival and MRD remission with blinatumomab vs. chemotherapy in children with first high-risk relapse B-ALL

    Locatelli, F.; Zugmaier, G.; Rizzari, C.; Morris, J. D.; Gruhn, B.; Klingebiel, T.; Parasole, R.; Linderkamp, C.; Flotho, C.; Petit, A.; et al. (2022)
  • Gender-related and geographic trends in interactions between radiotherapy professionals on Twitter

    Berger, T.; Payan, N.; Fleury, E.; Davey, A.; Bryce-Atkinson, Abigail; Vasquez Osorio, Eliana; Yang, Z.; McMullan, T.; Shelley, L. E. A.; Gasnier, A.; et al. (2022)
    Background and purpose: Twitter presence in academia has been linked to greater research impact which influences career progression. The purpose of this study was to analyse Twitter activity of the radiotherapy community around ESTRO congresses with a focus on gender-related and geographic trends. Materials and methods: Tweets, re-tweets and replies, here designated as interactions, around the ESTRO congresses held in 2012-2021 were collected. Twitter activity was analysed temporally and, for the period 2016-2021, the geographical span of the ESTRO Twitter network was studied. Tweets and Twitter users collated during the 10 years analysed were ranked based on number of 'likes', 're-tweets' and followers, considered as indicators of leadership/influence. Gender representation was assessed for the top-end percentiles. Results: Twitter activity around ESTRO congresses was multiplied by 60 in 6 years growing from 150 interactions in 2012 to a peak of 9097 in 2018. In 2020, during the SARS-CoV-2 pandemic, activity dropped by 60 % to reach 2945 interactions and recovered to half the pre-pandemic level in 2021. Europe, North America and Oceania were strongly connected and remained the main contributors. While overall, 58 % of accounts were owned by men, this proportion increased towards top liked/re-tweeted tweets and most-followed profiles to reach up to 84 % in the top-percentiles. Conclusion: During the SARS-CoV-2 pandemic, Twitter activity around ESTRO congresses substantially decreased. Men were over-represented on the platform and in most popular tweets and influential accounts. Given the increasing importance of social media presence in academia the gender-based biases observed may help in understanding the gender gap in career progression
  • Amplification of the PLAG-family genes-PLAGL1 and PLAGL2-is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification

    Keck, M. K.; Sill, M.; Wittmann, A.; Joshi, P.; Stichel, D.; Beck, P.; Okonechnikow, K.; Sievers, P.; Wefers, A. K.; Roncaroli, F.; et al. (2022)
    Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0-14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type. In addition, we report histology, patient characteristics, and survival data in this tumor type. We describe a biologically distinct pediatric CNS tumor type (n = 31 cases) that is characterized by focal high-level amplification and resultant overexpression of either PLAGL1 or PLAGL2, and an absence of recurrent genetic alterations characteristic of other pediatric CNS tumor types. Both genes act as transcription factors for a regulatory subset of imprinted genes (IGs), components of the Wnt/β-Catenin pathway, and the potential drug targets RET and CYP2W1, which are also specifically overexpressed in this tumor type. A derived PLAGL-specific gene expression signature indicates dysregulation of imprinting control and differentiation/development. These tumors occurred throughout the neuroaxis including the cerebral hemispheres, cerebellum, and brainstem, and were predominantly composed of primitive embryonal-like cells lacking robust expression of markers of glial or neuronal differentiation (e.g., GFAP, OLIG2, and synaptophysin). Tumors with PLAGL1 amplification were typically diagnosed during adolescence (median age 10.5 years), whereas those with PLAGL2 amplification were diagnosed during early childhood (median age 2 years). The 10-year overall survival was 66% for PLAGL1-amplified tumors, 25% for PLAGL2-amplified tumors, 18% for male patients, and 82% for female patients. In summary, we describe a new type of biologically distinct CNS tumor characterized by PLAGL1/2 amplification that occurs predominantly in infants and toddlers (PLAGL2) or adolescents (PLAGL1) which we consider best classified as a CNS embryonal tumor and which is associated with intermediate survival. The cell of origin and optimal treatment strategies remain to be defined.
  • Use of antihypertensive drugs and risk of cutaneous melanoma: a nationwide nested case-control study

    Ghiasvand, R.; Berge, L. A. M.; Andreassen, B. K.; Stenehjem, J. S.; Heir, T.; Karlstad, Ø.; Juzeniene, A.; Larsen, I. K.; Green, Adèle C; Veierød, M. B.; et al. (2022)
    Background: Most antihypertensives can induce dermal photosensitivity, which may increase melanoma risk. However, corroborating evidence is limited. We examined the associations between use of antihypertensives and melanoma risk. Methods: A nationwide nested case-control study was conducted using data from the Cancer Registry of Norway, the National Registry and the Norwegian Prescription Database in 2004-15. Ten controls were randomly selected for each melanoma case, matched on sex and birth year. The study included 12 048 cases and 117 895 controls. We estimated rate ratios (RRs) with 95% confidence intervals (CIs). All analyses were adjusted for ambient ultraviolet radiation (UVR). We additionally performed active comparator analyses, and sensitivity analyses by only including new users, distinguishing between exclusive and mixed users, allowing for different latency periods, and subgroup analyses by melanoma subtype and clinical stage. Results: Compared with non-use, we observed a slightly increased melanoma risk in users of diuretics (RR 1.08, CI 1.01-1.15), calcium-channel blockers (RR 1.10, CI 1.04-1.18) and drugs affecting the renin-angiotensin system (RR 1.10, CI 1.04-1.16), but not for beta blockers (RR 0.97, CI 0.92-1.03). We found no heterogeneity of associations by melanoma subtype or clinical stage and no dose-response relationship between the cumulative defined daily doses (DDDs) and melanoma. No interaction was found between cumulative DDDs and ambient UVR. Conclusions: Weak associations, with lack of a dose-response relationship and lack of interactions with ambient UVR, in the DDD analysis in this nationwide study do not support a causal relationship between antihypertensives and melanoma risk.
  • Differential integrated stress response and asparagine production drive symbiosis and therapy resistance of pancreatic adenocarcinoma cells

    Halbrook, C. J.; Thurston, G.; Boyer, S.; Anaraki, C.; Jiménez, J. A.; McCarthy, Amy; Steele, N. G.; Kerk, S. A.; Hong, H. S.; Lin, L.; et al. (2022)
    The pancreatic tumor microenvironment drives deregulated nutrient availability. Accordingly, pancreatic cancer cells require metabolic adaptations to survive and proliferate. Pancreatic cancer subtypes have been characterized by transcriptional and functional differences, with subtypes reported to exist within the same tumor. However, it remains unclear if this diversity extends to metabolic programming. Here, using metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses among neoplastic populations within individual human and mouse tumors. Furthermore, these populations are poised for metabolic cross-talk, and in examining this, we find an unexpected role for asparagine supporting proliferation during limited respiration. Constitutive GCN2 activation permits ATF4 signaling in one subtype, driving excess asparagine production. Asparagine release provides resistance during impaired respiration, enabling symbiosis. Functionally, availability of exogenous asparagine during limited respiration indirectly supports maintenance of aspartate pools, a rate-limiting biosynthetic precursor. Conversely, depletion of extracellular asparagine with PEG-asparaginase sensitizes tumors to mitochondrial targeting with phenformin.
  • Uncovering novel mutational signatures by de novo extraction with SigProfilerExtractor

    Islam, S. M. A.; Díaz-Gay, M.; Wu, Y.; Barnes, M.; Vangara, R.; Bergstrom, E. N.; He, Y.; Vella, M.; Wang, J.; Teague, J. W.; et al. (2022)
    Mutational signature analysis is commonly performed in cancer genomic studies. Here, we present SigProfilerExtractor, an automated tool for de novo extraction of mutational signatures, and benchmark it against another 13 bioinformatics tools by using 34 scenarios encompassing 2,500 simulated signatures found in 60,000 synthetic genomes and 20,000 synthetic exomes. For simulations with 5% noise, reflecting high-quality datasets, SigProfilerExtractor outperforms other approaches by elucidating between 20% and 50% more true-positive signatures while yielding 5-fold less false-positive signatures. Applying SigProfilerExtractor to 4,643 whole-genome- and 19,184 whole-exome-sequenced cancers reveals four novel signatures. Two of the signatures are confirmed in independent cohorts, and one of these signatures is associated with tobacco smoking. In summary, this report provides a reference tool for analysis of mutational signatures, a comprehensive benchmarking of bioinformatics tools for extracting signatures, and several novel mutational signatures, including one putatively attributed to direct tobacco smoking mutagenesis in bladder tissues.
  • SGOL1-AS1 enhances cell survival in acute myeloid leukemia by maintaining pro-inflammatory signaling

    Selkirk, Ewan; Patel, Rahima; Hoyle, A.; Lie-A-Ling, Michael; Smith, Duncan L; Swift, J.; Lacaud, Georges; Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK (2022)
    Epigenetic dysregulation is a key feature of most acute myeloid leukemia (AML). Recently, it has become clear that long noncoding RNAs (lncRNAs) can play a key role in epigenetic regulation, and consequently also dysregulation. Currently, our understanding of the requirements and roles of lncRNAs in AML is still limited. Here, using CRISPRi screening, we identified the lncRNA SGOL1-AS1 as an essential regulator of survival in THP-1 AML cells. We demonstrated that SGOL1-AS1 interacts with chromatin-modifying proteins involved in gene repression and that SGOL1-AS1 knockdown is associated with increased heterochromatin formation. We also observed that loss of SGOLl-AS1 results in increased apoptosis and the downregulation of pro-inflammatory genes. In AML patients, high expression of SGOL1-AS1 correlates with both pro-inflammatory gene expression and poor survival. Altogether, our data reveal that SGOL1-AS1 is an essential regulator of cell survival in AML cell lines and a possible regulator of pro-inflammatory signaling in AML patients.
  • Mitochondrial dysfunction compromises ciliary homeostasis in astrocytes

    Ignatenko, O.; Malinen, S.; Rybas, S.; Vihinen, H.; Nikkanen, J.; Kononov, Aleksander; Jokitalo, E. S.; Ince-Dunn, G.; Suomalainen, A.; Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland (2023)
    Astrocytes, often considered as secondary responders to neurodegeneration, are emerging as primary drivers of brain disease. Here we show that mitochondrial DNA depletion in astrocytes affects their primary cilium, the signaling organelle of a cell. The progressive oxidative phosphorylation deficiency in astrocytes induces FOXJ1 and RFX transcription factors, known as master regulators of motile ciliogenesis. Consequently, a robust gene expression program involving motile cilia components and multiciliated cell differentiation factors are induced. While the affected astrocytes still retain a single cilium, these organelles elongate and become remarkably distorted. The data suggest that chronic activation of the mitochondrial integrated stress response (ISRmt) in astrocytes drives anabolic metabolism and promotes ciliary elongation. Collectively, our evidence indicates that an active signaling axis involving mitochondria and primary cilia exists and that ciliary signaling is part of ISRmt in astrocytes. We propose that metabolic ciliopathy is a novel pathomechanism for mitochondria-related neurodegenerative diseases.
  • Efficacy and safety of zandelisib administered by intermittent dosing (ID) in patients with relapsed or refractory (R/R) follicular lymphoma (FL): Primary analysis of the global phase 2 study TIDAL

    Zelenetz, A. D.; Jurczak, W.; Ribrag, V.; Linton, Kim M; Collins, G. P.; Lopez-Jimenez, J.; Reddy, N.; Mengarelli, A.; Phillips, T. J.; Musuraca, G.; et al. (2022)
  • Results of the dinutuximab beta, bevacizumab, irinotecan and topotecan randomisations of the beacon-neuroblastoma Phase 2 trial by itcc and siopen

    Moreno, L.; Weston, R.; Owens, C.; Gray, J.; Barone, G.; Valteau-Couanet, D.; Simon, A. R. S.; Makin, Guy; Vaidya, S.; Gambart, M.; et al. (2022)
  • Author Correction: High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER(+) breast cancer

    Palafox, M.; Monserrat, L.; Bellet, M.; Villacampa, G.; Gonzalez-Perez, A.; Oliveira, M.; Brasó-Maristany, F.; Ibrahimi, N.; Kannan, S.; Mina, L.; et al. (2022)

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