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  • Comparative performance of lung cancer risk models to define lung screening eligibility in the United Kingdom

    Robbins, H.; Alcala, K.; Swerdlow, A.; Schoemaker, M.; Wareham, N.; Key, T.; Travis, R.; Brennan, P.; Crosbie, Philip A; Callister, M.; et al. (2021)
    Introduction: The National Health Service England (NHS) classifies individuals as eligible for lung cancer screening using two prediction models, PLCOm2012 and Liverpool Lung Project-v2 (LLPv2). However, no study has compared the performance of lung cancer risk models in the United Kingdom. Methods: We analysed current and former smokers aged 40-80 in the UK Biobank (N¼217,199), EPIC-UK (N¼30,982), and Generations Study (N¼25,849). We quantified model calibration (ratio of expected to observed cases, E/ O) and discrimination (AUC). Results: Risk discrimination in UK Biobank was best for the Lung Cancer Death Risk Assessment Tool (LCDRAT, AUC¼0.82, 95%CI¼0.81-0.84), followed by the LCRAT (AUC¼0.81, 95%CI¼0.79-0.82) and the Bach model (AUC¼0.80, 95%CI¼0.79-0.81) (Figure). Results were similar in EPIC-UK and the Generations Study. All models overestimated risk in all cohorts, with E/O in UK Biobank ranging from 1.30 for PLCOm2012 (95% CI¼1.23-1.36) to 2.16 for LLPv2 (95%CI¼2.05-2.28). Overestimation increased with area-level socioeconomic status. In the combined cohorts, USPSTF criteria classified 50.6% of future cases as screening-eligible. The LCDRAT and LCRAT identified 60.9%, followed by PLCOm2012 (58.3%), Bach (58.1%), and LLPv2 (53.6%). Conclusion: Discrimination of lung cancer risk models in UK cohorts was highest for LCDRAT and LCRAT, and lowest for LLPv2. Our results highlight the importance of context-specific validation for prediction tools.
  • A systematic review of prostate cancer heterogeneity: understanding the clonal ancestry of multifocal disease

    Erickson, A.; Hayes, A.; Rajakumar, T.; Verill, C.; Bryant, R. J.; Hamdy, F. C.; Wedge, David C; Woodcock, D. J.; Mills, I. G.; Lamb, A. D.; et al. (2021)
    Context: Studies characterising genomic changes in prostate cancer (PCa) during natural progression have greatly increased our understanding of the disease. A better understanding of the evolutionary history of PCa would allow advances in diagnostics, prognostication, and novel therapies that together will improve patient outcomes. Objective: To review the molecular heterogeneity of PCa and assess recent efforts to profile intratumoural heterogeneity and clonal evolution. Evidence acquisition: We screened a total of 1313 abstracts from PubMed published between 2009 and 2020, of which we reviewed 84 full-text articles. We excluded 49, resulting in 35 studies for qualitative analysis. Evidence synthesis: In studies of primary disease (16 studies, 4793 specimens), there is a lack of consensus regarding the monoclonal or polyclonal origin of primary PCa. There is no consistent mutation giving rise to primary PCa. Detailed clonal analysis of primary PCa has been limited by current techniques. By contrast, clonal relationships between PCa metastases and a potentiating clone have been consistently identified (19 studies, 732 specimens). Metastatic specimens demonstrate consistent truncal genomic aberrations that suggest monoclonal metastatic progenitors. Conclusions: The relationship between the clonal dynamics of PCa and clinical outcomes needs further investigation. It is likely that this will provide a biological rationale for whether radical treatment of the primary tumour benefits patients with oligometastatic PCa. Future studies on the mutational burden in primary disease at single-cell resolution should permit the identification of clonal patterns underpinning the origin of lethal PCa. Patient summary: Prostate cancers arise in different parts of the prostate because of DNA mutations that occur by chance at different times. These cancer cells and their origin can be tracked by DNA mapping. In this review we summarise the state of the art and outline what further science is needed to provide the missing answers.
  • Intrinsically connected: therapeutically targeting the cathepsin proteases and the Bcl-2 family of protein substrates as co-regulators of apoptosis

    Soond, S. M.; Kozhevnikova, M. V.; Savvateeva, L. V.; Townsend, Paul A; Zamyatnin, A. A., Jr.; Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Trubetskaya str. 8-2, 119991 Moscow, Russi (2021)
    Taken with the growing importance of cathepsin-mediated substrate proteolysis in tumor biology and progression, the focus and emphasis placed on therapeutic design and development is coming into fruition. Underpinning this approach is the invariable progression from the direction of fully characterizing cathepsin protease members and their substrate targets, towards targeting such an interaction with tangible therapeutics. The two groups of such substrates that have gained much attention over the years are the pro- and anti- apoptotic protein intermediates from the extrinsic and intrinsic signaling arms of the apoptosis pathway. As proteins that are central to determining cellular fate, some of them present themselves as very favorable candidates for therapeutic targeting. However, considering that both anti- and pro- apoptotic signaling intermediates have been reported to be downstream substrates for certain activated cathepsin proteases, therapeutic targeting approaches based on greater selectivity do need to be given greater consideration. Herein, we review the relationships shared by the cathepsin proteases and the Bcl-2 homology domain proteins, in the context of how the topical approach of adopting 'BH3-mimetics' can be explored further in modulating the relationship between the anti- and pro- apoptotic signaling intermediates from the intrinsic apoptosis pathway and their upstream cathepsin protease regulators. Based on this, we highlight important future considerations for improved therapeutic design.
  • Unsatisfactory quality of E. coli asparaginase biogenerics in India: Implications for clinical outcomes in acute lymphoblastic leukaemia

    Sidhu, J.; Gogoi, M. P.; Agarwal, P.; Mukherjee, T.; Saha, D.; Bose, P.; Roy, P.; Phadke, Y.; Sonawane, B.; Paul, Pritha; et al. (2021)
    Background: The biotherapeutic asparaginase is a cornerstone of therapy in acute lymphoblastic leukaemia (ALL). With limited access to the original native Escherichia coli-derived asparaginase (EcASNase), a variety of EcASNase biogenerics are used in low-middle-income countries (LMICs). The variable quality of these biogenerics potentially influences clinical outcomes. Procedure: Seven biogeneric EcASNases (P1-P7) marketed widely in India were evaluated, with P2 as an exemplar for in vivo monitoring. Therapeutic activity of P2 (10,000 IU/m2 /dose, intramuscular, every 72 hours) was monitored during induction therapy, and drug-related toxicities recorded. Molecular identity, purity and in vitro drug activity of seven biogenerics were characterised using multimodal analyses, and findings compared with reference EcASNase (R). Results: In patients (N = 62) receiving P2, subtherapeutic asparaginase activity (<100 U/L) was observed in 66% (46/70) of trough timepoints (72 hours postdose) during induction. Twelve patients (19%), 11 with high-risk ALL, developed hypersensitivity. Isoforms of EcASNase were identified in all seven biogenerics. All generic products contained impurities with batch-to-batch variability. These included high levels of protein aggregates and host cell protein contamination. In vitro assays of EcASNase activity and leukaemia cell line cytotoxicity were not discriminatory. Conclusions: Our findings confirm widespread concerns over the unsatisfactory quality and therapeutic activity of native EcASNase biogenerics marketed in LMICs. Appropriate use of these products requires monitored studies to identify clinical suitability and determine appropriate dosing and schedule. For large parts of the world, assured access to high-quality asparaginases remains an unmet therapeutic need.
  • Do traditional BMI categories capture future obesity? A comparison with trajectories of BMI and incidence of cancer

    Watson, Charlotte; Geifman, D. N.; Manchester Cancer Research Centre & NIHR Manchester Biomedical Research Centre, Manchester, UK (2020)
    In 2016, 13 specific obesity related cancers were identified by IARC. Here, using baseline WHO BMI categories, latent profile analysis (LPA) and latent class trajectory modelling (LCTM) we evaluated the usefulness of one-off measures when predicting cancer risk vs life-course changes. Our results in LPA broadly concurred with the three basic WHO BMI categories, with similar stepwise increase in cancer risk observed. In LCTM, we identified 5 specific trajectories in men and women. Compared to the leanest class, a stepwise increase in risk for obesity related cancer was observed for all classes. When latent class membership was compared to baseline BMI, we found that the trajectories were composed of a range of BMI (baseline) categories. All methods reveal a link between obesity and the 13 cancers identified by IARC. However, the additional information included by LCTM indicates that lifetime BMI may highlight additional group of people that are at risk.
  • Consensus for treatment of metastatic castration-sensitive prostate cancer: report from the first global prostate cancer consensus conference for developing countries (PCCCDC)

    Maluf, F. C.; Pereira, F. M. T.; Serrano Uson, P. L., Jr.; Bastos, D. A.; Rodrigues da Rosa, D. A.; Wiermann, E. G.; Schutz, F. A.; Kater, F. R.; de Oliveira, F. N. G.; Marques Monteiro, F. S.; et al. (2021)
    Purpose: International guideline recommendations may not always be extrapolated to developing countries where access to resources is limited. In metastatic castration-sensitive prostate cancer (mCSPC), there have been successful drug and imaging advancements that were addressed in the Prostate Cancer Consensus Conference for Developing Countries for best-practice and limited-resource scenarios. Methods: A total of 24 out of 300 questions addressed staging, treatment, and follow-up for patients with mCSPC both in best-practice settings and resource-limited settings. Responses were compiled and presented in percentage of clinicians supporting each response. Questions had 4-8 options for response. Results: Recommendations for staging in mCSPC were split but there was consensus that chest x-ray, abdominal and pelvic computed tomography, and bone scan should be used where resources are limited. In both de novo and relapsed low-volume mCSPC, orchiectomy alone in limited resources was favored and in relapsed high-volume disease, androgen deprivation therapy plus docetaxel in limited resources and androgen deprivation therapy plus abiraterone in high-resource settings were consensus. A 3-weekly regimen of docetaxel was consensus among voters. When using abiraterone, a regimen of 1,000 mg plus prednisone 5 mg/d is optimal, but in limited-resource settings, half the panel agreed that abiraterone 250 mg with fatty foods plus prednisone 5 mg/d is acceptable. The panel recommended against the use of osteoclast-targeted therapy to prevent osseous complications. There was consensus that monitoring of patients undergoing systemic treatment should only be conducted in case of prostate-specific antigen elevation or progression-suggestive symptoms. Conclusion: The treatment recommendations for most topics addressed differed between the best-practice setting and resource-limited setting, accentuating the need for high-quality evidence that contemplates the effect of limited resources on the management of mCSPC.
  • Correction: Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK 'Alert Level 4' phase of the B-MaP-C study

    Dave, R. V.; Kim, B.; Courtney, A.; O'Connell, R.; Rattay, T.; Taxiarchi, V. P.; Kirkham, J. J.; Camacho, E. M.; Fairbrother, P.; Sharma, N.; et al. (2021)
  • Generation of a mouse SWATH-MS spectral library to quantify 10148 proteins involved in cell reprogramming

    Ulanga, U.; Russell, M.; Patassini, Stefano; Brazzatti, J.; Graham, C.; Whetton, Anthony D; Graham, R. L. J.; Clinical Proteomics Research Group, Division of Molecular and Clinical Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road Manchester, Manchester, U (2021)
    Murine models are amongst the most widely used systems to study biology and pathology. Targeted quantitative proteomic analysis is a relatively new tool to interrogate such systems. Recently the need for relative quantification on hundreds to thousands of samples has driven the development of Data Independent Acquisition methods. One such technique is SWATH-MS, which in the main requires prior acquisition of mass spectra to generate an assay reference library. In stem cell research, it has been shown pluripotency can be induced starting with a fibroblast population. In so doing major changes in expressed proteins is inevitable. Here we have created a reference library to underpin such studies. This is inclusive of an extensively documented script to enable replication of library generation from the raw data. The documented script facilitates reuse of data and adaptation of the library to novel applications. The resulting library provides deep coverage of the mouse proteome. The library covers 29519 proteins (53% of the proteome) of which 7435 (13%) are supported by a proteotypic peptide.
  • Terahertz reading of ferroelectric domain wall dielectric switching

    Zhang, M.; Chen, Z.; Yue, Y. J.; Chen, T.; Yan, Z. N.; Jiang, Q. H.; Yang, B.; Eriksson, M.; Tang, Jianhua; Zhang, D.; et al. (2021)
    Ferroelectric domain walls (DWs) are important nanoscale interfaces between two domains. It is widely accepted that ferroelectric domain walls work idly at terahertz (THz) frequencies, consequently discouraging efforts to engineer the domain walls to create new applications that utilize THz radiation. However, the present work clearly demonstrates the activity of domain walls at THz frequencies in a lead-free Aurivillius phase ferroelectric ceramic, Ca0.99Rb0.005Ce0.005Bi2Nb2O9, examined using THz-time-domain spectroscopy (THz-TDS). The dynamics of domain walls are different at kHz and THz frequencies. At low frequencies, domain walls work as a group to increase dielectric permittivity. At THz frequencies, the defective nature of domain walls serves to lower the overall dielectric permittivity. This is evidenced by higher dielectric permittivity in the THz band after poling, reflecting decreased domain wall density. An elastic vibrational model has also been used to verify that a single frustrated dipole in a domain wall represents a weaker contribution to the permittivity than its counterpart within a domain. The work represents a fundamental breakthrough in understanding the dielectric contributions of domain walls at THz frequencies. It also demonstrates that THz probing can be used to read domain wall dielectric switching.
  • Consensus on the treatment and follow-up for metastatic castration-resistant prostate cancer: a report from the first global prostate cancer consensus conference for developing countries (PCCCDC)

    Maluf, F. C.; Pereira, F. M. T.; Silva, A. G.; Dettino, A. L. A.; Cardoso, A. P. G.; Sasse, A. S.; Soares, A.; Kann, A. G.; Herchenhorn, D.; Jardim, D. L. F.; et al. (2021)
    Purpose: To present a summary of the recommendations for the treatment and follow-up for metastatic castration-resistant prostate cancer (mCRPC) as acquired through a questionnaire administered to 99 physicians working in the field of prostate cancer in developing countries who attended the Prostate Cancer Consensus Conference for Developing Countries. Methods: A total of 106 questions out of more than 300 questions addressed the use of imaging in staging mCRPC, treatment recommendations across availability and response to prior drug treatments, appropriate drug treatments, and follow-up, and those same scenarios when limited resources needed to be considered. Responses were compiled and the percentages were presented by clinicians to support each response. Most questions had five to seven relevant options for response including abstain and/or unqualified to answer, or in the case of yes or no questions, the option to abstain was offered. Results: Most of the recommendations from this panel were in line with prior consensus, including the preference of a new antiandrogen for first-line therapy of mCRPC. Important aspects highlighted in the scenario of limited resources included the option of docetaxel as treatment preference as first-line treatment in several scenarios, docetaxel retreatment, consideration for reduced doses of abiraterone, and alternative schedules of an osteoclast-targeted therapy.
  • Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes

    Dentro, S. C.; Leshchiner, I.; Haase, K.; Tarabichi, M.; Wintersinger, J.; Deshwar, A. G.; Yu, K.; Rubanova, Y.; Macintyre, G.; Demeulemeester, J.; et al. (2021)
    Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types and identify cancer type-specific subclonal patterns of driver gene mutations, fusions, structural variants, and copy number alterations as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution and provide a pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.
  • Risks of basal cell and squamous cell carcinoma in psoriasis patients after treatment with biologic vs non-biologic systemic therapies

    Mason, K. J.; Burden, A. D.; Barker, J.; Lunt, M.; Ali, H.; Kleyn, C. E.; McElhone, K.; Soliman, M. M.; Green, Adèle C; Griffiths, C. E. M.; et al. (2021)
  • A TOR (target of rapamycin) and nutritional phosphoproteome of fission yeast reveals novel targets in networks conserved in humans

    Halova, Lenka; Cobley, D.; Franz-Wachtel, M.; Wang, T.; Morrison, K. R.; Krug, K.; Nalpas, N.; Maček, B.; Hagan, Iain M; Humphrey, S. J.; et al. (2021)
    Fluctuations in TOR, AMPK and MAP-kinase signalling maintain cellular homeostasis and coordinate growth and division with environmental context. We have applied quantitative, SILAC mass spectrometry to map TOR and nutrient-controlled signalling in the fission yeast Schizosaccharomyces pombe. Phosphorylation levels at more than 1000 sites were altered following nitrogen stress or Torin1 inhibition of the TORC1 and TORC2 networks that comprise TOR signalling. One hundred and thirty of these sites were regulated by both perturbations, and the majority of these (119) new targets have not previously been linked to either nutritional or TOR control in either yeasts or humans. Elimination of AMPK inhibition of TORC1, by removal of AMPKα (ssp2
  • Sunglasses to hide behind may also prevent melanoma of the eyes

    Dhomen, Nathalie; Mundra, Piyushkumar A; Marais, Richard; Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, SK10 4TG (2021)
    In 1967, Sandy Posey pronounced that sunglasses are essential beachwear ( ). Now, whole-genome sequencing reveals that ultraviolet radiation (UVR) can contribute to melanomas in the iris and conjunctiva, data that provide a molecular explanation for why it is important to protect our eyes from exposure to UVR.
  • Physical activity and cutaneous melanoma risk: A Norwegian population-based cohort study

    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. (2021)
    Physical activity (PA) is an important factor in cancer prevention, but positive association between PA and risk of cutaneous melanoma found in recent studies may complicate this strategy. Ultraviolet radiation (UVR) exposure during outdoor PA is a plausible explanation for a positive association. We investigated the associations between PA, UVR and melanoma risk in the Norwegian Women and Cancer cohort. Overall PA was reported by 151,710 women, aged 30-75 at inclusion, using a validated 10-point-scale at enrolment and during follow-up, together with recent numbers of sunburns, indoor tanning sessions and weeks on sunbathing vacations. Seasonal outdoor walking and seasonal PAs were recorded in subsamples (n = 102,671 and n = 29,077, respectively). Logistic and Cox regression were used. Mean follow-up was 18.5 years, and 1565 invasive incident melanoma cases were diagnosed. Overall PA was inversely associated with sunburns, while positively associated with sunbathing vacations and indoor tanning. Overall PA was not associated with melanoma risk in all body sites combined (ptrend = 0.61), but reduced risk was found in upper limb melanomas (hazard ratio (HR) = 0.70, 95% confidence interval (CI) 0.51-0.96; high versus low PA). Non-significant reduced risks were found for seasonal outdoor walking >2 h/day versus 30-60 min/day (summer HR = 0.81, 95% CI 0.66-1.00; autumn HR = 0.74, 95%CI 0.55-1.01). Seasonal PAs were not associated with melanoma risk. In conclusion, we found positive associations between overall PA and sunbathing vacations and indoor tanning, and, unlike literature, inverse association between overall PA and sunburns. Our results do not support a positive association between PA and melanoma risk in Norwegian women.
  • iRFP (near-infrared fluorescent protein) imaging of subcutaneous and deep tissue tumours in mice highlights differences between imaging platforms

    Hall, Callum; von Grabowiecki, Yannick; Pearce, Simon P; Dive, Caroline; Bagley, Steven; Muller, Patricia; Tumour Suppressors Group, CRUK Manchester Institute, University of Manchester, Alderley Park, Manchester, SK10 4T (2021)
    Background: In vivo imaging using fluorescence is used in cancer biology for the detection, measurement and monitoring of tumours. This can be achieved with the expression of fluorescent proteins such as iRFP, which emits light at a wavelength less attenuated in biological tissues compared to light emitted by other fluorescent proteins such as GFP or RFP. Imaging platforms capable of detecting fluorescent tumours in small animals have been developed but studies comparing the performance of these platforms are scarce. Results: Through access to three platforms from Xenogen, Bruker and Li-Cor, we compared their ability to detect iRFP-expressing subcutaneous tumours as well as tumours localised deeper within the body of female NSG mice. Each platform was paired with proprietary software for image analyse, but the output depends on subjective decisions from the user. To more objectively compare platforms, we developed an 'in house' software-based approach which results in lower measured variability between mice. Conclusions: Our comparisons showed that all three platforms allowed for reliable detection and monitoring of subcutaneous iRFP tumour growth. The biggest differences between platforms became apparent when imaging deeper tumours with the Li-Cor platform detecting most tumours and showing the highest dynamic range.
  • Statins reduce disease recurrence in patients with ulcerated primary melanoma

    von Schuckmann, L. A.; Khosrotehrani, K.; Ghiasvand, R.; Hughes, M. C. B.; van der Pols, J. C.; Malt, M.; Smithers, M.; Green, Adèle C; Department of Population Health, University of Queensland, Herston, Queensland, Australia (2021)
    Background: Statins may restrict cellular functions required for melanoma growth and metastasis. We examined whether long‐term statin use commenced before diagnosis of the primary is associated with reduced risk of melanoma recurrence. Patients and methods: We prospectively followed a cohort of patients newly diagnosed between 2010 and 2014 with localised tumour‐stage T1b to T4b melanoma in Queensland, Australia. We used Cox‐regression analyses to examine associations between long‐term statin use and melanoma recurrence for the entire cohort, and then separately by sex and by presence of ulceration due to evidence of effect modification. Results: Amongst 700 patients diagnosed with stage T1b to T4b primary melanoma (mean age 62, 59% male, 28% with ulcerated tumors), 94 patients (13%) developed melanoma recurrence within 2 years. Long‐term statin users (n = 204, 29%) had a significantly lower risk of disease recurrence compared to non‐users (Adjusted hazard ratio (HRadj) 0.55, 95% Confidence Interval (CI) 0.32–0.97) regardless of statin subtype or potency. Compared to non‐statin users, risk of recurrence was significantly decreased in male statin‐users (HRadj 0.39, 95% CI: 0.19–0.79) but not female statin users (HRadj 0.82, 95% CI: 0.29–2.27) and in statin‐users with ulcerated (HRadj 0.17, 95% CI: 0.05–0.52) but not non‐ulcerated (HRadj 0.91, 95% CI: 0.46–1.81) primary melanoma. Conclusion: Statins commenced before melanoma diagnosis, may reduce the risk of melanoma recurrence, especially in males and those with ulcerated tumors. Clinical trial evaluation of the potential role of statins in improving the prognosis of high‐risk melanoma is warranted.
  • Assessing drug development risk using big data and machine learning

    Vergetis, V.; Skaltsas, D.; Gorgoulis, Vassilis G; Tsirigos, A.; Intelligencia Inc., New York, New York. (2021)
    Identifying new drug targets and developing safe and effective drugs is both challenging and risky. Furthermore, characterizing drug development risk, the probability that a drug will eventually receive regulatory approval, has been notoriously hard given the complexities of drug biology and clinical trials. This inherent risk is often misunderstood and mischaracterized, leading to inefficient allocation of resources and, as a result, an overall reduction in R&D productivity. Here we argue that the recent resurgence of Machine Learning in combination with the availability of data can provide a more accurate and unbiased estimate of drug development risk.
  • Genetic and non-genetic mechanisms underlying cancer evolution

    Shlyakhtina, Yelyzaveta; Moran, Katherine L; Portal, Maximiliano M; Cell Plasticity and Epigenetics Lab. Cancer Research UK-Manchester Institute, The University of Manchester, Alderley Park, SK10 4TG, UK (2021)
    Cancer development can be defined as a process of cellular and tissular microevolution ultimately leading to malignancy. Strikingly, though this concept has prevailed in the field for more than a century, the precise mechanisms underlying evolutionary processes occurring within tumours remain largely uncharacterized and rather cryptic. Nevertheless, although our current knowledge is fragmentary, data collected to date suggest that most tumours display features compatible with a diverse array of evolutionary paths, suggesting that most of the existing macro-evolutionary models find their avatar in cancer biology. Herein, we discuss an up-to-date view of the fundamental genetic and non-genetic mechanisms underlying tumour evolution with the aim of concurring into an integrated view of the evolutionary forces at play throughout the emergence and progression of the disease and into the acquisition of resistance to diverse therapeutic paradigms. Our ultimate goal is to delve into the intricacies of genetic and non-genetic networks underlying tumour evolution to build a framework where both core concepts are considered non-negligible and equally fundamental.

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