Killcoyne S and Fitzgerald RC
Nat Rev Cancer (2021). DOI: 10.1038/s41568-021-00400-x
Cancer cells are shaped through an evolutionary process of DNA mutation, cell selection and population expansion. Early steps in this process are driven by a set of mutated driver genes and structural alterations to the genome through copy number gains or losses. Oesophageal adenocarcinoma (EAC) and the pre-invasive tissue, Barrett’s oesophagus (BE), provide an ideal example in which to observe and study this evolution. BE displays early genomic instability, specifically in copy number changes that may later be observed in EAC. Furthermore, these early changes result in patterns of progression (that is, ‘born bad’, gradual or catastrophic) that may help to describe the evolution of EAC. As only a small proportion of patients with BE will go on to develop cancer, a better understanding of these patterns and the resulting genomic changes should improve early detection in EAC and may provide clues for the evolution of cancer more broadly.
Nowicki-Osuch K, Zhuang L, Jammula S, Bleaney CW, Mahbubani KT, Devonshire G, Katz-Summercorn A, Eling N, Wilbrey-Clark A, Madissoon E, Gamble J, Di Pietro M, O’Donovan M, Meyer KB, Saeb-Parsy K, Sharrocks AD, Teichmann SA, Marioni JC, Fitzgerald RC
Science; 13 Aug 2021; DOI: 10.1126/science.abd1449
A study by a multidisciplinary group of scientists, led by Professor Rebecca Fitzgerald, found that a particular subtype of oesophageal cancer known as oesophageal adenocarcinoma is always preceded by Barrett’s oesophagus, and confirms the importance of screening for Barrett's.
The research team analysed tissue samples from patients with Barrett’s oesophagus and from organ donors who have never had the condition. Lead authors Dr Karol Nowicki-Osuch and Dr Lizhe Zhuang established a detailed ‘atlas’ of human cells and tissues from all possible origins of Barrett’s oesophagus. They found that all oesophageal adenocarcinoma cells begin as stomach cells before transforming into Barrett’s cells and then into cancer cells.
Yoon J, Joseph J, Waterhouse DJ, Borzy C, Siemens K, Diamond S, Tsikitis VL, Bohndiek SEJ
Biophotonics 2021, e202100078. doi.org/10.1002/jbio.202100078
A study led by Professor Sarah Bohndiek, University of Cambridge and Professor V Liana Tsikitis, Oregon Health and Science University sought to evaluate the potential of a hyperspectral endoscope (HySE) to enhance colonic polyp discrimination for detection and resection.
They designed, built and tested a new compact HySE in a proof-of-concept clinical study and successfully collected spectra from three tissue types in seven patients undergoing routine colonoscopy screening. The acquired spectral data from normal tissue and polyps, both pre- and post- resection, were subjected to quantitative analysis using spectral angle mapping and machine learning, which discriminated the data by tissue type, meriting further investigation of HySE as a clinical tool.
Freer-Smith C, Harvey-Kelly L, Mills K, Harrison H, Rossi SH, Griffin SJ, Stewart GD, Usher-Smith JA
BMJ Open 2021;11:e044961. DOI: 10.1136/bmjopen-2020-044961
This paper explores public attitudes towards screening for kidney cancer and assesses whether targeted screening of higher risk individuals might be possible. Published in BMJ Open, the research shows that most people think positively about potential kidney cancer screening and anticipate that they would attend if they were invited. Urine testing or low-dose computerised tomography (CT) scans, combined with lung screening, were the preferred test options. Several existing risk models are potentially useful in predicting who is more likely to get kidney cancer and could be used to identify those at higher risk for targeted screening. Using genetics or risk models, to determine eligibility for screening, would be acceptable to most people.
Waterhouse D, Januszewicz W, Ali S, Fitzgerald RC, di Pietro M, Bohndiek SE
Cancer Res May 26 2021 DOI: 10.1158/0008-5472.CAN-21-0474
A study lead by Dale Waterhouse, demonstrates the potential of spectral endoscopy to reveal disease-associated vascular changes and to provide high-contrast delineation of neoplasia in the esophagus.
Early detection of esophageal neoplasia enables curative endoscopic therapy, but the current diagnostic standard of care has low sensitivity because early neoplasia is often inconspicuous with conventional white-light endoscopy. Here, we hypothesized that spectral endoscopy could enhance contrast for neoplasia in surveillance of patients with Barrett's esophagus. A custom spectral endoscope was deployed in a pilot clinical study of 20 patients to capture 715 in vivo tissue spectra matched with gold standard diagnosis from histopathology.
McGinn J, Hallou A, Han S, Krizic K, Ulyanchenko S, Iglesias-Bartolome R, England FJ, Verstreken C, Chalut KJ, Jensen KB, Simons BD, Alcolea MP
Nat Cell Biol (2021) DOI: 10.1038/s41556-021-00679-w
Epithelial cells are highly dynamic and can rapidly adapt their behavior in response to tissue perturbations and increasing tissue demands. However, the processes that finely control these responses and, particularly, the mechanisms that ensure the correct switch to and from normal tissue homeostasis are largely unknown. Here we explore changes in cell behaviour happening at the interface between postnatal development and homeostasis in the epithelium of the mouse esophagus, as a physiological model exemplifying a rapid but controlled tissue growth transition.
Zou X, Koh GCC , Nanda AS, Degasperi A, Urgo K, Roumeliotis TI, Agu CA, Badja C, Momen S, Young J, Amarante TD, Side L, Brice G, Perez-Alonso V, Rueda D, Gomez C, Bushell W, Harris R, Choudhary JS, Genomics England Research Consortium, Jiricny J, Skarnes WC and Nik-Zainal S.
Nat Cancer (2021). https://doi.org/10.1038/s43018-021-00200-0
A new way to identify tumours that could be sensitive to particular immunotherapies has been developed using data from thousands of NHS cancer patient samples sequenced through the 100,000 Genomes Project.
Mutational signatures are imprints of pathophysiological processes arising through tumorigenesis. We generated isogenic CRISPR–Cas9 knockouts (∆) of 43 genes in human induced pluripotent stem cells, cultured them in the absence of added DNA damage and performed whole-genome sequencing of 173 subclones. ∆OGG1, ∆UNG, ∆EXO1, ∆RNF168, ∆MLH1, ∆MSH2, ∆MSH6, ∆PMS1 and ∆PMS2 produced marked mutational signatures indicative of them being critical mitigators of endogenous DNA modifications.
Gehrung M, Crispin-Ortuzar M, Berman AG, O'Donovan M, Fitzgerald RC, Markowetz F
Nat Medicine (2021), DOI:10.1038/s41591-021-01287-9
Artificial intelligence (AI) could help free up pathologist time and allow them to focus on diagnosing the most tricky cases of Barrett’s oesophagus, according to a Cancer Research UK-funded study.
Gonçalves S, Yin K, Ito Y, Chan A, Olan I, Gough S, Cassidy L, Serrao E, Smith S, Young A, Narita M, Hoare M
Cell Reports, Volume 34, Issue 11, 108860, March 16, 2021. DOI: 10.1016/j.celrep.2021.108860
Senescent cells trigger their own immune-mediated destruction, termed senescence surveillance. This is dependent on the inflammatory senescence-associated secretory phenotype (SASP), which includes COX2, an enzyme with complex roles in cancer. The role COX2 plays during senescence surveillance is unknown.
Gonçalves et al. identify COX2 as a regulator of senescence secretome composition through an autocrine feedback loop involving PGE2 and EP4. During hepatocyte senescence, Cox2 is critical to tumor suppression, Cxcl1 expression, the immune microenvironment, and immunemediated senescence surveillance, partially through PGE2.
Bach K, Pensa S, Zarocsinceva M, Kania K, Stockis J, Pinaud S, Lazarus KA, Shehata M, Simões BM, Greenhalgh AR, Howell SJ, Clarke RB, Caldas C, Halim TYF, Marioni JC, Khaled WT
Nature Communications, volume 12, Article number: 1502 (2021). DOI:10.1038/s41467-021-21783-3
Researchers may have found the earliest changes that occur in seemingly healthy breast tissue long before any tumours appear. The study, funded by Cancer Research UK, showed that before becoming cancerous, breast cells with the BRCA1 gene mutation undergo changes similar to those normally seen in late pregnancy. Not all women who have BRCA1 mutations will go on to develop cancer so for some, life-changing surgery may be unnecessary, or could at least be delayed until early warning signs are spotted.
Jones OT, Calanzani N, Saji S, Duffy SW, Emery J, Hamilton W, Singh H, de Wit NJ, Walter FM.
J Med Internet Res 2021;23(3):e23483. DOI: 10.2196/23483
Artificial Intelligence (AI) techniques can be applied to primary care data to facilitate the early diagnosis of cancer, according to the first international review of studies on this topic.
Breast Cancer Association Consortium; Easton DF et al.
N Engl J Med 2021; 384:428-439. DOI: 10.1056/NEJMoa1913948
A study led by Doug Easton (Director of the Centre for Cancer Genetic Epidemiology, member of the Early Detection Programme) is the most ambitious project carried out to date to shed light on the role of heredity in breast cancer. The analysis of samples from over 113,000 women reveals the nine most important genes that increase the risk of breast cancer. The research, published in the New England Journal of Medicine on 4th February 2021, was undertaken by a large international consortium of 250 researchers from over 25 countries, coordinated from Cambridge.
Liu S, Shen M, Hsu E-C, Zhang CA, Garcia-Marques F, Nolley R, Koul K, Rice MA, Aslan M, Pitteri SJ, Massie C, George A, Brooks JD, Gnanapragasam VJ, Stoyanova T.
Br J Cancer (2020). DOI:10.1038/s41416-020-01200-0
Publication from principal investigators Mr Vincent Gnanapragasam & Assistant Professor Tanya Stoyanova from work supported by a joint pump-priming award from the Cancer Research UK Cambridge Centre Early Detection Programme and the Canary Center at Stanford.
Hamilton W, Abel G, Crosbie EJ, Rous B, Walter FM
PLOS Medicine, published: October 28 2020. DOI:10.1371/journal.pmed.1003295
A blood test already available to GPs in the UK is more predictive of ovarian cancer than previously thought and could also help pick up other forms of cancer.
Fitzpatrick CRM, Wilson A, Sawyer TW, Christopher PJ, Wilkinson TD, Bohndiek SE, Gordon GSD.
OSA Continuum 3, 2660-2679 (2020), published: October 15 2020. DOI:10.1364/OSAC.395498
Quantitative phase imaging is becoming widely used in microscopy to elucidate previously unresolvable features based on their scattering behaviour and refractive index contrast, for example structural tissue changes indicative of diseases such as cancer. Bringing such measurements into an endoscopic setting could aid clinical decision making by enhancing contrast for early stage disease in vivo. A range of diagnostic approaches are currently being developed for capsule endoscopes; this work provides a preliminary look at some key considerations for bringing phase imaging into this setting.
Ou HL, Hoffmann R, González‐López C, Doherty G, Korkola JE, Muñoz‐Espín D
Molecular Oncology, published: September 27 2020. DOI: 10.1002/1878-0261.12807
This review piece from the Muñoz‐Espín lab highlights the occurrence and impact of senescence in neoplasia and advanced tumours, and recapitulates cutting-edge technologies for detecting senescence with significant potential for clinical utilisation. We anticipate these detection tools may facilitate a more precise monitoring of early tumours and their microenvironment, and a response assessment of patients to therapy in the near future.
González‐Gualda E, Baker AG, Fruk L, Muñoz‐Espín D
FEBS Journal, published: September 22 2020. DOI: 10.1111/febs.15570
A review piece from the Muñoz‐Espín lab - The reliable assessment and identification of senescence is not only crucial for better understanding its underlying biology, but also imperative for the development of diagnostic and therapeutic strategies aimed at targeting senescence in the clinic.
Ferrandino G, Orf I, Smith R, Calcagno M, Thind AK, Debiram-Beecham I, Williams M, Gandelman O, de Saedeleer A, Kibble G, Lydon AM, Mayhew CA, Allsworth M, Boyle B, van der Schee MP, Allison M, Hoare M, Snowdon VK.
Clinical and Translational Gastroenterology: September 2020 - Volume 11 - Issue 9 - p e00239 DOI: 10.14309/ctg.0000000000000239
Liver cirrhosis and its complication — hepatocellular carcinoma (HCC) — have been associated with increased exhaled limonene. It is currently unclear whether this increase is more strongly associated with the presence of HCC or with the severity of liver dysfunction.
Arteaga I, Fagan Robinson K, McDonald M,
BMJ Opinion, published: September 10 2020.
Opinion piece funded by Early Detection Programme pump priming award with so-called 'hard-to-reach' communities: Look for the super-locals to access "hard to reach" groups.
Killcoyne S, Gregson E, Wedge D, Woodcock DJ, Eldridge MD, de la Rue R, Miremadi A, Abbas S, Blasko A, Kosimidou C, Januszewicz W, Jenkins AV, Gerstung M, Fitzgerald RC
Nature Medicine, published: September 7 2020. DOI:10.1038/s41591-020-1033-y
DNA from tissue biopsies taken from patients with Barrett’s oesophagus – a risk factor for oesophageal cancer – could show which patients are most likely to develop the disease eight years before diagnosis, suggests a study led by researchers at the University of Cambridge and EMBL’s European Bioinformatics Institute (EMBL-EBI).
Usher Smith J, Simmons RK, Rossi SH, Stewart GD,
Nature Reviews Urology, published: August 28 2020. DOI:10.1038/s41585-020-0363-3
Renal cell carcinoma (RCC) incidence is increasing worldwide. A high proportion of individuals are asymptomatic at diagnosis, but RCC has a high mortality rate. These facts suggest that RCC meets some of the criteria for screening, and a new analysis shows that screening for RCC could potentially be cost-effective. This perspective article considers the current evidence on renal cancer screening.
Fitzgerald RC, Di Pietro M, O’Donovan M, Maroni R, Muldrew B, Debiram-Beecham I, Gehrung M, Offman J, Tripathi M, Smith SG, Aigret B, Walter FM, Rubin G, Sasieni P
The Lancet, published: August 1 2020. DOI:10.1016/S0140-6736(20)31099-0
Treatment of dysplastic Barrett's oesophagus prevents progression to adenocarcinoma; however, the optimal diagnostic strategy for Barrett's oesophagus is unclear. The Cytosponge-trefoil factor 3 (TFF3) is a non-endoscopic test for Barrett's oesophagus. The aim of this study was to investigate whether offering this test to patients on medication for gastro-oesophageal reflux would increase the detection of Barrett's oesophagus compared with standard management.
Di Pietro M, Modolell I, O’Donovan M, Price C, Debiram-Beecham I, Pilonis ND, Fitzgerald RC
The Lancet Gastroenterology and Hepatology, published: July 30 2020. DOI: 10.1016/S2468-1253(20)30242-9
During the COVID-19 pandemic, endoscopy services were severely curtailed—eg, in England, UK, a 30% reduction of diagnostic endoscopies has been reported for the period between January and April, 2020, compared with the same period in 2019, with an estimated 750 oesophagogastric cancers going undiagnosed. A delay in oesophageal cancer diagnosis could adversely affect outcomes, such as has previously been seen with low endoscopy referral rates being linked with poor outcomes from oesophageal cancer. This paper outlines how the Cytosponge was used for some patients referred for urgent endoscopy during this time.
Pashayan N, Antoniou AC, Ivanus U, Esserman LJ, Easton DF, French D, Sroczynski G, Hall P, Cuzick J, Evans DG, Simard J, Garcia-Closas M, Schmutzler R, Wegwarth O, Pharoah P, Moorthie S, De Montgolfier S, Baron C, Herceg Z, Turnbull C, Balleyguier C, Rossi PG, Wesseling J, Ritschie D, Tischkowitz M, Broeders M, Reisel D, Metspalu A, Callender T, de Koning H, Devilee P, Delaloge S, Schmidt MK and Widschwendter M.
Nature Reviews Clinical Oncology, Published: June 18 2020. doi: 10.1038/s41571-020-0388-9
The European Collaborative on Personalised Early Detection and Prevention of Breast Cancer (ENVISION) brings together several international research consortia working on different aspects of the personalised early detection and prevention of breast cancer. In a consensus conference held in 2019, the members of this network identified research areas requiring development to enable evidence-based personalised interventions that might improve the benefits and reduce the harms of existing breast cancer screening and prevention programmes. The implementation of such programmes would require health-care systems to be open to learning and adapting, the engagement of a diverse range of stakeholders and tailoring to societal norms and values, while also addressing the ethical and legal issues. In this Consensus Statement, we discuss the current state of breast cancer risk prediction, risk-stratified prevention and early detection strategies, and their implementation. Throughout, we highlight priorities for advancing each of these areas.
Wan JCM, Heider K, Gale D, Murphy S, Fisher E, Mouliere F, Ruiz-Valdepenas A, Sntonja A, Morris J, Chandrananda D, Marshall A, Gill AB, Chan PY, Barker E, Young G, Cooper WN, Hudecova I, Marass F, Mair R, Brindle K, Stewart G, Abraham JE, Caldas C, Rassl D, Rintoul RC, Alifrangis C, Middleton M, Gallagher FA, Parkinson C, Durrani A, McDermott U, Smith CG, Massie CM, Corrie PG, Rosenfeld N
Science Translational Medicine, Published: June 17 2020: Vol. 12, Issue 548. doi: 10.1126/scitranslmed.aaz8084
A new method of analysing cancer patients’ blood for evidence of the disease could be up to ten times more sensitive than previous methods according to new research funded by Cancer Research UK.
In the coming years, this method and others based on this approach could lead to tests that more accurately determine if a patient is likely to relapse after having treatment, and could pave the way for the development of pinprick home blood tests to monitor patients.
The technique uses personalised genetic testing of a patient’s tumour to search blood samples for hundreds of different genetic mutations in circulating tumour DNA (ctDNA); DNA released by cancer cells into the bloodstream.
Combined with new methods to analyse this data to remove background noise and enhance the signal, the team was able to reach a level of sensitivity that in some cases could find one mutant DNA molecule amongst a million pieces of DNA – approximately ten times more sensitive than previous methods.
Chopra N, Tovey H, Pearson A, Cutts R, Toms C, Proszek P, Hubank M, Dowsett M, Dodson A, Daley F, Kriplani D, Gevensleben H, Davies HR, Degasperi A, Roylance R, Chan S, Tutt A, Skene A, Evans A, Bliss JM, Nik-Zainal S, Turner NC .
Nat. Commun, published: May 29 2020. DOI:10.1038/s41467-020-16142-7
We apply our mutational-signature-based algorithm, HRDetect, into a proof-of-principle clinical trial, RIO (EudraCT 2014-003319-12), where patients with a very aggressive form of breast cancer called triple negative breast cancer, are given PARP-inhibition as a first line agent in a two-week window. We demonstrate that HRDetect is able to identify TNBCs that have a functional HR-deficiency and that this is associated with activity to PARP-inhibition. This was a really important trial that has opened RCTs to our clinical algorithm.
Colom B, Alcolea MP, Piedrafita G, Hall MWJ, Wabik A, Dentro SC, Fowler JC, Herms A, King C, Ong SH, Sood RK, Gerstung M, Martincorena I, Hall BA and Jones PH
Nature Genetics, Published: May 18 2020. doi: 10.1038/s41588-020-0624-3
The expansion of ‘mutant’ cells that could lead to cancer is often kept in check by their neighbours, research from the Wellcome Sanger Institute, the University of Cambridge and their collaborators has found. The team discovered that when equally-matched cells in the oesophagus of mice coincided, they acted as a brake on one another’s growth.
The study, in Nature Genetics, describes the ‘rules of the game’ of competition between oesophageal cells for the first time. By understanding these rules, the hope is that therapies can be developed to reduce the competitiveness of mutant clone cells that are more likely to become cancerous.
Clones are communities of cells descended from a single stem cell through the normal process of cell division. Tissues in the human body consist of patchworks of clones, with DNA mutations that occur naturally throughout life being passed on from parent to daughter cell.
Pashayan N and Pharoah PDP.
Science, Published: May 8 2020. doi: 10.1126/science.aaz2078
In this Science Perspective article, the authors caution that earlier detection and an apparent increase in survival may not always signify improved prognosis because some patients will die at the same time despite earlier detection of their tumour, and some patients will die of other causes.
They go on to discuss the particular issues with screening – where an early detection test is given to large groups of the healthy population with the intention of detecting cancer at an early stage when it can be cured and before it has spread. The success of screening for various cancers is dependent on how quickly different tumours grow, when a tumour is likely to spread, how sensitive screening is at detecting small tumours, and how often screening occurs.
Using breast screening as an example, they point out that to detect the most aggressive cancers early enough to be curable, screening would need to detect tumours smaller than currently possible and would need to take place more frequently than at present. They also highlight the risk of overdiagnosis and overtreatment if early detection tests are not able to distinguish between fast-growing aggressive tumours and slow-growing indolent tumours.
Zhou Y, Abel GA, Hamilton W, Singh H, Walter FM and Lyratzopoulos G.
Elsevier, Published online: April 22 2020. doi: 10.1016/j.canep.2020.101703
Sub-optimal use or interpretation of imaging investigations prior to diagnosis of certain cancers may be associated with less timely diagnosis, but pre-diagnostic imaging activity for urological cancer is unknown.
Kim L, Boxall N, George A, Burling K, Acher P, Aning J, McCracken S, Page T and Gnanapragasam VJ.
BMC Medicine, published April 17 2020. DOI: 10.1186/s12916-020-01548-3
The clinical pathway to detect and diagnose prostate cancer has been revolutionised by the use of multiparametric MRI (mpMRI pre-biopsy). mpMRI however remains a resource-intensive test and is highly operator dependent with variable effectiveness with regard to its negative predictive value. Here we tested the use of the phi assay in standard clinical practice to pre-select men at the highest risk of harbouring significant cancer and hence refine the use of mpMRI and biopsies.
Wajs E, Rughoobur G, Burling K, George A, Flewitt AJ and Gnanapragasam VJ.
Nanoscale, published April 15 2020. DOI: 10.1039/d0nr00416b
Easy monitoring of prostate specific antigen (PSA) directly from blood samples would present a significant improvement as compared to conventional diagnostic methods. In this work, a split mode thin film bulk acoustic resonator (TFBAR) device was employed for the first time for label-free measurements of PSA concentrations in the whole blood and without sample pre-treatment. The surface of the sensor was covalently modified with anti-PSA antibodies and demonstrated a very high sensitivity of 101 kHz mL ng−1 and low limit of detection (LOD) of 0.34 ng mL−1 in model spiked solutions. It has previously been widely believed that significant pre-processing of blood samples would be required for TFBAR biosensors. Importantly, this work demonstrates that this is not the case, and TFBAR technology provides a cost-effective means for point-of-care (POC) diagnostics and monitoring of PSA in hospitals and in doctors’ offices. Additionally, the accuracy of the developed biosensor, with respect to a commercial auto analyser (Beckman Coulter Access), was evaluated to analyse clinical samples, giving well-matched results between the two methods, thus showing a practical application in quantitative monitoring of PSA levels in the whole blood with very good signal recovery.
Estela González‐Gualda, Marta Páez‐Ribes, Beatriz Lozano‐Torres, David Macias, Joseph R. Wilson III, Cristina González‐López, Hui‐Ling Ou, Sofía Mirón‐Barroso, Zhenguang Zhang, Araceli Lérida‐Viso, Juan F. Blandez, Andrea Bernardos, Félix Sancenón, Miguel Rovira, Ljiljana Fruk, Carla P. Martins, Manuel Serrano, Gary J. Doherty, Ramón Martínez‐Máñez, Daniel Muñoz‐Espín.
Aging Cell, published: March 31 2020. DOI: 10.1111/acel.13133.
Pharmacologically active compounds with preferential cytotoxic activity for senescent cells, known as senolytics, can ameliorate or even revert pathological manifestations of senescence in numerous preclinical mouse disease models, including cancer models. However, translation of senolytic therapies to human disease is hampered by their suboptimal specificity for senescent cells and important toxicities that narrow their therapeutic windows. We have previously shown that the high levels of senescence-associated lysosomal b-galactosidase (SA-b-gal) found within senescent cells can be exploited to specifically release tracers and cytotoxic cargoes from galactose-encapsulated nanoparticles within these cells. Here we show that galacto-conjugation of the BCL-2 family inhibitor navitoclax results in a potent senolytic prodrug (Nav-Gal), that can be preferentially activated by SA-b-gal activity in a wide range of cell types. Nav-Gal selectively induces senescent cell apoptosis and has a higher senolytic index than navitoclax (through reduced activation in non-senescent cells). Nav-Gal enhances the cytotoxicity of standard senescence-inducing chemotherapy (cisplatin) in human A549 lung cancer cells. Concomitant treatment with cisplatin and Nav-Gal in vivo results in the eradication of senescent lung cancer cells and significantly reduces tumour growth. Importantly, galacto-conjugation reduces navitoclax-induced platelet apoptosis in human and murine blood samples treated ex vivo, and thrombocytopaenia at therapeutically-effective concentrations in murine lung cancer models. Taken together, we provide a potentially versatile strategy for generating effective senolytic prodrugs with reduced toxicities.
Watson CJ, Papula AL, Poon GYP, Wong WH, Young AL, Druley TE, Fisher DS and Blundell JR.
Science (2020), published March 27 2020. DOI: 10.1126/science.aay9333
Cancer is evolution at the cellular level. As we age, we acquire mutations in the cells that make up our tissues. Whilst the vast majority of these mutations are harmless, some of them increase the Darwinian ‘fitness’ of cells, allowing them to expand and outcompete our healthy cells. These expansions increase the chance of accumulating further cancer-causing mutations and can thus increase the risk of developing cancer. A major question in the field of early cancer detection is therefore: which specific mutations enable cells to expand most rapidly, and thus might confer the highest risk of cancer? Blood’s relative ease of sampling has resulted in the generation of a huge amount of genomic data in recent years and this provides us with an ideal opportunity to answer this question.
Archer, S, de Villiers CB, Scheibl F, Carver T, Hartley S, Lee A, Cunningham AP, Easton DF, McIntosh JG, Emery J, Tischkowitz M, Antoniou AC and Walter FM.
PLOS One Journal, published March 6 2020. DOI: 10.1371/journal.pone.0229999
There is a growing focus on the development of multi-factorial cancer risk prediction algorithms alongside tools that operationalise them for clinical use. BOADICEA is a breast and ovarian cancer risk prediction model incorporating genetic and other risk factors. A new user-friendly Web-based tool (CanRisk.org) has been developed to apply BOADICEA. This study aimed to explore the acceptability of the prototype CanRisk tool among two healthcare professional groups to inform further development, evaluation and implementation.
Freeman K, Dinnes J, Chuchu N, Takwoingi Y, Bayliss SE, Matin RN, Jain A, Walter FM, Williams HC and Deeks, JJ.
BMJ (2020), published February 10 2020. DOI: 10.1136/bmj.m127
Skin cancer is one of the most common cancers in the world, and the incidence is increasing. As skin cancer smartphone applications provide a technological approach to assist people with suspicious lesions to decide whether they should seek further medical attention, this study was undertaken to examine the validity and accuracy of these applications.
Click here for the commentary by Ben Goldacre.
Degasperi A, Dias Amarante T, Czarnecki J, Shooter S, Zou X, Glodzik D, Morganella S, Nanda AS, Badja C, Koh G, Momen SE, Georgakopoulos-Soares I, Dias JML, Young J, Memari Y, Davies H, Nik-Zainal S
Nat Cancer, published: February 17 2020. DOI:10.1038/s43018-020-0027-5
We highlight how the vast number of mutation patterns that we call mutational signatures in human cancers demonstrate some inter-tissue variation, and we present a practical framework for how to use mutational signatures to stratify patient cancers more accurately. We also advance one of our clinical algorithms called HRDetect which helps to identify tumors with HR-deficiency more accurately across all tumour types.
Noorani A, Li X, Goddard M, Crawte J, Alexandrov LB, Secrier M, Eldridge MD, Bower L, Weaver J, Lao-Sirieix P, Martincorena I, Debiram-Beecham I, Gerhan N, MacRae S, Malhotra S, Miremadi A, Thomas T, Galbraith S, Petersen L, Preston SD, Gilligan D, Hindmarsh A, Hardwick RH, Stratton MR, Wedge DC and Fitzgerald RC.
Nature Genetics (2020), published January 6 2020. DOI: 10.1038/s41588-019-0551-3
This paper studies the pattern and timing of metastatic spread in esophageal adenocarcinoma (EAC) because of the the poor outcomes. 388 samples from across 18 individuals with EAC were analysed using whole-genome sequencing and phylogenetic analysis and showed that in 90% of patients multiple subclones from the primary tumor spread very rapidly from the primary site to form multiple metastases. These include lymph nodes and distant tissues- a mode of dissemination also called 'clonal diaspora'. Metastatic subclones at autopsy were present in tissue and blood samples from earlier time points. These findings will impact the understanding and clinical evaluation of EAC.
Gordon GSD, Joseph J, Alcolea MP, Sawyer T, Williams C, Fitzpatrick CRM, Jones PH, di Pietro M, Fitzgerald RC, Wilkinson TD and Bohndiek SE.
Journal of Biomedical Optics 24(12), 126004 (2019), published December 16 2019. DOI: 10.1117/1.JBO.24.12.126004
Phase and polarisation of coherent light are highly perturbed by interaction with microstructural changes in premalignant tissue, holding promise for label-free detection of early tumours in endoscopically accessible tissues such as the gastrointestinal tract. Flexible optical multicore fiber (MCF) bundles used in conventional diagnostic endoscopy and endomicroscopy scramble phase and polarization, restricting clinicians instead to low-contrast amplitude-only imaging. We apply a transmission matrix characterisation approach to produce full-field en-face images of amplitude, quantitative phase, and resolved polarimetric properties through an MCF. We first demonstrate imaging and quantification of biologically relevant amounts of optical scattering and birefringence in tissue-mimicking phantoms. We present an entropy metric that enables imaging of phase heterogeneity, indicative of disordered tissue microstructure associated with early tumours. Finally, we demonstrate that the spatial distribution of phase and polarisation information enables label-free visualisation of early tumours in esophageal mouse tissues, which are not identifiable using conventional amplitude-only information.
Paez-Ribes M, González-Gualda E, Doherty GJ, Muñoz‐Espín D
EMBO Molecular Medicine (2019), e10234, published November 19 2019. DOI: 10.15252/emmm.201810234
Organismal ageing is a complex process driving progressive impairment of functionality and regenerative potential of tissues. Cellular senescence is a state of stable cell cycle arrest occurring in response to damage and stress and is considered a hallmark of ageing. Senescent cells accumulate in multiple organs during ageing, contribute to tissue dysfunction and give rise to pathological manifestations. Senescence is therefore a defining feature of a variety of human age‐related disorders, including cancer, and targeted elimination of these cells has recently emerged as a promising therapeutic approach to ameliorate tissue damage and promote repair and regeneration. In addition, in vivo identification of senescent cells has significant potential for early diagnosis of multiple pathologies. Here, we review existing senolytics, small molecules and drug delivery tools used in preclinical therapeutic strategies involving cellular senescence, as well as probes to trace senescent cells. We also review the clinical research landscape in senescence and discuss how identifying and targeting cellular senescence might positively affect pathological and ageing processes.
Aboy M, Crespo C, Liddell K, Minssen T, Liddicoat J
Nature Biotechnology 37, 513–518, published May 3 2019. DOI: 10.1038/s41587-019-0111-5
Six years on this paper looks at the impact of the US Supreme Court decision in the Mayo v. Prometheus case on patent subject-matter eligibility and the prosecution of biotech-related patent applications before the US Patent and Trademark Office.
Waterhouse DJ, Fitzpatrick CRM, Pogue BW, O'Connor JPB & Bohndiek SE
Nature Biomedical Engineering. Published April 29, 2019. doi: 10.1038/s41551-019-0392-5
We have worked with the author of the original roadmap for cancer imaging biomarkers, Prof. James O’Connor, and leading biophotonics expert Prof. Brian Pogue to develop a dedicated roadmap for clinical implementation tailored specifically to optical-imaging biomarkers. The perspective draws on two case studies: the endoscopic visualisation of dysplasia in Barrett’s oesophagus in secondary care and the detection of malignant melanoma in primary care. These are used to identify key characteristics that are important for successful clinical implementation and highlight key decision points in the pathway.
J Yoon, Joseph J, Waterhouse DJ, Luthman AS, Gordon GSD, di Pietro M, Januszewicz W, Fitzgerald RC & Bohndiek SE
Nature Communications. Published April 23, 2019. doi: 10.1038/s41467-019-09484-4
Hyperspectral imaging (HSI) enables visualisation of morphological and biochemical information, which could improve disease diagnostic accuracy. Unfortunately, the wide range of image distortions that arise during flexible endoscopy in the clinic have made integration of HSI challenging. To address this challenge, we demonstrate a hyperspectral endoscope (HySE) that simultaneously records intrinsically co-registered hyperspectral and standard-of-care white light images, which allows image distortions to be compensated computationally and an accurate hyperspectral data cube to be reconstructed as the endoscope moves in the lumen. Evaluation of HySE performance shows excellent spatial, spectral and temporal resolution and high colour fidelity. Application of HySE enables: quantification of blood oxygenation levels in tissue mimicking phantoms; differentiation of spectral profiles from normal and pathological ex vivo human tissues; and recording of hyperspectral data under freehand motion within an intact ex vivo pig oesophagus model. HySE therefore shows potential for enabling HSI in clinical endoscopy.
Barclay ME, Lyratzopoulos G, Walter FM, Jefferies S, Peake MD & Rintoul RC
BMJ journal Thorax. Published February 18, 2019. doi: 10.1136/thoraxjnl-2018-212456
Collaborative research by statistician Matt Barclay (Public Health and Primary Care) with Georgios Lyratzopoulos, Fiona Walter (Public Health and Primary Care), Sarah Jefferies (CUH, Oncology), Michael Peake (University of Leicester) and Robert Rintoul (Oncology) strongly suggests that lung cancer follow-up should be extended from five to ten years.
Five-year survival of patients with lung cancer has doubled in England during the past 15 years as lung cancer treatment has become more effective. This new study, published in the BMJ journal Thorax, finds that amongst lung cancer survivors, particularly women, there is a higher risk of getting a second smoking-related cancer for at least a decade from the time of the first primary lung cancer diagnosis. The population-based cohort study shows that those aged 50–79 at first diagnosis are at particularly high risk.
The new evidence strongly suggests the need for extended lung cancer follow-up and surveillance for other smoking-related cancers including head and neck, laryngeal and oesophageal squamous cell carcinoma, will need careful evaluation.
Lee A, Mavaddat N, Wilcox AN, Alex P. Cunningham AP, Carver T, Hartley S, de Villiers CB, Izquierdo A, Simard J, Schmidt MK, Walter FM, Chatterjee N, Garcia-Closas M, Tischkowitz M, Pharoah P, Easton DF & Antoniou AC
Genetics in Medicine. Published January 15, 2019. doi: 10.1038/s41436-018-0406-9
Cambridge researchers have developed an online calculator to be used in GP surgeries, which should enable high levels of breast cancer risk stratification in the general population and women with family history. BOADICEA is the first comprehensive calculator for the risk of developing the disease combining information on family history and more than 300 genetic indicators for breast cancer, with other factors such as weight, age at menopause, alcohol consumption and use of hormone replacement therapy. It is anticipated this will facilitate informed decision-making on individualised prevention therapies and screening for breast cancer.
Blundell JR, Schwartz K, Francois D, Fisher DS, Sherlock G and Levy SF.
Nature. Published December 31, 2018. doi: 10.1038/s41559-018-0758-1
The dynamics of genetic diversity in clonal populations is poorly understood, yet has important implications for treatment of microbial infections and cancer. In this study we combined a novel DNA barcoding technology in yeast, mathematical modelling and single-cell derived sequencing to probe the genetic diversity of clonally evolving cell populations. We found that there are predictable expansions and crashes in genetic diversity that emerge due to the population dynamics. Exploiting these neutral oscillations could have important implications for how we treat diseases (e.g. cancer) caused by clonal evolution of large cell populations.
Martincorena I, Fowler JC, Wabik A, Lawson ARJ, Abascal F, Hall MWJ, Cagan A, Murai K, Mahbubani K, Stratton MR, Fitzgerald RC, Handford PA, Campbell PJ, Saeb-Parsy K, Jones PH.
Science. Published October 18, 2018. doi: 10.1126/science.aau3879
The extent to which cells in normal tissues accumulate mutations throughout life is poorly understood - some mutant cells expand into clones that can be detected by genome sequencing. This paper mapped mutant clones in normal esophageal epithelium from nine donors which showed that mutations accumulated with age and were caused mainly by intrinsic mutational processes. The authors noted that, even if they do not contribute to carcinogenesis, drivers of benign clonal expansions could still appear as recurrently mutated genes in cancer genomes owing to their high mutation frequency in the normal cells from which tumors evolve. Better understanding of the mutational landscape in normal tissues may thus help refine current catalogs of cancer-driver genes, with important implications for early diagnosis and targeted therapy.
Murai K, Skrupskelyte G, Piedrafita G, Hall M, Kostiou V, Ong SH, Nagy T, Cagan A, Goulding D, Klein AM, Hall BA, Jones PH.
Cell Stem Cell. Published online September 27, 2018. doi: 10.1016/j.stem.2018.08.017
This study argues that the patchwork of clones carrying oncogenic mutations in sun-exposed human epidermis is shaped by both phenotypic adaptation and cell competition. Understanding how mutant progenitor clones interact is key to understanding not only epidermal physiology, but also the formulation of rational approaches to prevent malignant transformation.
Further information and animation on Wellcome Sanger Institute website
Pashayan N, Morris S, Gilbert FJ, Pharoah P
JAMA Oncol. Published online July 5, 2018. doi:10.1001/jamaoncol.2018.1901
In this cost-effectiveness study, a life-table model of a hypothetical cohort of 364 500 women finds that targeting screening to women at higher risk of breast cancer is associated with reduced overdiagnosis and reduced cost of screening without compromising quality-adjusted life-years gained and while maintaining reduced breast cancer deaths. This suggests that the cost-effectiveness and the benefit-to-harm ratio of breast screening programs could be improved by adopting a risk-stratified screening strategy.
Abelson S, Collord G, Vassiliou G, Gerstung M, Shlush LL and collaborators
Nature volume 559, pages 400–404 (2018). DOI: 10.1038/s41586-018-0317-6
Cambridge researchers and their international collaborators have found that patients with AML had genetic changes in their blood years before they suddenly developed the disease, reported in a study in Nature. Further research could allow earlier detection and monitoring of people at risk of AML in the future, and open the prospect of developing ways to reduce the likelihood of developing this cancer.
Wajs E, Rughoobur G, Flewitt A
Nanoscale, 2018, DOI: 10.1039/C8NR04665D
Publication from Andrew Flewitt et al from work supported by a pump-priming award from the Cancer Research UK Cambridge Centre Early Detection Programme [CRUK grant ref: A20976]