Early Detection related publications from the University of Cambridge

Covid-19 test and trace: Look for the super-locals to access “hard to reach” groups

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.

Genomic copy number predicts esophageal cancer years before transformation

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).

Current evidence on screening for renal cancer

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.

Cytosponge-trefoil factor 3 versus usual care to identify Barrett's oesophagus in a primary care setting: a multicentre, pragmatic, randomised controlled trial

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.

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Use of Cytosponge as a triaging tool to upper gastrointestinal endoscopy during the COVID-19 pandemic

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.

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Personalized early detection and prevention of breast cancer: ENVISION consensus statement

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.

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ctDNA monitoring using patient-specific sequencing and integration of variant reads

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.

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Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer

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.

Spatial competition shapes the dynamic mutational landscape of normal esophageal epithelium

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.

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Perspective: The challenge of early detection in cancer

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.

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Imaging activity possibly signalling missed diagnostic opportunities in bladder and kidney cancer: A longitudinal data-linkage study using primary care electronic health records

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.

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Clinical utility and cost modelling of the phi test to triage referrals into image-based diagnostic services for suspected prostate cancer: the PRIM (Phi to RefIne Mri) study

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.

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A novel split mode TFBAR device for quantitative measurements of prostate specific antigen in a small sample of whole blood

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.

Galacto‐conjugation of Navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity

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.

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The evolutionary dynamics and fitness landscape of clonal hematopoiesis

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.

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Evaluating clinician acceptability of the prototype CanRisk tool for predicting risk of breast and ovarian cancer: A multi-methods study

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.

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Algorithm based smartphone apps to assess risk of skin cancer in adults: systematic review of diagnostic accuracy studies

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.

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A practical framework and online tool for mutational signature analyses show inter-tissue variation and driver dependencies

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.

Genomic evidence supports a clonal diaspora model for metastases of esophageal adenocarcinoma

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.

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Quantitative phase and polarization imaging through an optical fiber applied to detection of early esophageal tumorigenesis

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.

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Targeting senescent cells in translational medicine

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.

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Mayo's impact on patent applications related to biotech, diagnostics, and personalized medicine?

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.

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A roadmap for the clinical implementation of optical-imaging biomarkers

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.

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A clinically translatable hyperspectral endoscopy (HySE) system for imaging the gastrointestinal tract

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.

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Incidence of second and higher order smoking-related primary cancers following lung cancer: a population-based cohort study

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.

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BOADICEA: a comprehensive breast cancer risk prediction model incorporating genetic and nongenetic risk factors

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.

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The dynamics of adaptive genetic diversity during the early stages of clonal evolution

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.

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Somatic mutant clones colonize the human esophagus with age

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.

Epidermal tissue adapts to restrain progenitors carrying clonal p53 mutations

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

Cost-effectiveness and benefit-to-harm ratio of risk-stratified screening for breast cancer: A Life-Table Model

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.

Prediction of acute myeloid leukaemia risk in healthy individuals

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.

Split resonances for simultaneous detection and control measurements in a single Bulk Acoustic Wave (BAW) sensor

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]

A versatile drug delivery system targeting senescent cells

Muñoz-Espín D, Rovira M, Galiana I, Giménez C, Lozano-Torres B, Paez-Ribes M, Llanos S, Chaib S, Muñoz-Martín M, Ucero AC, Garaulet G, Mulero F, Dann SD, VanArsdale T, Shields D, Bernardos A, Murguía JR, Martínez-Máñez R, Manuel Serrano M.

EMBO Molecular Medicine (2018) e9355. Published online 16.07.2018. doi: 10.15252/emmm.201809355

A brief summary of the paper by lead author Daniel Muñoz-Espín

Problem

Senescent cells are present in many diseases where they play an active pathological role. A common feature of senescent cells is their high content of lysosomes. Here, it is reported a pharmacological vehicle with lysosomal tropism that preferentially releases drugs into senescent cells.

Results

Drugs encapsulated with galacto-oligosaccharides (gal-encapsulation) are released into cells after digestion with lysosomal b-galactosidase and this happens more efficiently in senescent cells. We demonstrate that gal-encapsulated drugs are preferentially released into damaged tissues containing senescent cells, such as bleomycin-induced lung fibrosis in mice. The release of gal-encapsulated doxorubicin into fibrotic lungs results in remarkable reduction in the abnormal amount of collagen present and in recovery of respiratory function. In the case of xenograft tumors, mice are treated with senescence-inducing chemotherapy, and concomitant treatment with gal-encapsulated doxorubicin results in full tumor regression. Gal-encapsulation has the additional advantage of reducing the exposure of non-target organs to the drugs.

Impact

This study presents proof of principle for the biological activity of a versatile encapsulation method that allows to deliver small molecules preferentially in diseased tissues containing senescent cells. This may open new diagnostic and therapeutic opportunities for severe diseases, such as pulmonary fibrosis, and in premalignant lesions accumulating senescent cells. It may also serve as a companion treatment for cancer chemotherapy.


Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets

Wedge DC, Gundem G, Eeles RA, Mitchell T, Woodcock DJ, Martincorena I, Ghori M, Zamora J, Butler A, Whitaker H, Kote-Jarai Z, Alexandrov LB, Van Loo P, Massie CE , Dentro S, Warren AY, Verrill C, Berney DM, Dennis N, Merson S, Hawkins S, Howat W, Lu Y, Lambert A, Kay J, Kremeyer B, Karaszi K, Luxton H, Camacho N, Marsden L, Edwards S, Matthews L, Bo V, Leongamornlert D, McLaren S, Ng A, Yu Y, Zhang H, Dadaev T, Thomas S, Easton DF, Ahmed M, Bancroft E, Fisher C, Livni N, Nicol D, Tavare S, Gill P, Greenman C, Khoo V, van As N, Kumar P, Ogden C, Cahill D, Thompson A, Mayer E, Rowe E, Dudderidge T, Gnanapragasam V, Shah NC, Raine K, Jones D, Menzies A, Stebbings L, Teague J, Hazell S, Corbishley C, CAMCAP Study Group, de Bono J, Attard G, Isaacs W, Visakorpi T, Fraser M, Boutros PC, Bristow RG, Workman P, Sander C, The TCGA Consortium, Hamdy FC, Futreal A, McDermott U, Al-Lazikani B, Lynch AG, Bova GS, Foster CS, Brewer DS, Neal DE, Cooper CS and Eeles RA.

Nature Genetics, April 16, 2018, doi: 10.1038/s41588-018-0086-z

The CRUK Prostate Cancer ICGC group have identified new driver genes and 80 markers for drug sensitivity studies. The Cambridge translational prostate cancer group and the international team of collaborators sequenced 112 prostate cancer genomes and integrated data from over 900 prostate cancer cases. Analysis of this large cohort allowed the identification of early events in prostate tumourigenesis, as well as markers of aggressive disease and leads for precision medicine studies in early stage cancers. The study is published in Nature Genetics and was funded mainly by CRUK.

Reimagining the diagnostic pathway for gastrointestinal cancer

Rubin G, Walter F, Emery J & de Wit N.

Nature Reviews Gastroenterology & Hepatology. February 7, 2018, doi:(3):10.1038/nrgastro.2018.1

This Perspectives article in Nature Reviews highlights that a crisis is looming for the diagnosis of gastrointestinal (GI) cancers. In the UK, urgent referrals for suspected lower gastrointestinal cancer have increased by 78% in the past 6 years, with parallel increases in endoscopy and imaging activity. This paper presents a reimagined diagnostic pathway for GI cancer in which the relationship between medical specialists and generalists could be redefined to make better use of the skills of each, while delivering optimal clinical outcomes and a good patient experience.

Author Dr Fiona Walter, head of the Cancer Group at the Primary Care Unit and Director of the CanTest Collaborative, comments: "This paper exemplifies the work of CanTest, our Cancer Research UK Catalyst award. We are developing strategies to accelerate improvement in cancer outcomes through implementation in primary care of diagnostic testing to support early detection of cancer. Our research aims to systematically evaluate new tests leading to not only optimal clinical outcomes, but also improved quality and patient safety and more cost-effective health care."

Cost-effectiveness of population-based BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, PALB2 mutation testing in unselected general population women

Manchanda R, Patel S, Gordeev V, Antoniou AC, Smith S, Lee A, Hopper JL, Maclnnis RJ, Turnbull C, Ramus Simon A Gayter SJ, Pharoah PDP, Menon U, Jacobs I, Menon U, Jacobs I and Legood R.

JNCI: Journal of the National Cancer Institute, January 18, 2018, doi: 10.1093/jnci/djx265

Screening the entire population for breast and ovarian cancer gene mutations, as opposed to just those at high-risk of carrying this mutation, is cost effective and could prevent more ovarian and breast cancers than the current approach, according to research led by Queen Mary University of London.

Determination of complex subclonal structures of haematological malignancies by multiplexed genotyping of blood progenitor colonies

Nice FL, Massie CE, Klampfl T and Green AR.

Elsevier. October 9, 2017, doi: 10.1016/j.exphem.2017.09.011

This publication presents a strategy of highly multiplexed genotyping of burst forming unit-erythroid (BFU-E) colonies based on NGS results to assess subclonal tumour structure. This allowed for the generation of complex clonal hierarchies and determination of order of mutation acquisition far more accurately than was possible from NGS data alone.

Appraising the relevance of DNA copy number loss and gain in prostate cancer using whole genome DNA sequence data

Camacho N, van Loo P, Edwards S, Kay JD, Matthews L, Haase K, Clark J, Dennis N, Thomas S, Kremeyer B, Zamora J, Butler AP, Gundem G, Merson S, Luxton H, Hawkins S, Ghori M, Marsden L, Lambert A, Karaszi K, Pelvender G, Massie CE, Kote-Jarai Z, Raine K, Jones D, Howat WJ, Hazell S, Livin N, Fisher C, Ogden C, Kumar P, Thompson A, Nicol D, Mayer E, Dudderidge T, Yu Y, Zhang H, Shah NC, Gnanapragasam VJ, CRUK-ICGC Prostate Group, Isaacs W, Visakorpi T, Hamdy F, Berney D, Verrill C, Warren AY, Wedge DC, Lynch AG, Foster CS, Lu YJ, Bova GS, Whitaker HC, McDermott U, Neal DE, Eeles R, Cooper CS and Brewer DS.

PLoS Med, September 25, 2017, doi: 10.137/journal.pgen.1007001

A variety of models have been proposed to explain regions of recurrent somatic copy number alteration (SCNA) in human cancer. This study employs Whole Genome DNA Sequence (WGS) data from tumor samples (n = 103) to comprehensively assess the role of the Knudson two hit genetic model in SCNA generation in prostate cancer.

The dynamics of adaptive genetic diversity during the early stages of clonal evolution

Blundell JR, Schwartz K, Francois D, Fischer DS, Sherlock G and Levy SF.

bioRxiv. July 31, 2017, doi: 10.1101/170589

In this publication barcode lineage tracking, sequencing of adaptive clones, and mathematical modelling of mutational dynamics are combined to understand diversity changes during experimental evolution.

An OFF-ON two-photon fluorescent probe for tracking cell senescence in vivo

Lozano-Torres B, Galiana I, Rovira M, Garrido E, Chaib S, Bernardos A, Muñoz-Espín D, Serramo M, Martínez-Máñez R and Sancenón F.

Journal of the American Chemical Society. June 18, 2017, doi: 10.1021/jacs.7b04985

A naphthalimide-based two-photon probe (AHGa) for the detection of cell senescence is designed. The probe contains a naphthalimide core, an l-histidine methyl ester linker, and an acetylated galactose bonded to one of the aromatic nitrogen atoms of the l-histidine through a hydrolyzable N-glycosidic bond. Probe AHGa is transformed into AH in senescent cells resulting in an enhanced fluorescent emission intensity. In vivo detection of senescence is validated in mice bearing tumor xenografts treated with senescence-inducing chemotherapy.

A scalable double-barcode sequencing platform for characterization of dynamic protein-protein interactions

Schlecht U, Liu Z, Blundell JR, St. Onge RP and Levy SF.

Nature Communications 8. May 25, 2017, doi: 10.1038/ncomms15586

Several large-scale efforts have systematically cataloged protein-protein interactions (PPIs) of a cell in a single environment. However, little is known about how the protein interactome changes across environmental perturbations. Current technologies only assay one PPI at a time, therefore a highly parallel protein-protein interaction sequencing (PPiSeq) platform is developed that uses a novel double barcoding system in conjuction with the dihydrofolate reductase protein-fragment complementation assay in Saccharomyces cerevisiae.

Meta-analysis of the prevalence of renal cancer detected by abdominal ultrasonography

Rossi SH, Hsu R, Blick C, Goh V, Nathan P, Nicol D, Fleming S, Sweeting M, Wilson EC, Stewart GD

British Journal of Surgery, April 13, 2017, 104: 648–659. doi: 10.1002/bjs.10523

The potential for an ultrasound-based screening programme for renal cell carcinoma (RCC) to improve survival through early detection has been the subject of much debate. The prevalence of ultrasound-detected asymptomatic RCC is an important first step to establishing whether a screening programme may be feasible. This meta-analysis suggests that screening 1000 individuals would result in four patients undergoing further imaging of a renal mass, and that at least one of these patients would be diagnosed with RCC . The majority (84%) of tumours screen-detected by ultrasound were early stage (T1–T2 N0).

Liquid biopsies come of age: towards implementation of circulating tumour DNA

Wan JCM, Massie C, Garcia-Corbacho J, Mouliere F, Brenton JD, Caldas C, Pacey S, Baird R, Rosenfeld N.

Nat. Rev. Cancer February 2017 (online). doi:10.1038/nrc.2017.7

Improvements in genomic and molecular methods are expanding the range of potential applications for circulating tumour DNA (ctDNA), both in a research setting and as a ‘liquid biopsy’ for cancer management. This paper appraises potential approaches to ctDNA analysis and considers applications in personalised oncology and in cancer research.

Acceptability of the Cytosponge procedure for detecting Barrett’s oesophagus: a qualitative study

Freeman M, Offman J, Walter FM, Sasieni P, Smith SG.

BMJ Open 2017;7: e013901. February 7, 2017. doi:10.1136/bmjopen-2016-013901

This paper describes a study into the acceptability of the Cytosponge, a novel sampling device to detect Barrett’s oesophagus (BE), a precursor to oesophageal adenocarcinoma (EAC), among people with risk factors for this condition. These qualitative data suggest the Cytosponge was acceptable to the majority of participants with risk factors for BE.

Robust, universal biomarker assay to detect senescent cells in biological specimens

Evangelou K, Lougiakis N, Rizou SV, Kotsinas A, Kletsas D, Muñoz-Espín D, Kastrinakis NG, Pouli N, Marakos P, Townsend P, Serrano M, Bartek J and Gorgoulis VG.

Aging Cell. November 17, 2016, doi: 10.1111/acel.12545

Cellular senescence contributes to organismal development, aging, and diverse pathologies, yet available assays to detect senescent cells remain unsatisfactory. This publication proposes a new hybrid histo-/immunochemical method, easy to perform, reliable, and universally applicable to assess senescence in biomedicine, from cancer research to gerontology.

Development of a comprehensive genotype-to-fitness map of adaption-driving mutations in yeast

Venkataram S, Dunn B, Li Y, Agarwala A, Chang J, Ebel ER, Geiler-Samerotte K, Hérissant L, Blundell JR, Levy SF and Fisher DS.

CellPress volume 166, Issue 6. September 8 2016, doi: 10.1016/j.cell.2016.08.002

Adaptive evolution plays a large role in generating the phenotypic diversity observed in nature, yet current methods are impractical for characterizing the molecular basis and fitness effects of large numbers of individual adaptive mutations. In this publication, a DNA barcoding approach was used to generate the genotype-to-fitness map for adaptation-driving mutations from a Saccharomyces cerevisiae population experimentally evolved by serial transfer under limiting glucose.

Design and validation of a near-infrared fluorescence endoscope for detection of early esophageal malignancy

Waterhouse DJ, Joseph J, Neves AA, di Pietro M, Brindle KM, Fitzgerald RC, Bohndiek SE.

J. Biomed. Opt. 21(8), 084001 (Aug 04, 2016). doi:10.1117/1.JBO.21.8.084001.

This paper describes the synthesis of near-infrared (NIR) fluorescent wheat germ agglutinin (WGA-IR800CW) and the construction of a clinically translatable bimodal NIR and white light endoscope to combat the lack of contrast in white light endoscopy when imaging patients with suspected Barrett’s oesophagus.

Regulators of genetic risk of breast cancer identified by integrative network analysis

Castro MAA, de Santiago I, Campbell TM, Vaughn C, Hickey TE, Ross E, Tilley WD, Markowetz F, Ponder BA, Meyer KB.

Nat Genet. 48(1):12-21 (2016).

The network approach used here provides a foundation for determining the regulatory circuits governing breast cancer as well as other disease settings, to identify targets for intervention.

Analysis of dysplasia in patients with Barrett’s esophagus based on expression pattern of 90 genes

Varghese S, Newton R, Ross-Innes CS, Lao-Sirieix P, Krishnadath KK, O’Donovan M, Novelli M, Wernisch L, Bergman J, Fitzgerald RC.

Gastroenterology 2015 Nov 149(6) 1511-18 Epub 2015.

This paper discovers and validates a 90 gene panel to accurately identify patients with low grade dysplasia in Barrett’s oesophagus who are at high risk of progression.

Single-pixel phase-corrected fiber bundle endomicroscopy with lensless focussing capability.

Gordon GSD, Joseph J, Bohndiek SE, Wilkinson TD.

J. Lightwave Technol, 2015, 33 (16): 3419-3425.

This study paves the way for the use of optical phase for lensless focusing in endoscopy.

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