Early Detection related publications from the University of Cambridge

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.

Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin

Martincorena I, Roshan A, Gerstung M, Ellis P, Van Loo P, McLaren S, Wedge DC, Fullam A, Alexandrov LB, Tubio JM, Stebbings L, Menzies A, Widaa S, Stratton MR, Jones PH*, Campbell PJ*. (*co-corresponding authors).

Science 2015, 880-86. May 22, 2015. 348, doi: 10.1126/science.aaa6806

This paper describes how aged sun-exposed skin is a patchwork of thousands of evolving clones with over a quarter of cells carrying cancer-causing mutations while maintaining the physiological functions of the epidermis.

Symptoms and other factors associated with time to presentation and diagnosis and stage at diagnosis of lung cancer: a prospective cohort study

Walter FM, Rubin G, Bankhead C, Morris HC, Hall N, Mills K, Dobson C, Rintoul R, Hamilton W and Emery J.

Brit J Cancer. 2015 Mar 31;112 Suppl: S6-S13. doi: 10.1038/bjc.2015.30. PMID: 25734397.

This study found that haemoptysis is the strongest symptom predictor of lung cancer but occurs in only a fifth of patients, calling for programmes of early diagnosis to focus on multiple symptoms and their evolution.

Dissecting the role of the ϕ29 terminal protein DNA binding residues in viral DNA replication

Holguera I, Muñoz-Espín D and Salas M.

Nucleic Acids Research. February 26, 2015, doi: 10.1093/nar/gkv127

This publication describes the involvement of the TP N-terminal domain residues responsible for DNA binding in the different stages of viral DNA replication by assaying the in vitro activity of purified TP N-terminal mutant proteins.

Evaluation of a minimally invasive cell sampling device coupled with assessment of trefoil factor 3 expression for diagnosing Barrett’s esophagus: a multi-centre case-control study

Ross-Innes CS, Debiram-Beecham I, O'Donovan M, Walker E, Varghese S, Lao-Sirieix P, Lovat L, Griffin M, Ragunath K, Haidry R, Sami SS, Kaye P, Novelli M, Disep B, Ostler R, Aigret B, North BV, Bhandari P, Haycock A, Morris D, Attwood S, Dhar A, Rees C, Rutter MD, Sasieni PD, Fitzgerald RC.

BEST2 Study Group. PLoS Med 2015 Jan 29;12(1) eCollection 2015 Jan.

This paper describes the results of a case:control study using the Cytosponge in over 1,000 patients and shows that it is safe, acceptable and has a high degree of accuracy.

Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis

Weaver JMJ, Ross-Innes C, Shannon N, Lynch AG, Forshew T, Barbera M, Murtaza M, Ong C-AJ, Lao-Sirieix P, Dunning MJ, Smith L, Smith ML, Anderson CL, Carvalho B, O'Donovan M, Underwood TJ, May AP, Grehan N, Hardwick R, Davies J, Oloumi A, Aparicio S, Caldas C, Eldridge MD, Edwards PA, Rosenfeld N, Tavaré S and Fitzgerald RC.

OCCAMS Consortium. (2014) Nat Genet. 2014 Aug;46(8):837-43. doi: 10.1038/ng.3013. Epub 2014 Jun 22.

This paper demonstrates for the first time that somatic mutations occur early in pre-invasive disease and careful ordering of events is required in order to develop effective biomarker strategies for Early Detection.

Breast-cancer risk in families with mutations in PALB2

Antoniou AC, Casadei S, Heikkinen T, Barrowdale D, Pylkäs K, Roberts J, Lee A, Subramanian D, De Leeneer K, Fostira F, Tomiak E, Neuhausen SL, Teo ZL, Khan S, Aittomäki K, Moilanen JS, Turnbull C, Seal S, Mannermaa A, Kallioniemi A, Lindeman GJ, Buys SS, Andrulis IL, Radice P, Tondini C, Manoukian S, Toland AE, Miron P, Weitzel JN, Domchek SM, Poppe B, Claes KB, Yannoukakos D, Concannon P, Bernstein JL, James PA, Easton DF, Goldgar DE, Hopper JL, Rahman N, Peterlongo P, Nevanlinna H, King MC, Couch FJ, Southey MC, Winqvist R, Foulkes WD and Tischkowitz M.

N Engl J Med. 2014, Aug 7 2014;371(6):497-506.

This study determined that loss-of-function mutations in PALB2 are an important cause of hereditary breast cancer, with respect to both frequency of mutations and risk associated with them.

Preferences for cancer investigation: a vignette-based study of primary care attenders

Banks J, Hollinghurst S, Bigwood L, Peters TJ, Walter FM and Hamilton W.

Lancet Oncol. 2014;15(2):232-40. doi: 10.1016/S1470-2045(13)70588-6.

This paper investigated the barriers to presentation in primary care, symptom recognition and referral for specialist investigation in lung, pancreatic and colorectal cancers.

GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer.

Pharoah PD, Tsai YY, Ramus SJ, Phelan CM, Goode EL, Lawrenson K, et al.

Nat Genet. 45, 362-70 (2013).

The result of this study was evidence for functional mechanisms underlying susceptibility and pathogenesis of ovarian cancer.