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]
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
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.
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.
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.
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.
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."
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.