Recent publications co-authored by our Programme Members

Multimodality approaches to screening for lung cancer

21 August, 2019 - Clinical Oncology - Robert Rintoul and Nitzan Rosenfeld

Despite modest improvements in 1- and 5-year survival lung cancer remains the most common cause of cancer death in the UK [1]. Unfortunately, around 70% of lung cancers are diagnosed at stage III or IV where the options for treatment with curative intent are greatly reduced [1]. Although targeted therapies and immunomodulators are improving life expectancy in advanced disease they have efficacy in only a small proportion of cases and long-term survival remains low....

SDHC epi-mutation testing in gastrointestinal stromal tumours and related tumours in clinical practice.

15 July, 2019 - Scientific reports - Rogier ten Hoopen, Olivier Giger and Ramesh Bulusu

Abstract: The enzyme succinate dehydrogenase (SDH) functions in the citric acid cycle and loss of function predisposes to the development of phaeochromocytoma/paraganglioma (PPGL), wild type gastrointestinal stromal tumour (wtGIST) and renal cell carcinoma. SDH-deficient tumours are most commonly associated with a germline SDH subunit gene (SDHA/B/C/D) mutation but can also be associated with epigenetic silencing of the SDHC gene. However, clinical diagnostic testing for an SDHC epimutation is not widely available. The objective of this study was to investigate the indications for and the optimum diagnostic pathways for the detection of SDHC epimutations in clinical practice. SDHC promoter methylation analysis of 32 paraffin embedded tumours (including 15 GIST and 17 PPGL) was performed using a pyrosequencing technique and correlated with SDHC gene expression. SDHC promoter methylation was identified in 6 (18.7%) tumours. All 6 SDHC epimutation cases presented with SDH deficient wtGIST and 3/6 cases had multiple primary tumours. No case of constitutional SDHC promoter hypermethylation was detected. Whole genome sequencing of germline DNA from three wtGIST cases with an SDHC epimutation, did not reveal any causative sequence anomalies. Herein, we recommend a diagnostic workflow for the detection of an SDHC epimutation in a service setting.

A hypercoagulable state leading to venous limb gangrene associated with occult lung adenocarcinoma

May 2019 - Clinical Case Reports - Robert Rintoul & David Gilligan

Abstract: We report a case of lung adenocarcinoma-associated hypercoagulability leading to venous limb gangrene, managed successfully with argatroban and then dabigatran. Use of idarucizumab permitted diagnostic investigations, leading to targeted antineoplastic therapy with crizotinib, surgical resection with curative intent, and continued survival over 2 years after the index event.

Isolation and propagation of primary human cholangiocyte organoids for the generation of bioengineered biliary tissue

20 May, 2019 - Nature protocols - Kourosh Saeb-Parsy

Pediatric liver transplantation is often required as a consequence of biliary disorders because of the lack of alternative treatments for repairing or replacing damaged bile ducts. To address the lack of availability of pediatric livers suitable for transplantation, we developed a protocol for generating bioengineered biliary tissue suitable for biliary reconstruction. Our platform allows the derivation of cholangiocyte organoids (COs) expressing key biliary markers and retaining functions of primary extra- or intrahepatic duct cholangiocytes within 2 weeks of isolation. COs are subsequently seeded on polyglycolic acid (PGA) scaffolds or densified collagen constructs for 4 weeks to generate bioengineered tissue retaining biliary characteristics. Expertise in organoid culture and tissue engineering is desirable for optimal results. COs correspond to mature functional cholangiocytes, differentiating our method from alternative organoid systems currently available that propagate adult stem cells. Consequently, COs provide a unique platform for studies in biliary physiology and pathophysiology, and the resulting bioengineered tissue has broad applications for regenerative medicine and cholangiopathies.

Functional linkage of gene fusions to cancer cell fitness assessed by pharmacological and CRISPR-Cas9 screening.

16 May, 2019 - Nature Communications - Ultan McDermott

Many gene fusions are reported in tumours and for most their role remains unknown. As fusions are used for diagnostic and prognostic purposes, and are targets for treatment, it is crucial to assess their function in cancer. To systematically investigate the role of fusions in tumour cell fitness, we utilized RNA-sequencing data from 1011 human cancer cell lines to functionally link 8354 fusion events with genomic data, sensitivity to >350 anti-cancer drugs and CRISPR-Cas9 loss-of-fitness effects. Established clinically-relevant fusions were identified. Overall, detection of functional fusions was rare, including those involving cancer driver genes, suggesting that many fusions are dispensable for tumour fitness. Therapeutically actionable fusions involving RAF1, BRD4 and ROS1 were verified in new histologies. In addition, recurrent YAP1-MAML2 fusions were identified as activators of Hippo-pathway signaling in multiple cancer types. Our approach discriminates functional fusions, identifying new drivers of carcinogenesis and fusions that could have clinical implications.

Making an IMPACT: A priority setting consultation exercise to improve outcomes in patients with locally advanced, recurrent and metastatic colorectal cancer

7 May, 2019 - European Journal of Surgical Oncology - Nicky Fearnhead

Abstract: The IMPACT (Improving the Management of Patients with Advanced Colorectal Tumours) initiative was established by the Association of Coloproctology of Great Britain and Ireland in 2017 as a consortium of surgeons (colorectal, hepatobiliary, thoracic), oncologists, radiologists, pathologists, palliative care physicians, patients, carers and charity stakeholders who will work together to improve outcomes in patients with advanced and metastatic colorectal cancer. To establish this initiative, better information is required to establish how further intervention is focused. This paper details the approaches used, and outcomes generated, from a priority setting exercise to inform the design of the IMPACT initiative.

Transcriptomic profiling reveals three molecular phenotypes of adenocarcinoma at the gastro-esophageal junction

3 May, 2019 - International Journal of Cancer - Richard Hardwick

Abstract: Cancers occurring at the gastro-esophageal junction (GEJ) are classified as predominantly esophageal or gastric, which is often difficult to decipher. We hypothesised that the transcriptomic profile might reveal molecular subgroups which could help to define the tumor origin and behaviour beyond anatomical location. The gene expression profiles of 107 treatment-naïve, intestinal type, gastro-esophageal adenocarcinomas were assessed by the Illumina-HTv4.0 beadchip. Differential gene expression (limma), unsupervised subgroup assignment (mclust), and pathway analysis (gage) were undertaken in R statistical computing and results were related to demographic and clinical parameters....

Straight-to-test for the two-week-wait colorectal cancer pathway under the updated NICE guidelines reduces time to cancer diagnosis and treatment

May 2019 - The Annals of the RCS - Nigel Hall

Abstract: The 2015 National Institute for Health and Care Excellence guidelines widened the referral criteria for the two-week-wait pathway for suspected lower gastrointestinal cancer. We implemented a straight-to-test protocol to accommodate the anticipated increase in referrals. We evaluated the impact of these changes for relevant pathway metrics and clinical outcomes using a retrospective cohort study with historic controls. Conclusion: Our straight-to-test protocol has resulted in a reduction in times to cancer diagnosis and cancer treatment, despite an increase in the number of referrals. The new referral criteria have considerable resource implications, but their implementation did not result in an increase in the total number of cancers diagnosed.

 

 

[18F]fludeoxyglucose PET/CT in small-cell lung cancer: Analysis of the CONVERT randomized controlled trial

16 April, 2019 - Journal of Thoracic Oncology - Susan Harden

Abstract: We used phase-3 CONVERT trial data to investigate the impact of 18fludeoxyglucose (18F-FDG) PET/CT in small-cell lung cancer (SCLC). Conclusion - in CONVERT, survival outcomes were not significantly different in patients staged with or without 18F-FDG PET/CT. However, this analysis cannot support the use or omission of 18F-FDG PET/CT due to study limitations.

Prophylactic Irradiation of Tracts in Patients With Malignant Pleural Mesothelioma: An Open-Label, Multicenter, Phase III Randomized Trial

28 March, 2019 - Journal of Clinical Oncology - Robert Rintoul

Purpose: Prophylactic irradiation to the chest wall after diagnostic or therapeutic procedures in patients with malignant pleural mesothelioma (MPM) has been a widespread practice across Europe, although the efficacy of this treatment is uncertain. In this study, we aimed to determine the efficacy of prophylactic radiotherapy in reducing the incidence of chest wall metastases (CWM) after a procedure in MPM. Conclusion: There is no role for the routine use of prophylactic irradiation to chest wall procedure sites in patients with MPM.

Cancer Treatment in the Genomic Era

22 March, 2019 - Annual Review of Biochemistry - Gary Doherty

Abstract: The complexity of human cancer underlies its devastating clinical consequences. Drugs designed to target the genetic alterations that drive cancer have improved the outcome for many patients, but not the majority of them. Here, we review the genomic landscape of cancer, how genomic data can provide much more than a sum of its parts, and the approaches developed to identify and validate genomic alterations with potential therapeutic value. We highlight notable successes and pitfalls in predicting the value of potential therapeutic targets and discuss the use of multi-omic data to better understand cancer dependencies and drug sensitivity. We discuss how integrated approaches to collecting, curating, and sharing these large data sets might improve the identification and prioritization of cancer vulnerabilities as well as patient stratification within clinical trials. Finally, we outline how future approaches might improve the efficiency and speed of translating genomic data into clinically effective therapies and how the use of unbiased genome-wide information can identify novel, predictive biomarkers that can be either simple or complex.

The potential of breath analysis to improve outcome for patients with lung cancer

1 March, 2019 - Journal of Breath Research

Lung cancer remains the most common cause of cancer related death in both the UK and USA. Development of diagnostic approaches that have the ability to detect lung cancer early are a research priority with potential to improve survival. Analysis of exhaled breath metabolites, or volatile organic compounds (VOCs) is an area of considerable interest as it could fulfil such requirements. Numerous studies have shown that VOC profiles are different in the breath of patients with lung cancer compared to healthy individuals or those with non-malignant lung diseases. This review provides a scientific and clinical assessment of the potential value of a breath test in lung cancer. It discusses the current understanding of metabolic pathways that contribute to exhaled VOC production in lung cancer and reviews the research conducted to date. Finally, we highlight important areas for future research and discuss how a breath test could be incorporated into various clinical pathways.

Directed tubule growth from giant unilamellar vesicles in a thermal gradient

13 Feb, 2019 - Soft Matter

We demonstrate experimental control over tubule growth in giant unilamellar vesicles with liquid-liquid phase coexistence, using a thermal gradient to redistribute lipid phase domains on the membrane. As studied previously, the domains of the less abundant phase always partition towards hotter temperatures, depleting the cold side of the vesicle of domains. We couple this mechanism of domain migration with the inclusion of negative-curvature lipids within the membrane, resulting in control of tubule growth direction towards the high temperature. Control of composition determines the interior/exterior growth of tubules, whereas the thermal gradient regulates the length of the tubule relative to the vesicle radius. Maintaining lipid membranes under non-equilibrium conditions, such as thermal gradients, allows the creation of thermally-oriented protrusions, which could be a key step towards developing functional materials or artificial tissues. Interconnected vesicle compartments or ejected daughter vesicles as transport intermediaries towards hot/cold are just two possibilities.

Bcl9 and Pygo synergise downstream of Apc to effect intestinal neoplasia in FAP mouse models

13 February, 2019 - Nature Communications

Abstract: Bcl9 and Pygo are Wnt enhanceosome components that effect β-catenin-dependent transcription. Whether they mediate β-catenin-dependent neoplasia is unclear. Here we assess their roles in intestinal tumourigenesis initiated by Apc loss-of-function (ApcMin), or by Apc1322T encoding a partially-functional Apc truncation commonly found in colorectal carcinomas. Intestinal deletion of Bcl9 extends disease-free survival in both models, and essentially cures Apc1322T mice of their neoplasia. Loss-of-Bcl9 synergises with loss-of-Pygo to shift gene expression within Apc-mutant adenomas from stem cell-like to differentiation along Notch-regulated secretory lineages. Bcl9 loss also promotes tumour retention in ApcMin mice, apparently via relocating nuclear β-catenin to the cell surface, but this undesirable effect is not seen in Apc1322T mice whose Apc truncation retains partial function in regulating βcatenin. Our results demonstrate a key role of the Wnt enhanceosome in β-catenindependent intestinal tumourigenesis and reveal the potential of BCL9 as a therapeutic target during early stages of colorectal cancer.

Cell Model Passports-a hub for clinical, genetic and functional datasets of preclinical cancer models.

8 January, 2019 - Nucleic Acids Research

Abstract: In vitro cancer cell cultures are facile experimental models used widely for research and drug development. Many cancer cell lines are available and efforts are ongoing to derive new models representing the histopathological and molecular diversity of tumours. Cell models have been generated by multiple laboratories over decades and consequently their annotation is incomplete and inconsistent. Furthermore, the relationships between many patient-matched and derivative cell lines have been lost, and accessing information and datasets is time-consuming and difficult. Here, we describe the Cell Model Passports database; cellmodelpassports.sanger.ac.uk, which provides details of cell model relationships, patient and clinical information, as well as access to associated genetic and functional datasets. The Passports database currently contains curated details and standardized annotation for >1200 cell models, including cancer organoid cultures. The Passports will be updated with newly derived cell models and datasets as they are generated. Users can navigate the database via tissue, cancer-type, genetic feature and data availability to select a model most suitable for specific applications. A flexible REST-API provides programmatic data access and exploration. The Cell Model Passports are a valuable tool enabling access to high-dimensional genomic and phenotypic cancer cell model datasets empowering diverse research applications.

Somatic mutant clones colonize the human esophagus with age

23 November, 2018 - Science - Kourosh Saeb-Parsy

Abstract: 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. We mapped mutant clones in normal esophageal epithelium from nine donors (age range, 20 to 75 years). Somatic mutations accumulated with age and were caused mainly by intrinsic mutational processes. We found strong positive selection of clones carrying mutations in 14 cancer genes, with tens to hundreds of clones per square centimeter. In middle-aged and elderly donors, clones with cancer-associated mutations covered much of the epithelium, with NOTCH1 and TP53 mutations affecting 12 to 80% and 2 to 37% of cells, respectively. Unexpectedly, the prevalence of NOTCH1 mutations in normal esophagus was several times higher than in esophageal cancers. These findings have implications for our understanding of cancer and aging.