Welcome to The Christie Research Publications Repository
The repository contains the research outputs from staff and students at The Christie NHS Foundation Trust and Cancer Research UK Manchester Institute.
Current Repository Content:
Over 7000 peer reviewed articles, reviews and selected publications from 1933 onwards.
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Genomic copy number predicts esophageal cancer years before transformationRecent studies show that aneuploidy and driver gene mutations precede cancer diagnosis by many years1-4. We assess whether these genomic signals can be used for early detection and pre-emptive cancer treatment using the neoplastic precursor lesion Barrett's esophagus as an exemplar5. Shallow whole-genome sequencing of 777 biopsies, sampled from 88 patients in Barrett's esophagus surveillance over a period of up to 15 years, shows that genomic signals can distinguish progressive from stable disease even 10 years before histopathological transformation. These findings are validated on two independent cohorts of 76 and 248 patients. These methods are low-cost and applicable to standard clinical biopsy samples. Compared with current management guidelines based on histopathology and clinical presentation, genomic classification enables earlier treatment for high-risk patients as well as reduction of unnecessary treatment and monitoring for patients who are unlikely to develop cancer.
Clinical and translational research challenges in neuroendocrine tumoursNeuroendocrine tumours (NETs) represent a range of neoplasms that may arise from any (neuro)endocrine cell situated in any part of the human body. As any other rare diseases, NETs face several difficulties in relation to research. This review will describe some of the main challenges and proposed solutions faced by researchers with expertise in rare malignancies. Some of the most common challenges in clinical and translational research are enumerated in this review, covering aspects from clinical, translational and basic research. NETs being a heterogeneous group of diseases and a limited sample size of clinical and translational research projects are the main challenges. Challenges with NETs lay over the disparities between healthcare models to tackle rare diseases. NETs add an extra layer of complexity due to a numerous group of different entities. Prospective real-world data trials are an opportunity for rare cancers with the revolution of electronic health technologies. This review explores potential solutions to these challenges that could be useful not only to the NET community but also to other rare tumours researchers.
In vivo binding of recombination proteins to non-DSB DNA lesions and to replication forksHomologous recombination (HR) has been extensively studied in response to DNA double-strand breaks (DSBs). In contrast, much less is known about how HR deals with DNA lesions other than DSBs (e.g., at single-stranded DNA) and replication forks, despite the fact that these DNA structures are associated with most spontaneous recombination events. A major handicap for studying the role of HR at non-DSB DNA lesions and replication forks is the difficulty of discriminating whether a recombination protein is associated with the non-DSB lesion per se or rather with a DSB generated during their processing. Here, we describe a method to follow the in vivo binding of recombination proteins to non-DSB DNA lesions and replication forks. This approach is based on the cleavage and subsequent electrophoretic analysis of the target DNA by the recombination protein fused to the micrococcal nuclease.
When what you see is not always what you get: raising the bar of evidence for new diagnostic imaging modalitiesEven though prostate-specific membrane antigen (PSMA)-positron emission tomography (PET)-computed tomography (CT) is more accurate than conventional imaging in prostate cancer patients, its impact on patient-relevant outcomes is unknown. We argue that more evidence is required before using PSMA-PET-CT as the standard of care for staging.
Multi-site clonality analysis uncovers pervasive heterogeneity across melanoma metastasesMetastatic melanoma carries a poor prognosis despite modern systemic therapies. Understanding the evolution of the disease could help inform patient management. Through whole-genome sequencing of 13 melanoma metastases sampled at autopsy from a treatment naïve patient and by leveraging the analytical power of multi-sample analyses, we reveal evidence of diversification among metastatic lineages. UV-induced mutations dominate the trunk, whereas APOBEC-associated mutations are found in the branches of the evolutionary tree. Multi-sample analyses from a further seven patients confirmed that lineage diversification was pervasive, representing an important mode of melanoma dissemination. Our analyses demonstrate that joint analysis of cancer cell fraction estimates across multiple metastases can uncover previously unrecognised levels of tumour heterogeneity and highlight the limitations of inferring heterogeneity from a single biopsy.