Analysis of inherited genetic vulnerabilities associated with the onset of multiple cancers
To start: September 2017 Sponsor: Cancer Research UK KHP Centre Stipend: £ 21,000 per annum Eligibility: MSc or MRes in Biology, Genetics, Bioinformatics or equivalent, UK/EU citizenship
Project Our groups have recently reported that patients with multiple but genetically independent bowel cancers inherit damages in immune-related genes1. These patients also show high levels of T-cells in the surface epithelium and in the lamina propria of the gut mucosa and more neutrophil infiltrates in the tumour. These observations suggest that damaged immune genes could modify the immune cell composition of the gut mucosa by inducing perturbations in the homeostatic immune network thus favouring multiple tumorigenic events.
The aim of this PhD project is to test whether genetic aberrations in immune-related genes lead to inherited vulnerabilities towards multiple tumours regardless of the anatomical site or, rather, they have a specific role in the gastrointestinal tract, where immunity, microbioma and other environmental factors cooperate to create a tumour inductive and/or supportive environment.
The study will analyse genomic and clinical data from 40 primary tumour sites (including upper and lower GI) gathered from The Cancer Genome Atlas and the International Cancer Genome Consortium. Germline sequencing reads from all patients will be realigned using the same analytical pipeline to allow uniform variant calling. Damaging alterations will be identified, carefully quality checked and further analysed with our recently developed algorithm, MEGA-V2. MEGA-V is a statistical framework specifically designed to identify genes and biological processes that are significantly altered in the cohort under study, in this case patients with multiple cancers. The availability of large data sets from thousands cancer samples will allow several comparisons at different levels of granularity. For example, we will test what genes and/or biological processes are damaged in patients with different types of gastrointestinal cancer. We will also verify whether these genes and processes are the same in people with multiple cancers at other sites. Clinical data will be used to infer associations between damaged processes and patient relapse, survival, response to therapy. Obtained results will be validated in samples from the KHP cancer biobank to confirm the occurrence of specific genetic mutations, perturbed gene expression or staining of particular markers.
Solid statistical background and independence in computer programming will be favourable. The candidate will work in a multidisciplinary team of computational and wet-lab scientists addressing various aspects of cancer genetics. The Ciccarelli group is currently seconded to the Francis Crick Institute, a new biomedical research facility that opened in 2016. Regular meetings with the second supervisor, Prof Jo Spencer, and her team will be planned and the student will benefit from a broad range of scientific activities hosted both at the Crick and King’s.
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-- 1. Cereda M, Gambardella G, Benedetti L, Iannelli F, Guerra R, Mourikis TP, Puccio I, Patel D, Basso G, Sinha S, Laghi L, Spencer J, Rodriguez-Justo M, Ciccarelli FD Patients with genetically heterogeneous synchronous colorectal cancer carry rare damaging germline mutations in immune-related genes (2016) Nature Communications 7 2. Gambardella G, Cereda M, Benedetti L, Ciccarelli FD MEGA-V: detection of altered biological gene sets in patient cohorts (2017) Bioinformatics btw209
Supervisors Dr Francesca Ciccarelli, School of Cancer Sciences, King’s College London and The Francis Crick Institute Prof Jo Spencer, School of Transplantation, Immunology, Infection & Inflammation Sciences, King’s College London
Location: The Francis Crick Institute, London, where the Ciccarelli group is seconded. For further inquiries please contact firstname.lastname@example.org
Application closing date: 22 June 2017
How to apply Applicants should apply via the King's online application form https://apply.kcl.ac.uk/login.
When completing the application form please do the following to ensure that you apply for the right programme/studentship: - Under 'type of programme' choose 'Research Degrees. 'Enter 'Cancer' in the keyword box and click 'search'. From the list displayed select 'Cancer Studies Research Division MPhil/PhD (fulltime)' - Please select September 2017 as the start date - Under the research proposal section, please remember to add ‘Ciccarelli’ in the supervisor's 'Name' field. Please also state the project title ‘Analysis of inherited genetic vulnerabilities associated with the onset of multiple cancers’ where requested. - Include the following reference: 2017/CANCER/S7
IMPORTANT Please ensure that you specify Ciccarelli as the supervisor. Incomplete applications or those without all required documents/information will not be considered by the department until received. Further details For administrative and application process enquiries please liaise with the Admissions Office through your online application portal. For scientific/technical/project enquiries please contact Francesca.email@example.com