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PhD Cancer Genetics - Examining how telomere dysfunction drives the evolution of the cancer genome

  • Full or part time
    Prof D Baird
  • Application Deadline
    Sunday, March 01, 2020
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

Telomeres are structures that cap the ends of eukaryotic chromosomes, preventing the recognition and repair of the natural chromosomal terminus by the DNA damage response (DDR) apparatus. As a consequence of end-replication losses, telomeres shorten with on-going cell division. Short telomeres can elicit a TP53-dependent cell cycle arrest, referred to as replicative senescence, that provides a stringent tumour suppressive function. However, in the absence of a functional DDR checkpoint response, on-going cell division results in continued telomere erosion and ultimately the loss of the end-capping function. Telomeres can then be targeted for DNA repair, resulting in telomere fusion, the formation of dicentric chromosomes and the initiation of cycles of anaphase-bridging, breakage and fusion. The ensuing cellular crisis leads to a strong selection pressure for the up-regulation of telomere maintenance mechanisms, principally telomerase activity, that facilitates the escape from crisis. This process is considered a key mutational mechanism that drives genomic instability and clonal evolution during malignant progression. We investigated the impact of a telomere-driven crisis on the structural integrity of the genome by undertaking whole genome sequence (WGS) analyses of clonal populations of cells that had escaped crisis. Quantification of large-scale structural variants revealed patterns of rearrangement consistent with chromothripsis but formed in the absence of functional NHEJ pathways. Rearrangements frequently consisted of short fragments with complex mutational patterns, with a repair topology that deviated from randomness demonstrating repair preferentially restricted to local regions or exchange between specific loci. Telomere involvement was evidenced by an enrichment in fold-back inversions demarcating clusters of rearrangements. Our data support the view that chromothriptic rearrangements, that occur during a telomere-driven crisis, arise via a replicative repair process involving template switching. This project will focus on understanding the mutational impact of telomere dysfunction on the evolving cancer genome.

This Cancer Research UK funded 4-year bioinformatics based studentship will apply our unique analytical systems, for the analysis of telomere fusion events at the single-molecule level and for the characterisation of complex events in genomic data. The primary objective will be to mine these data using our previously developed bioinformatic pipelines to identify signatures of telomere dysfunction. The project will have a focus on breast and colorectal cancer.

This project will provide an understanding as to how telomere dysfunction, a major mutational mechanism in cancer, impacts the evolving cancer genome. This may lead to enhanced prognostic and predictive information, as well as increased potential for early cancer diagnosis. A deeper understanding of the mechanisms by which telomeres modulate the cancer genome could open up new therapeutic opportunities.

The studentship will provide training in cancer biology, DNA repair and telomere biology provided by Professor Baird. The approaches taken will be primarily bioinformatics based and thus will provide a significant training opportunity (provided by Dr Kez Cleal) developing analytical skills to interpret phenotypic, functional and genomic data sets. The student will apply statistical and machine learning methods, structural variant quantification and DNA assembly, with opportunities for developing novel bioinformatics tools and algorithms. Programming experience in a scripting language (Python/R), or compiled language (C/C++ etc.) would be beneficial, or experience in statistical methods, or the analysis of High Throughput Sequencing data.

Funding Notes

The studentship is generously funded by Cancer Research UK
Open to all UK/EU students without further restrictions
Full UK/EU tuition fees (any eligible non-home fee paying candidate must fund the remainder of the overseas fee themselves)
Doctoral stipend matching UK Research Council National Minimum.
Additional funding is available over the course of the programme and will cover costs such as research consumables and training.

References

Applicants should possess a minimum of an upper second class Honours degree, master's degree, or equivalent in a relevant subject.
Applicants whose first language is not English are normally expected to meet the minimum University requirements (e.g. 6.5 IELTS)

This studentship has a start date of October 2020. In order to be considered you must submit a formal application via Cardiff University’s online application service. (To access the system click 'Apply Online' at the bottom of this advert)
There is a box at the top right of the page labelled ‘Apply’, please ensure you select the correct ‘Qualification’ (Doctor of Philosophy), the correct ‘Mode of Study’ (Full Time) and the correct ‘Start Date’ (October 2020). This will take you to the application portal.
In order to be considered candidates must submit the following information:

• Supporting statement
• CV
• Qualification certificates
• References x 2 (optional but will strengthen your application)
• Proof of English language (if applicable)

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