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Profiling the landscape and evolution of complex structural variants and copy number changes across sarcomas

  • Full or part time
    Dr P Van Loo
  • Application Deadline
    Tuesday, November 12, 2019
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

Project Description

This 4-year PhD studentship is offered in Dr Peter Van Loo’’s Group based at the Francis Crick Institute (the Crick).

Sarcomas are tumours of mesenchymal origin, encompassing approximately 1% of adult cancers and 15% of childhood cancers. They represent a collection of individually rare cancer types that are often understudied. Through the 100,000 Genomes Project, the UK sarcoma community has collected whole-genome sequences of >1,700 cancer samples from >1,300 sarcoma patients. This now allows us an exciting and unprecedented view into the genomics of these cancers. As part of the Sarcoma GeCIP (Genomics England Clinical Interpretation Partnership), the Cancer Genomics group has taken the lead in the somatic genomics analyses of these sarcomas.

Cancers acquire somatic mutations as they evolve, including single-nucleotide variants, insertions and deletions, structural variants and copy number alterations. A tumour’s genome therefore carries an archaeological record of its evolutionary past, and much of this history can be reconstructed from its genome sequence [1, 2]. Interestingly, some mutational processes, such as chromothripsis [3], can generate large numbers of changes to the genome in a single event. Such punctuated events can substantially reconfigure the cancer genome, leading to large leaps in tumour evolution. Chromothripsis is observed in multiple cancer types, and is particularly common in several sarcomas. In addition, sarcomas can show extensive aneuploidy and a high frequency of whole-genome duplications, leading to complex karyotypes [4].

In this project, we will leverage the Sarcoma GeCIP whole-genome sequencing data to profile the landscape of copy number changes and structural variants across sarcomas, focusing specifically on chromothripsis, complex structural variants, and copy number changes. We aim to chart the mutational processes causing structural variants and copy number changes that shape the genomes of different sarcomas. In addition, we will study how these events drive tumorigenesis, and when they occur in the evolution of sarcomas. This will allow important insights into how sarcomas evolve.

Candidate background
This position is suitable for a quantitative scientist (e.g. statistician, physicist, mathematician, bioinformatician) with a strong interest in biology/biomedicine, or a biologist with an interest in and talent for computational analyses.

Talented and motivated students passionate about doing research are invited to apply for this PhD position. The successful applicant will join the Crick PhD Programme in September 2020 and will register for their PhD at one of the Crick partner universities (Imperial College London, King’s College London or UCL).

Applicants should hold or expect to gain a first/upper second-class honours degree or equivalent in a relevant subject and have appropriate research experience as part of, or outside of, a university degree course and/or a Masters degree in a relevant subject.

APPLICATIONS MUST BE MADE ONLINE VIA OUR WEBSITE (ACCESSIBLE VIA THE ‘APPLY NOW’ LINK ABOVE) BY 12:00 (NOON) 13 NOVEMBER 2019. APPLICATIONS WILL NOT BE ACCEPTED IN ANY OTHER FORMAT.

Funding Notes

Successful applicants will be awarded a non-taxable annual stipend of £22,000 plus payment of university tuition fees. Students of all nationalities are eligible to apply.

References

1. Nik-Zainal, S., Van Loo, P., Wedge, D. C., Alexandrov, L. B., Greenman, C. D., Lau, K. W., . . . Breast Cancer Working Group of the International Cancer Genome Consortium (2012)

The life history of 21 breast cancers.

Cell 149: 994-1007. PubMed abstract

2. Gerstung, M., Jolly, C., Leshchiner, I., Dentro, S. C., Gonzalez, S., Rosebrock, D., . . . Loo, P. V. (2018)

Preprint: The evolutionary history of 2,658 cancers.

Available at: BioRxiv. https://www.biorxiv.org/content/biorxiv/early/2018/09/12/161562.full.pdf

3. Stephens, P. J., Greenman, C. D., Fu, B., Yang, F., Bignell, G. R., Mudie, L. J., . . . Campbell, P. J. (2011)

Massive genomic rearrangement acquired in a single catastrophic event during cancer development.

Cell 144: 27-40. PubMed abstract

4. Steele, C. D., Tarabichi, M., Oukrif, D., Webster, A. P., Ye, H., Fittall, M., . . . Pillay, N. (2019)

Undifferentiated sarcomas develop through distinct evolutionary pathways.

Cancer Cell 35: 441-456 e448. PubMed abstract



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