Francis Crick Institute
Crick Cancer Clinical Research Fellow Programme
Three-Year Clinical Research Training Fellowships 2016
Names of project supervisors:
Crick supervisor: Peter Van Loo
CRUK Centre/University supervisor: Adrienne M. Flanagan(UCL Cancer Institute)
Title of research project:
Molecular archaeology of cancer
Description of the research project:
Changes to the genome drive cancer. The cancer genome can be profiled by massively
parallel sequencing and this has in recent years revolutionized our understanding of
cancer.
As somatic mutations mark the genome, a cancer’s genome contains within it an
archaeological record of its past. We pioneered methods to disentangle a tumour’s
subclonal architecture and life history from sequencing data (Nik-Zainal et al. (2012), Cell
149:994-1007). We expect that such “molecular archaeology” approaches, applied to
cancer on a large scale, would give profound insights into carcinogenesis and cancer
evolution.
Through large-scale international projects, a few thousand cancers have now been wholegenome sequenced, and we are applying our approaches to this combined dataset, in the
context of the International Cancer Genome Consortium (ICGC) Pan-Cancer Analysis of
Whole Genomes (PCAWG) initiative. The potential of whole-genome sequencing of cancers
to revolutionise clinical practice has also been recognised by the NHS, and approximately
half of Genomics England’s 100,000 genomes project is being steered to sequencing
cancers.
In this project, we aim to further develop molecular archaeology approaches and apply
them to the wealth of cancer data generated by the 100,000 genomes project over the
next few years. We can construct life histories of thousands of tumours from their genome
sequences, using both driver and passenger mutations. By obtaining detailed timelines of
many cancers’ evolutionary histories, we will identify the initiating events of cancer
development, and the events that are under selection later in a cancer’s lifetime,
including those that play a role in tumour malignancy. In addition, these analyses will
allow blueprints of the subclonal architecture across cancer types in unprecedented detail
and on an unprecedented number of cases, allowing a glimpse into a tumour’s future.
We have recently shown that such molecular archaeology approaches allow unique insights
into cancer evolution, particularly when multiple samples are sequenced, over multiple
time points (Bolli et al. (2014), Nature Communications 5:2997), through multi-region
sequencing (Cooper et al., Nature Genetics 47:367-372), or across multiple metastases
(Gundem et al., Nature 520:353-357). As such, we are particularly interested in applying
these approaches across cases with multiple samples (either temporal and/or spatial), and
we expect that the 100,000 genomes project will generate such data for a substantial
number of cancers.
This project is suitable for a candidate in medical training with an interest in
bioinformatics and computational biology. Previous experience in programming is
considered an advantage, but is not mandatory. However, the candidate must be eager to
work in a computational environment.
References:
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Nik-Zainal, S., Van Loo, P., Wedge, D.C. et al.(2012) The life history of 21 breast
cancers. Cell, 149:994-1007.
Behjati, S., Tarpey, P.S., Presneau, N.,et al. (2013). Distinct H3F3A and H3F3B
driver mutations define chondroblastoma and giant cell tumor of bone. Nature
Genetics, 45:1479-1482.
Bolli, N., Avet-Loiseau, H., Wedge, D.C., Van Loo, P.,et al. (2014). Heterogeneity
of genomic evolution and mutational profiles in multiple myeloma. Nature
Communications, 5:2997.
Cooper, C.S., Eeles, R., Wedge, D.C., Van Loo, P. et al. (2015). Analysis of the
genetic phylogeny of multifocal prostate cancer identifies multiple independent
clonal expansions in neoplastic and morphologically normal prostate tissue.
Nature Genetics, 47:367-372.
Gundem, G., Van Loo, P., Kremeyer, B.,et al. (2015). The evolutionary history of
lethal metastatic prostate cancer. Nature, 520:353-357.
Summarise the medical/clinical component of the research, as well as the relevance to
the Crick Cancer CRF programme:
Through the 100,000 Genomes Project, the NHS aims to bring genomics into the clinic. This
project leverages those data to gain insight into tumour evolution, directing future
diagnostic, monitoring and therapeutic approaches. The UCLH BRC is making a substantial
investment to support the 100,000 Genomes Project, both through its pilot project and in
the main study. The UCLH BRC is also involved in the National Institute for Health Research
Health Informatics Collaboration (HIC), a programme that aims to make NHS clinical data
more readily available and accessible to researchers, industry and the NHS community, and
is likely to provide the IT support for the Genome Medicine Centres.
This project aligns with UCLH BRC’s strategy to build on existing strengths by collaborating
with affiliated research groups. It also fits with the BRC Cancer Programme strategy which
aims to take innovations in basic science and help to apply them to patient care. A major
focus of the cancer programme is to study how cancers initiate and evolve in time and
space, which this project addresses.
Project supervisors’ contact details:
Crick supervisor:
Name: Peter Van Loo
Telephone: 020 7269 3083
Email: Peter.VanLoo@crick.ac.uk
CRUK Centre / University supervisor:
Name: Adrienne M. Flanagan
Telephone: 020 7679 6304 (PA – Jasmine Childs-Fegredo)
Email: a.flanagan@ucl.ac.uk