Capture Hi-C approach to discovering somatic mutations in long-range regulatory elements of breast cancer genes

Exome and whole genome sequencing of large series of matched tumour and germline DNA samples has led to the identification of somatically mutated cancer genes for a wide spectrum of site-specific cancers, including breast cancer. Cataloguing driver somatic mutations is important for understanding the aetiology of these site-specific cancers and for informing future strategies for stratified medicine. To date, the vast majority of driver mutations that have been identified map to coding sequences; while this may reflect a fundamental feature of cancer biology it may also reflect the search strategies used to identify these mutations.

In a recent analysis of 360 breast cancers Rheinbay and colleagues (Rheinbay et al; 2017) used a targeted sequencing approach to increase their coverage and reduce their search-space for non-coding mutations. They focussed on gene-promoters and identified nine promoter elements with significant burden or clustering of mutations. They concluded that non-coding promoter mutations occur at similar frequencies to coding driver mutations.

By contrast to promoter elements which are accurately mapped within the human genome, the locations of gene-distal regulatory elements remain largely unknown. We have developed a high-throughput, high-resolution chromatin interaction method (Capture Hi-C) for the identification of such long-range regulatory elements. The aim of this proposal is to use Capture Hi-C to define gene-distal regulatory elements for 727 cancer genes and determine whether mutations in this class of element occur at a similar frequency to those in promoters and coding-sequences.

This project, which is focussed on breast cancer, will combine laboratory based experimental techniques with bioinformatics analysis of publicly available data (whole genome sequencing data, regulatory and epigenetic data) and de novo targeted sequencing data. Laboratory techniques will include Capture Hi-C, targeted sequencing and functional characterisation of putative non-coding driver mutations. Bioinformatics analyses will include array design, Capture Hi-C data analysis, analysis of whole genome sequencing and targeted sequencing data.

Candidate profile
Candidates must have a first class or upper second class honours BSc Honours/MSc or equivalent in Life Sciences with some experience of Bioinformatics (course module, postgraduate course, undergraduate project involving Bioinformatics)

How to apply
Full details about these studentship projects, and the online application form, are available on our website, at: www.icr.ac.uk/phds Applications for all projects should be made online. Please ensure that you read and follow the application instructions very carefully.

Closing date: Monday 20th November 2017
Applicants should be available for interview 29h and 30th January 2018.

Please apply via the ICR vacancies web portal https://studentapps.icr.ac.uk/login

Download a PDF of the complete project proposal:

https://d1ijoxngr27nfi.cloudfront.net/default-document-library/download-a-pdf-of-the-complete-project-proposal04882ecb659564f3a772ff0000325351.pdf