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WORKPACKAGE 2

Comprehensive genomic characterization of DCIS

Hypothesis-driven questions

We seek to exploit the knowledge and genomic analytical tools developed on a cohort of 560 breast cancer genomes. This is the largest collection of WGS cancers of a single cancer type to date with the products of this WGS breast cancer dataset including: 1,628 putative driver mutations in 93 genes,

 

twelve base substitution signatures, two indel signatures, six rearrangement signatures and copy number profiles. These will be applied on DCIS samples – in order to identify and understand critical genetic and signature profiles that are informative for indolence or aggressiveness in DCIS.

Key distinguishing properties of indolent versus aggressive DCIS

  • What are the key driver mutations that differentiate aggressive from indolent DCIS?
  • Are there mutational signatures that differentiate aggressive from indolent DCIS and can these be used to gain more understanding into the biological factors that cause DCIS?
  • What are the differences in overall transcriptomic profiles between aggressive and indolent DCIS?
  • What are the differences in overall methylation profiles between aggressive and indolent?
  • What are the effects of radiotherapy treatment on DCIS?
  • Given the wealth of driver and mutational signature data that are already available on primary breast cancers, can we compare DCIS to invasive breast cancers to understand the biology and trajectory of DCIS?

Accelerating translation into the clinic

  • Can we design integrative predictors of outcome or estimators of biological status that could be informative for optimal treatment based on the data obtained through this endeavour?
  • Can we test these hypotheses in prospective DCIS trials going forward?

WP lead

Dr. Serena Nik-Zainal

CRUK Advanced Clinician Scientist

Academic Department of Medical Genetics

University of Cambridge, Cambridge CB2 0QQ, UK

Co-I

Prof. Dr. Jacco van Rheenen

Group Leader Division of Molecular Pathology

The Netherlands Cancer Institute, Amsterdam, The Netherlands

 

Collaborators

Dr Helen Davies

Wellcome Trust Sanger Institute, Hinxton, UK

 

Professor Ian Tomlinson

Institute of Cancer and Genomic Sciences

University of Birmingham, Birmingham, UK

Workpackage 2 is responsible for the project objective to sequence 1920 DCIS samples.

Milestones

2.1Complete list of drivers and signatures including contributions of each signature to each sample of Phase I samples
2.2Integrative genome profiles per patient of Phase I samples
2.3Sftp site for data sharing up and running
2.4Analysis TCs commence
2.5Sequencing Plan for Phase II
2.6Complete list of drivers and signatures including contributions of each signature to each sample of Phase II sample
2.7Integrative genome profiles per patient of Phase II samples