cliniCIN: Targeting the roots of chromosomal instability in cancer

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GOAL: Overcoming the genomic complexity of cancers with high chromosomal instability by using signatures of ongoing mutational processes as biomarkers for drug response.BACKGROUND: Chromosomal instability is a hallmark of most lethal cancers. Highly unstable tumours have few biomarkers to guide treatment decisions and patient survival has not improved for decades. My team pioneered approaches to dissect chromosomal instability using genome-wide DNA copy number patterns, so called CIN signatures, which are characteristic for different types of instability and underlying mutational processes. In pilot studies we found that CIN signatures predict drug response. Signature analysis focuses on the cause, rather than the consequence of chromosomal instability, and thus represents a radical departure from previous personalised medicine approaches. APPROACH: Here, I am building on genomic and computational technologies I have developed to design biomarkers for treating cancers with high chromosomal instability. I propose a novel single cell DNA sequencing approach to identify ongoing mutational processes from unique events in individual cells. This pharmacogenomic test is a major advance, because it allows to separate ongoing mutational processes, which are actively contributing to cancer development, from extinct mutational processes, which left marks in the genome but are no longer active. I will systematically identify robust and predictive biomarkers of drug response in a comprehensive experimental plan across five highly unstable cancers (esophageal, lung, pancreatic, ovarian and triple negative breast cancer) and measure the heterogeneity of CIN across tumour microenvironments in patients undergoing neo-adjuvant treatment. IMPACT: This pioneering project will result in fundamental insights into how cancers with different types of chromosomal instability react to drugs and how to exploit genomic complexity for patient benefit in cancers of unmet clinical need.