Award Title: Early detection of clinically-relevant mutational signatures
Funder: Cancer Research UK

Abstract: Background: Mutational-signatures are a read-out of the cellular abnormalities that arise in a cell as it turns from being normal to being malignant. Already, my team has shown that mutational signatures can be informative of DNA repair defects that may be targets for therapeutic intervention. Critical to the success of this proposal is our unique position as a pioneering team in comprehensive genomic characterisation and in clinical applications of mutational signatures.   The overarching principle in this proposal is to advance ways of using mutational-signatures in order to detect a shift in physiological state. This is irrespective of whether they are known abnormalities (e.g. DNA repair deficiencies) or functional abnormalities that are less well-defined (e.g. replication stress). These physiological shifts could be an indicator of early cancer development, or a harbinger of poor clinical outcome. They may be ideal candidates for early detection, serving as a biomarker for medical intervention.   Aims and Methods: There are three inter-related objectives. First, we will apply computational methods on cancer data and experimental data to identify on-going mutational-signatures that may be clinically important. Second, once these have been identified, we will develop the assays to be able to detect these clinically-relevant mutational signatures from samples where there are limiting DNA quantities (e.g. from a blood test). Third, we will test our assays on patient samples to understand whether they truly have clinical utility.  How the results of this research will be used: We anticipate being able to delineate clinically-relevant mutational signatures and to find ways of utilising them as biomarkers as early as possible during a patient’s cancer journey, ideally, from something as simple as a blood test.

Lay Abstract: Background: Mutational-signatures are a read-out of the cellular abnormalities that arise in a cell as it turns from being normal to being malignant. Already, my team has shown that mutational signatures can be informative of DNA repair defects that may be targets for therapeutic intervention. Critical to the success of this proposal is our unique position as a pioneering team in comprehensive genomic characterisation and in clinical applications of mutational signatures.   The overarching principle in this proposal is to advance ways of using mutational-signatures in order to detect a shift in physiological state. This is irrespective of whether they are known abnormalities (e.g. DNA repair deficiencies) or functional abnormalities that are less well-defined (e.g. replication stress). These physiological shifts could be an indicator of early cancer development, or a harbinger of poor clinical outcome. They may be ideal candidates for early detection, serving as a biomarker for medical intervention.   Aims and Methods: There are three inter-related objectives. First, we will apply computational methods on cancer data and experimental data to identify on-going mutational-signatures that may be clinically important. Second, once these have been identified, we will develop the assays to be able to detect these clinically-relevant mutational signatures from samples where there are limiting DNA quantities (e.g. from a blood test). Third, we will test our assays on patient samples to understand whether they truly have clinical utility.  How the results of this research will be used: We anticipate being able to delineate clinically-relevant mutational signatures and to find ways of utilising them as biomarkers as early as possible during a patient’s cancer journey, ideally, from something as simple as a blood test.

Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health Categories: CANCER AND NEOPLASMS