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Final Report Summary - NOCOSMIC (Prioritization of non-coding somatic mutations in cancer)

The purpose of this project, as outlined in Annex I of the Grant Agreement, was to allow me (Dr. Simon Furney – the Experienced Researcher) to achieve research independence in the field of cancer genomics. In order to achieve this, through developing a niche area of expertise and enhancing my research management and dissemination skills, five main objectives were set: (i) To obtain greater experience in research project management by managing the financial and research aspects of the fellowship. (ii) To conduct the proposed research project to understand the role of non-coding mutations in cancer by developing a method to prioritize non-coding somatic mutations that could contribute to tumourigenesis. (iii) To acquire a deeper understanding of the processes involved in genomic evolution. (iv) To develop my dissemination and outreach skills and activities. (v) To apply for independent funding focusing in the niche of cancer evolution.

For each of the project’s objectives objective, I describe the work carried out to achieve the objective and the main results:

(i) To obtain greater experience in research project management, I managed all financial and research aspects of the project from the beginning. To assist with this I completed several career development courses run by the Host Institution. In addition, I was awarded a number of small independent grants totalling €47,000 during the lifetime of the project, and I have managed all financial and research aspects relating to these grants, including obtaining ethical permission to conduct the research projects.

(ii) To understand the role of non-coding mutations in cancer I designed a method to prioritize non-coding somatic mutations that could contribute to tumourigenesis. This method identifies regions of the genome that are more frequently mutated compared to flanking regions and that have mutations at bases that are more highly conserved by analyzing 50bp windows spanning the entire human genome. The application of this method to 1349 whole cancer genomes from a variety of cancer types enabled the identification of regions, both coding and non-coding, that are recurrent targets of somatic mutations in cancer. In addition, using both recurrence and information on evolutionary conservation to score regions of the genome as potential driver mutations identified putative driver regions that include both well known drivers as well as novel recurrently mutated regions. A manuscript detailing the results has been drafted for submission to the journal BMC Genomics.

(iii) To acquire a deeper understanding of the processes involved in genomic evolution I engaged with the Scientist in Charge by attending lab. meetings. In addition, I started a number of collaborations focusing on evolutionary cancer genomics. These included (1) a breast cancer project with the €7.5M Irish Cancer Society Collaborative Research Centre, BREAST-PREDICT, (2) a renal cancer project with researchers at the Francis Crick Institute, London, (3) colorectal and breast cancer projects with researchers at the Royal College of Surgeons Ireland, and (4) colorectal cancer projects with researchers at the Centre for Colorectal Disease, St. Vincent’s University Hospital, Dublin, (5) melanoma projects with researchers at the Cancer Research UK Manchester Institute, (6) a neuroblastoma project with researchers at Systems Biology Ireland, (7) a rectal cancer project with researchers at the University of Texas MD Anderson Cancer Center and (8) I am an official international collaborator in the Genomics England (100,000 Genomes Project) Clinical Interpretation Partnership (GeCIP) for melanoma. These projects have enabled me to develop a broad understanding of the evolutionary processes driving tumour development and response to treatment. The expected outcome from these collaborations is >8 peer-reviewed publications, and currently I have one manuscript under review and three manuscripts in preparation from these collaborations.

(iv) To develop my dissemination and outreach skills, I undertook several activities and opportunities. I added to my supervision experience by co-supervising a postgraduate Ph.D. student and I acted as the primary supervisor of a Master’s student. I supervised two undergraduate students, through the University College Dublin School of Medicine and Medical Science Student Summer Research Awards. In addition, I designed and delivered lectures in “Personalized Cancer Medicine” and “An Introduction to Clinical Bioinformatics and Next Generation Sequencing” at University College Dublin. I disseminated my research to the scientific community through oral and poster presentations at national and international conferences. In particular, I was awarded the Irish Association for Cancer Research’s Senior Young Scientist Award 2016, based on my submitted abstract and research achievements to date. I published a peer-reviewed article in a high-impact journal (Annals of Oncology) as corresponding author and have several manuscripts in review or in preparation based on the work undertaken during the project. I engaged with the public on-line through Twitter and in person at public events.

(v) To apply for independent funding focusing in the niche of cancer evolution. During the fellowship, I was awarded a number of small grants totalling €47,000. I identified the Science Foundation Ireland President of Ireland Young Researcher Award as a relevant independent funding opportunity and submitted the required pre-proposal. Based on this, Science Foundation Ireland invited me to submit a full proposal, which is currently under review.

Conclusions and potential impact:

The purpose of the project was to allow me to achieve research independence in the field of cancer genomics. The project enabled me to take giant strides towards realizing this goal, and recently this has been achieved as I have been employed as an Early Career Independent Investigator in the University College Dublin School of Medicine Centre for Bioinformatics on a fixed-term contract. Furthermore I have been interviewed for a permanent lectureship in Clinical Bioinformatics in the School of Medicine at University College Dublin. I have been invited to apply for a prestigious Science Foundation Ireland President of Ireland Young Researcher Award, which is currently under review. In addition, the project has enabled me to start multiple collaborative research projects nationally and internationally, the impact of which is expected to be several peer-reviewed publications in cancer genomics over the next 12-24 months. Furthermore, the application of the novel methodology developed in the research project has demonstrated that using both mutation recurrence and evolutionary conservation to score regions of the genome as potential driver regions can identify putative driver regions that include both well-known drivers as well as novel candidate non-coding regions of the cancer genome. This is of relevance and interest to the cancer genomics research community.

My background in next generation sequencing and bioinformatics has accelerated progress in these fields in the School of Medicine at UCD and its affiliated hospital group (Ireland East Hospital Group - IEHG), and specifically I have been heavily involved in the development of a new Precision Medicine Facility at UCD. This development of this facility is expected to have a significant impact nationally for clinicians and patients and marks a key milestone for the IEHG and UCD. It provides the most comprehensive and advanced genomics platform for life science and biomedical research in Ireland and enables UCD and the IEHG to provide the most advanced healthcare to its patients.

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