Clonal dynamics and mutational landscape of normal and cancerous tissues in cancer predisposition syndromes

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Cancer predisposition syndrome, also called inherited cancer predisposition, or familial cancers are usually caused by pathogenic mutation(s) that are inherited from one or both parents and increase the risk of developing cancer at an earlier age compared to the risk for the general population. Although all the cells in the offspring carry the same pathogenic mutation(s), yet only some cell types are sensitive to these changes and transform into malignant tumours. Moreover, some tumours emerge early in these individuals (during childhood), such as sarcoma, while others take longer to form, such as breast cancer (usually it appears around the age of 20 and above). Despite the huge effort in the field to understand tumorigenesis in individuals with cancer predisposition syndromes, yet the cellular processes that cause malignant transformation in some cells but not in every single cell in the body remain unknown. The aim of this study is to:1) Generate a comprehensive mutational landscape across histological normal tissues of individuals with Li-Fraumeni syndrome, which is a type of inherited cancer; 2) Identify factors that cause an early tumour transformation in some cells compared to tumours that emerge later in life;3) Investigate DNA modifications, such as changes in methylation, which may play a role in malignant transformation across different cell types. The results from this study will help us better understand how malignant transformation occurs in some cells in individuals with cancer predisposition syndromes. The outcome will provide important insights into cancer risk and development in general.