Understanding Tumour Predisposition in Asia (UToPIA) Study: From Patient-Centred Research to the Clinic.

Background: Cancer is a major focus of the precision medicine initiative. While the clinical validity, utility and actionability of testing at-risk individuals for high penetrance tumour predisposition genes (TPGs) is clear, 40% of individuals who undergo clinical testing today are found to have a genetic variant of unknown significance (VUS). Our proposal seeks to address and understand VUS in TPGs identified in Singaporeans through (1) selecting individuals with VUS for functional evaluation and following up carriers with TPG VUS longitudinally to correlate with clinical outcomes. Methods: Mutations in DNA repair pathway genes are responsible for the majority of tumour susceptibility we see in the clinic and are important targets for precision medicine. We will prioritise VUS in the DNA damage and repair Fanconi Anemia (FA) pathway, specifically germline FANCI variants for functional analysis using patient-derived lymphoblastoid cell lines. In parallel, we will also evaluate selected patients with digenic/ oligogenic germline variants in the FA pathway to better understand gene-gene interactions clinically. We will prospectively follow-up patients with a TPG VUS for evidence of overt clinical tumour development. Feasibility: All patient material needed for this study is available. The study team has demonstrated the needed clinical, technical and scientific expertise for the proposed experiments with support from senior members of the study team. Clinical Significance: Our team has shown that successful classification of a VUS not only directly allows affected patients to receive prompt care; but also aids variant classification efforts globally. Data from this study will further inform on the optimal management of individuals with VUS in TPGs and will be used to guide future health policy decision-making.