Somatic mutations are small DNA errors that accumulate in the genome of ageing cells. These mutations sporadically result in a cellular growth advantage, especially when they occur in cancer genes. The sequential accumulation of these so-called driver mutations eventually leads to the formation of malignant tumors. Recent evidence suggests that they also underlie micro-clone formation in multiple histologically normal epithelial tissues, providing new insights in early human carcinogenesis. Despite the high incidence of head and neck (HN) cancers, nothing is currently known about mutational clonality in HN epithelia. This PhD project aims to characterize the somatic mutational landscape of the HN region, using a broad range of post-mortem tissues obtained from clinically well-annotated whole-body donors, following a methodology that we developed recently. We will use deep exome sequencing to identify HN mutational clonality and the different mutagenic influences (e.g., cigarette smoke). The gene expression consequences of these clonal oncogenic alterations will be determined using emerging spatial transcriptomics technologies. By spatially mapping clone-specific gene expression signatures, we aim to provide the first evidence for the presence (or absence) of clonal interdependency. Results from this project will provide the first spatially resolved catalogue of HN mutational clonality, providing new insights in HN carcinogenesis.