A Clinically Annotated Post-Mortem Approach to Study Multi-Organ Somatic Mutational Clonality in Histologically Healthy Tissues

Recent research on histologically healthy human tissues identified omnipresent mutational microclones, driven by somatic mutations known to be responsible for carcinogenesis (e.g., in TP53 or NOTCH1 ). These new insights are fundamentally changing current tumour evolution models, with broad oncological implications. Most studies are based on surgical remnant tissues, which are not available for many organs and rarely in a pan-organ setting (multiple organs from the same individual). Here, we describe an approach based on clinically annotated post-mortem tissues, derived from whole-body donors that are routinely used for educational purposes at human anatomy units. We validated this post-mortem approach using UV-exposed and unexposed epidermal skin tissues and confirm the presence of positively selected NOTCH1/2-, TP53 - and FAT1 -driven clones. No selection signals were detected in a set of immune genes or housekeeping genes. Additionally, we provide the first evidence for smoking-induced clonal changes in oral epithelia, likely underlying the origin of head and neck carcinogenesis. In conclusion, the whole-body donor-based approach provides a nearly unlimited healthy tissue resource to study mutational clonality and gain fundamental mutagenic insights in the presumed earliest stages of tumour evolution.