A clinically annotated post-mortem approach to study multi-organ somatic mutational clonality in normal tissues

Abstract

Recent research on normal human tissues identified omnipresent clones of cells, driven by somatic mutations known to be responsible for carcinogenesis (e.g., in TP53 or NOTCH1). These new insights are fundamentally changing current tumor 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 tumor evolution.

The Role of TP53 in Adaptation and Evolution

“…Driver mutations are under positive selection since they offer an evolutionary advantage to cells. Studies have supported the hypothesis that somatic driver mutations being under selection exists also in normal tissues, sometimes in higher frequencies than in the malignant tissues [45]. This phenomenon is not fully understood, and it shows the complexity of tumor evolution from first mutation to a benign growth and, eventually, to cancer [44].…”

Is the world ready for human germline genetic editing using CRISPR/Cas9?

“…Therefore, cleavage style embryos in humans are naturally aneuploid-mosaic, where mechanisms are in place to eliminate the abnormal cells. This absence of a cell cycle checkpoint in embryos may even lead to mutations in adulthood [51]. Up until now, PGT-A has relied on two outdated assumptions: that human cells are euploid, and if not, they indicate disease, and that a small sample of DNA can represent the entirety of the organism.…”