Hallmarks of cancers arising in FA individuals

During tumorigenesis, the cells of all types of solid cancers arising in adults undergo a multi-step process from a healthy, non-transformed cell to low-grade and high-grade dysplasia, carcinoma in situ , and invasive cancer (36) (Fig. 2A). The early stages of this process are reversible, but when a “point of no return” is reached, an aggressive carcinoma forms, which via the spreading of metastases will eventually lead to patient mortality. In cancer patients in the general population, this multi-step tumorigenesis process takes decades, but in FA individuals it can take only months to a few years.
Transformed cells acquire a conserved set of cancer hallmarks During tumorigenesis, including self-sufficiency in growth signals, insensitivity to antigrowth signals, and tissue invasion and metastasis (37). These are altered functional capabilities, the accumulation of which allows malignant cells to survive, proliferate, and disseminate. The hallmarks are outcomes of specific cell fate-controlling regulatory pathways, which in turn are affected by cancer driver gene mutations (38). Environmental factors, like lifestyle decisions on diet, physical activity, and smoking, modulate these pathways. In addition, germline mutations may accelerate tumorigenesis like in the Li-Fraumeni syndrome (36). In contrast, 100% of all cancers arising in FA individuals (here termed “FA cancers”) are based on heredity of a defective FA/BRCA pathway of DNA repair. Therefore, genome instability & mutation prominently affects other physiological processes, which can result in the emergence of additional hallmarks, such as polymorphic microbiomes, tumor-promoting inflammation, deregulating cellular metabolism, activating invasion & metastasis, senescent cells, avoiding immune destruction, and non-mutational epigenetic reprogramming. These eight hallmarks of FA cancers (Fig. 2B) summarize clinical, cellular and molecular observations in the field (39) (Box 1). They overlap largely with the latest version of 14 hallmarks of cancer (40). However, while in the general population the order in which the cancer hallmarks are established, as well as the underlying mechanisms, varies significantly, in FA cancers the hallmark “genome instability & mutation” always emerges first. For example, we illustrate five real cases of tumorigenesis in FA individuals (Fig. 2CBox 1). Note that these also demonstrate that in FA cancers there is variability in the order of appearance of subsequent hallmarks.