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. 2C, Box 1). Note that these also demonstrate that in FA cancers
there is variability in the order of appearance of subsequent hallmarks.