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Solimando et al. J Cancer Metastasis Treat 2022;8:9 https://dx.doi.org/10.20517/2394-4722.2021.166 Page 3 of 12
the stem cell compartments, mostly quiescent, and is retained. Thus, it is not unlikely that the lifetime risk
of cancers increases in tissue with a high proliferation rate of stem cells, with some malignancies being more
common, such as colorectal cancer and basal cell carcinoma, and some relatively infrequent, e.g.,
[16]
sarcomas . Hematological malignancies are characterized by an intermediate rate of dividing stem cells.
Nonetheless, it is estimated that one protein-coding mutation every ten years happens in HSC. Given that
about 50,000-200,000 HSCs per person are present, by the age of 70, hundreds of somatic mutations are
accumulated in the hematopoietic tissue, known to also be mutated in hematological malignancies . The
[17]
vast majority of DNA is represented by a non-coding one, with 1%-3% containing protein-coding
sequences, with the acquisition of somatic mutations being a stochastic process. Therefore, most mutations
are inconsequential. Nevertheless, the mutation can occasionally alter tumor proto-oncogene, leading to
[17]
clonal expansion and subsequent development of hematological malignancies . Therefore, it is essential to
pinpoint that somatic mosaicism is present in most tissues, constituted by inconsequential mutations.
Conversely, clonal hematopoiesis represents a tiny portion of somatic mosaicism. Hematological cancers
represent a minority of clonal hematopoiesis . To better understand somatic mosaicism, it is pivotal to
[15]
recapitulate the hematopoietic stem cell life cycle and recognize early mosaicism, resulting in a relatively
sizable clone and late mosaicism, being harbored by the progeny of the HSC. From a detection standpoint,
these mutations can be detected by next-generation sequencing approaches (NGS) or by ultra-deep NGS
and whole-genome sequencing approaches (WGS), which have a broad coverage. The sensitivity in
detecting most mutations is high with the latter [18,19] , not necessarily implying that those patients have clonal
hematopoiesis. In the case of mutations affecting tumor suppressors or oncogenes, leading to increased
stem cell fitness, an expansion of the HSC, progenitors, and immature cells can happen, due to genetic
alterations involving the coding regions. An expansion of clonal cells can be realized [20-22] . Limiting the
detection analysis to targeted sequencing of the genes frequently mutated in cancer or looking at WGS and
WES from the cancer-associated mutations perspective only, the detectability of clonal hematopoiesis is
estimated in approximately 10% of elderly subjects .
[15]
The underlying mechanism of clonal hematopoiesis is relatively simple, with the fraction of clonal cells
being represented by the fraction of mutant cells over normal unmutated polyclonal hematopoietic cells.
Thus, the fraction of clonal cells can be increased by the enhanced number of expanded mutant cells or by
the decrease of normal cells, mostly due to HSC alterations [15,23] .
The clonal expansion is related to the increased stem cell fitness and the mutant cells’ expansion, with
relative preservation of normal polyclonal hematopoiesis. Aging is the second mechanism by which the
enhanced fraction of clonal cells is related to the attrition of HSC in the polyclonal hematopoiesis
[24]
counterpart . Different models have explained clonal hematopoiesis due to increased HSC fitness and
genetic driven HSC attrition. The computational approach pioneered the comprehensive explanation,
pointing toward a role of mutations in favoring asymmetric self-renewal, where a mutation can also have a
negative effect causing a division into differentiated cells and, therefore, the disappearance of the mutated
stem cells or a neutral effect when the number of the mutated stem cells remains the same . The
[25]
mathematical model supported this hypothesis by correlating the size of the clone with the age of the
individual. The computational results show that mutations with high fitness led to a rapid expansion of
HSC clones. Contrariwise, mutations with moderate fitness will expand much more slowly, and mutations
with low impact will remain stable or disappear over time . Watson et al. also considered previously
[25]
[25]
published data and described a high correlation between mathematical prediction and the type of mutation,
modeling the prediction on several mutations described in clonal hematopoiesis. They also reported that
mutations correlated with myelodysplastic syndromes and acute myeloid leukemia are not common in the
[25]
genome .