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CLL pathogenesis and management
Figure 3. Recurrently mutated genes and pathways in chronic lymphocytic leukemia. The main molecular pathways affected by mutations in chronic lymphocytic leukemia are depicted. Genes mutated at higher frequencies (>5%) in newly diagnosed patients are highlighted in bold.
POT1 in U-CLL), whereas others are seen in both sub- types; (ii) age of the patients: MYD88 mutations seem to be more frequent in younger patients; (iii) disease evolu- tion: some mutations (SF3B1, POT1, ATM) are more fre- quent in patients requiring therapy compared to those with stable disease, and some others (TP53, BIRC3, MAP2K1, NOTCH1) are more frequent in patients with progressive disease after chemoimmunotherapy (CIT).3,4,59 The co-occurrence of many of these driver alterations within the same tumor complicates the analysis of their relative clinical relevance. For instance, mutations in SF3B1, POT1 or XPO1 are generally associated with poor prognosis, but they rarely appear on their own.13 This has led some investigators to propose a multi-hit model in which the accumulation of driver mutations, regardless of the individual genes targeted by each of these mutations, gradually impairs patients’ outcome.3,13 Indeed, the sur- vival of patients in whom no driver aberrations are iden- tified is comparable to that of individuals in the general population, further reinforcing this concept.3
Deep, targeted next-generation sequencing has revealed that subclonal mutations (i.e., those present in only a fraction of tumor cells) can be detected for all driv- er genes and are associated with rapid disease progression
and poor outcome.11–13 This is particularly relevant for TP53 mutations given the fact that, as explained below, CLL therapy is based on the presence or absence of these mutations. The current consensus is that, apart from clon- al mutations, subclonal mutations with a variant allelic frequency ranging from 5 to 10% (and therefore below the threshold of detection by conventional molecular techniques) could also be reported, whereas those with a variant allelic frequency lower than 5% should not, but there is much controversy around these issues and this recommendation may well change in the future.60,61 Furthermore, the analysis of clonal and subclonal aberra- tions has also allowed the reconstruction of each tumor’s phylogeny. Thus, clonal aberrations, which are mostly structural abnormalities [e.g. trisomy 12, del(13q)] gener- ally correspond to earlier driving events, while subclonal mutations in driver genes (e.g., SF3B1, POT1, NOTCH1) are acquired later over the course of the disease.13
Moreover, some genes appear to be specifically selected at relapse. For instance, small clones harboring TP53 mutations typically expand and dominate the disease after CIT, which explains the poor prognosis associated with these subclonal mutations.12,62 Apart from TP53, mutations in IKZF3 and SAMHD1 have also been recur-
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