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E. Campo et al.
rearrangements in a localized region of the genome, have also been identified in some patients with CLL,46-48 usually associated with TP53 and SETD2 mutations.6,49
Apart from TP53, the most frequent mutations associat- ed with disease outcomes in CLL are found in the ATM, BIRC3, NOTCH1, and SF3B1 genes.6,31,50-53 These and other mutations have been associated with the development of high-risk disease, with a higher incidence of these muta- tions being found in fludarabine-refractory CLL than in untreated CLL.6,52,54-56 The impacts of these mutations on outcomes in CLL are outlined in Table 1 but the clinical value of each of them remains to be established.57
IGHV gene status
Another important CLL feature that affects prognosis is the IGHV gene mutation status. The clinical course is gen- erally more aggressive in patients with unmutated IGHV genes than in those with mutated IGHV genes.58,59 TP53 mutations may be found in both mutated and unmutated CLL, but are usually associated with unmutated CLL.56 Immunogenetic studies have recently revealed that approximately one third of patients with CLL carry quasi- identical or stereotyped B-cell receptors (BCR) and can be grouped into subsets that share clinico-biological features and outcome.57
What is TP53?
Over 50% of human cancers carry TP53 gene muta-
tions,60 and the importance of TP53 in tumor development is highlighted by the increased incidence of cancer before the age of 30 in patients with Li-Fraumeni syndrome, which results from germline mutations in the TP53 gene.61
TP53 encodes the tumor-suppressor protein p53, which has numerous cellular activities including regulation of the cell cycle and apoptosis, and promotion of DNA repair in response to cellular stress signals such as DNA dam- age.60,62,63 Following DNA damage, p53 triggers either apoptosis or G1 cell-cycle arrest until the cell has complet- ed DNA repair processes, thereby preventing replication of potentially harmful genetic abnormalities.62
What are the different types of TP53 aberration and how do they affect p53 function and pathogenicity?
TP53 aberrations can arise through deletion of the TP53 locus on chromosome 17 (17p13.1) or gene mutations including missense mutations, insertions or deletions (indels), nonsense mutations or splice-site mutations. Gene mutations are heavily concentrated in the DNA- binding domain, encoded by exons 4–8 of the TP53 gene, but mutations can also appear in the oligomerization domain or C-terminal domain.33,63-65 del(17p) and/or TP53 mutations in various combinations can result in the loss of wildtype p53 function in CLL (Figure 1).12,28,29,31,33 Six ‘hotspot’ codons in particular (codons 175, 245, 248, 249, 273, and 282) are affected at elevated frequency.33,63,66 This is in line with a disease-specific TP53 mutational profile in CLL.66
The most commonly found mutations in TP53 are mis- sense mutations in the coding region of TP53, which lead to an amino acid change in the p53 protein and account for approximately 75% of TP53 mutations identified.33,60,63 Missense mutations may result in expression of a mutated p53 protein that cannot activate the p53 tumor-suppres- sive transcriptional response, have dominant-negative effects over any remaining wildtype p53, and/or could gain oncogenic functions independent of wildtype p53,5,33,60,64 illustrating their pathogenic and prognostic impact even if occurring in one copy (mono-allelic) of TP53 with retention of a potentially functional allele.32 In contrast, del(17p), frameshift mutations, indels, nonsense mutations, and splice-site mutations result in loss of func- tional p53, and although functional p53 may still be expressed in the presence of a second wildtype allele, this has not been proven to diminish the adverse prognostic impact of such abnormalities (Figure 2).33
Based on data obtained from Sanger sequencing, approximately 80% of patients harboring del(17p) also carry TP53 mutations in the second allele.8,30,67 Overall, del(17p) associated with TP53 mutations is the most com- mon abnormality affecting the TP53 gene in CLL, account- ing for approximately two-thirds of cases.8,10,30,33 The
Figure 1. Loss of wildtype (wt) p53 function in chronic lymphocytic leukemia can occur as a result of del(17p) and/or TP53 mutations.12,28,29,31,33 The most common cause of TP53 aberrations is the result of a combination of TP53 mutation and del(17p), which accounts for up to two-thirds of all TP53 aberrations.
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haematologica | 2018; 103(12)