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TP53 aberrations in CLL
vival and impaired response to chemoimmunotherapy.8-12 Until recently, the only effective treatments available for patients with CLL harboring TP53 aberrations were alem- tuzumab and allogeneic hematopoietic stem cell trans- plantation.13-17 New small-molecule inhibitors that are effi- cacious in patients harboring TP53 aberrations are now available, including the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, the phosphatidylinositol 3-kinase (PI3K) inhibitor idelalisib, and the BCL2 inhibitor veneto- clax.18-26 Identifying TP53 aberrations is therefore impor- tant for determining the most appropriate course of treat- ment for patients with CLL.27
Several diagnostic techniques are currently in routine use for the identification of TP53 aberrations. A substan- tial proportion of TP53 aberrations involve TP53 muta- tions in the absence of del(17p).12,28-31 Therefore, while del(17p) is routinely identified by fluorescence in situ hybridization (FISH), FISH testing alone may potentially fail to identify approximately 30-40% of patients with TP53 aberrations, i.e those carrying only mutations in the gene.32,33 Thus, it is critical to test for relevant TP53 mutations, using Sanger sequencing or high-throughput sequencing technologies, in addition to FISH detection of del(17p), and both tests should be performed before each line of therapy to select appropriate treatment, as TP53 aberrations may emerge during the disease course and after previous treatment.27,31,34 The European Research Initiative on CLL (ERIC) has implemented a certification program (known as the TP53 Network) for clinical laboratories performing analysis of TP53 aberra-
Table 1. Overview of genetic complexity in chronic lymphocytic leukemia.
tions in order to improve the reliability of TP53 muta- tion analysis and to spread knowledge on testing for TP53 aberrations in routine clinical practice, with the final aim of optimizing treatment choices and patients’ outcomes.35
Genetic aberrations in chronic lymphocytic leukemia
Genetic aberrations identified in CLL include genomic abnormalities and specific gene mutations.6,36 Combinations of these aberrations, along with immunoglobulin heavy variable (IGHV) mutation status, result in biological and clinical subgroups associated with varying outcomes.10,11,37,38 An overview of the genetic aber- rations frequently found in CLL is provided in Table 1.
Chromosomal abnormalities frequently found in CLL include del(13q), trisomy 12, del(11q), and del(17p);4 other less frequent abnormalities have also been identified such as amplifications of chromosome 2p or 8q, and deletions in chromosomes 8p and 15q.4,36
Using conventional karyotyping of stimulated lympho- cytes, the presence of three or more chromosomal abnor- malities, known as a complex karyotype, has been associ- ated with worse disease outcomes.39-42 Similar results have been obtained using arrays for DNA copy number alter- ations to detect genomic complexity.37,43 There is a strong association of complex karyotype with TP53 aberrations leading to genetic instability, but a complex karyotype has been demonstrated to be an independent prognostic factor for poor overall survival.28,39,40,44,45 Chromothripsis-like pat- terns, defined by tens to hundreds of chromosomal
Genetic aberration
Chromosomal abnormalities
Frequency in Time to first PFS untreated treatment (median,
OS (median, months)
31–33a 72–79a 97–114a 113–133a
-
21–90b
15–34b
28–90b 26–85b
RPS15: reduced OS
Coexistence with References other genetic aberrations
TP53 mutations (4, 8, 11, 28, 56)
ATM and/or SF3B1, BIRC3 mutations (4, 11, 28, 56)
NOTCH1 mutations (4, 11, 28, 56)
miRNA 15a/16-1 encoded within DLEU2 (4, 11, 28, 56) intron in 13q23
patients (median, months)
del(17p) 4–8.5% 9
months)
- - - -
-
4–23b
18–86b
5–43b 8–40b
RPS15:
Gene mutation
del(11q) Trisomy 12 del(13q)
Other (e.g. amp[2p]; amp[8q]; del[8p]; del[15q]; and del[6q])
TP53
NOTCH1
SF3B1 ATM
Other (e.g. FAT1,
17–18% 12–16% 35–55%
2–7%
5–12%
10–14%
9–14% 11–26%
13 33 92
-
4–58
5–42
2–86
Significantly reduced independently of del(11q)
-
-
The majority of clonal mutations are associated with del(17p) Mostly associated with U-CLL
Mostly in U-CLL (82%)
Frequently associated with trisomy 12
Found together with TP53 mutations in some studies, but not in others
ATM and del(11q) occur mostly in U-CLL
RPS15 can be exclusive of TP53 mutations
(4, 11, 28, 56)
(5, 6, 8, 10, 28, 31, 36, 56, 73, 110)
(6, 10, 28, 31, 36, 56)
(5, 6, 28, 31, 36)
(5, 6, 28, 31, 36, 56)
(36, 52, 54, 73)
MYD88, POT1, and RPS15) PFS: progression-free survival; WT: wild type.
reduced PFS
U-CLL: IGHV unmutated CLL; aIn previously untreated patients bAcross all lines of treatment in chemoimmunotherapy studies. CLL: chronic lymphocytic leukemia; OS: overall survival;
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