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TP53 aberrations in CLL
<10% of alleles within the cancer cell population remains an unresolved issue and there is not enough evidence to make therapeutic decisions based on mutations unde- tectable by Sanger sequencing. This conclusion should be always stated when reporting variants present at a fre- quency of below 10%.
Outside of the context of research, determination of TP53 status at diagnosis may not be required; initiation of first-line treatment can be deferred until patients have symptomatic active disease irrespective of TP53 status.82-85
Naming, reporting, and pathogenicity of mutations
The consistent use of nomenclature in managing DNA sequence mutations is essential for concise communica- tion of diagnostic testing and genetic risk assessment.60 In clinical practice, aberrations are often referred to as mutations, and are referred to as such in clinical reports. However, one must note that the more accurate techni- cal term is ‘variant’. It is recommended that mutations are named according to the Human Genome Variation Society guidelines, or according to American College of Medical Genetics guidelines on mutations and mutation pathology in the case of germline mutations.86,87 Description of mutations at the DNA level using the sta- ble Locus Reference Genomic reference sequence is rec- ommended to enable comparison across studies and databases.88
The pathogenicity of more frequent TP53 mutations is well known, with functional analyses demonstrating that all TP53 hot-spot mutations result in a clear loss of p53 activity.5,60 The pathogenicity of some less frequently occurring TP53 mutations may be less clear, particularly in the case of missense mutations which can have varied functional consequences.5,33,60,64
A combination of factors are considered when deter- mining whether a mutation is likely to be pathogenic, including whether the mutation results in an amino acid
change, whether the mutation is found in a conserved region of the genome or hotspot region, and whether there is a predicted functional effect of the amino acid splicing change on the protein or post-translational modi- fication.60 Pathogenicity assessments should be performed by experienced diagnosticians, follow standardized proce- dures, and be documented. TP53 locus-specific databases are available and are important tools for analyzing and assessing the pathogenicity of TP53 mutations. These are the IARC TP53 database (http://p53.iarc.fr/), the TP53 website (http://p53.fr/), and the Seshat online software (http://p53.fr/tp53-database/seshat). The Seshat online software, for example, provides a quality check of the mutation nomenclature, generates a description of the mutation, and assesses the pathogenicity of each mutation with the use of specific algorithms. Structural and func- tional information for each mutation is also produced.35,89
Clinical implications of TP53 aberrations
Patients with del(17p) and/or TP53 mutations usually
respond poorly to the standard first-line chemoim- munotherapy, and have an aggressive disease course.8-12 In the CLL8 study comparing first-line treatment with flu- darabine plus cyclophosphamide or fludarabine plus cyclophosphamide with rituximab, TP53 aberrations were found to be the strongest prognostic markers in multivari- able analyses and were associated with markedly reduced progression-free survival and overall survival (Figure 4).10 Both in front-line and relapsed/refractory settings, treat- ment with bendamustine plus rituximab was also shown to be associated with low response rates and poor survival outcomes in patients with CLL harboring TP53 aberra- tions.90 Consequently, chemoimmunotherapy is no longer considered standard therapy for patients with TP53 aber- rations. Until recently, the anti-CD52 antibody alem- tuzumab was considered to be the only effective agent available for patients with TP53 aberrations, despite an
Figure 4. Progression-free and overall survival according to TP53 status in the CLL8 study.10 Re-published with permission from The American Society of Hematology, from: Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Stilgenbauer S et al. Blood. 2014;123(21):3247-3254; permission conveyed through Copyright Clearance Center, Inc. FC: fludarabine plus cyclophosphamide; FCR: fludarabine plus cyclophosphamide plus rituximab; mut: mutated; OS: overall survival; PFS: progression-free survival; WT: wild-type.
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