The tumor suppressor gene TP53 codes for a central regulator of the DNA-damage-response pathway, and its activation leads to cell-cycle arrest and DNA repair, apoptosis, or senescence through both transcription-dependent and transcriptional-independent activities.TP53 may be disrupted in CLL by deletions, mutations or a combination of both (Figures 1A & 2).[19–25] The deletion of 17p13 always contains the TP53 locus, and in consecutive series is found in 3–8% unselected CLL at diagnosis and in 8–12% CLL at the time of first-line treatment.[4–7,19–25] Conversely, specific subgroups of patients affected by fludarabine-refractory CLL or Richter syndrome show a higher incidence of 17p13 deletion that may be detected in up to 30–40% of cases.[8,9,23]
Prevalence of (A) TP53, (B) NOTCH1, (C) SF3B1 and (D) BIRC3 lesions in different chronic lymphocytic leukemia clinical phases.
CLL: Chronic lymphocytic leukemia; F: Fludarabine; MBL: Monoclonal B-cell lymphocytosis.
Data taken from [9,10,13,16,17,24].
Prevalence and distribution of TP53, BIRC3, SF3B1 and NOTCH1 lesions in fludarabine-refractory chronic lymphocytic leukemia. (A) Heat map showing the mutual relationship of genetic lesions in fludarabine-refractory CLL. Rows correspond to identical lesions, and columns represent individual patients color-coded based on the molecular status (white: absence of the lesion; red: presence of the lesion). (B) Prevalence of TP53 disruption (orange), BIRC3 disruption (red), SF3B1 mutations (yellow) and NOTCH1 mutations (green) in fludarabine-refractory CLL.
CLL: Chronic lymphocytic leukemia.
Data taken from .
Mutations represent the most frequent form of TP53 inactivation in CLL and are frequently (80–90% of cases) accompanied by the loss of the second allele through 17p13 deletion.[4–7,20–25] At diagnosis, the incidence of TP53 mutation has been reported to be 4–8%.[20–23,25] As the disease progresses, the incidence of TP53 mutations increases to 10–12% at the time of first-line treatment,[4–7] 40% in fludarabine-refractory CLL[8,9] and 50–60% in Richter syndrome. Overall, 95% of mutations are localized within the central DNA-binding domain of TP53, impairing DNA binding and transactivation of target gene. Most (~75%) TP53 mutations are represented by missense substitutions leading to amino acid changes, while the remaining mutations are truncating lesions. A significant proportion of mutations recurrently targets 'hot-spot' codons. These mutations either directly disrupt the DNA-binding domain of TP53 or cause conformational changes of the TP53 protein, thus leading to severely impaired TP53 function.
The clinical importance of TP53 abnormalities in CLL is tightly linked to the poor prognosis marked by this genetic lesion and its close association with poor outcome and refractoriness, as documented by a number of observational studies and prospective trials led in both the chemotherapy and immunochemotherapy era.[4–9,19–25]
Among unselected newly diagnosed CLL, patients harboring 17p13 deletion have the worst outcome, with an estimated median OS of 3–5 years. This is consistent with the notion that newly diagnosed CLL with 17p13 deletion frequently (~50% of cases) present in advanced stage or show a rapidly progressive disease that requires treatment shortly after diagnosis (median time to first treatment of 9 months). However, it is important to stress that there is a small subgroup of patients with 17p13 deletion (and mostly mutated IGHV genes) who may exhibit stable disease for years without treatment indications.
The outcome of patients with 17p13 deletion and need for treatment is very poor. Patients with 17p13 deletion will very rarely achieve complete response after chemo-/chemoimmuno-therapy, as demonstrated by the German CLL Study Group (GCLLSG) CLL8 trial, in which the group without 17p13 deletion had a complete response rate of 21.8% (in the arm containing fludarabine + cyclophosphamide: FC) or 44.1% (in the arm containing fludarabine + cyclophosphamide + rituximab: FCR) compared with 2.3% among patients with 17p13 deletion (both arms) and LRF CLL4 trial, in which the group of patients with 17p13 deletion had a very low rate (5%) of complete/nodular partial response. This translates into an estimated OS in the range of 2–3 years from the time of front-line treatment for 17p13 deleted patients.[4,6]
Among CLL harboring TP53 abnormalities, mutations of TP53 co-occurred with deletion of the corresponding locus in approximately 70% of cases, consistent with a dual hit mechanism of inactivation. The remaining approximately 30% of cases have 17p13 deletion in the absence of TP53 mutations (~20%) or TP53 mutations in the absence of 17p13 deletion (~10%). A number of retrospective studies suggest that, in addition to 17p13 deletion, TP53 mutations, even in the absence of 17p13 deletion, also predict poor outcome in CLL.[20–23] These observations have been confirmed within the frame of two large prospective studies led in the setting of previously untreated cases. In the GCLLSG CLL4 trial, no complete response was observed in patients with TP53 mutations, and the median progression-free survival (PFS: 23.3 vs 62.2 months) and OS (29.2 vs 84.6 months) were significantly decreased in cases with TP53 mutations (both p < 0.001) compared with cases lacking TP53 mutations, respectively. Importantly, in this trial, patients with 17p13 deletion and patients with TP53 mutations in the absence of the 17p13 deletion displayed similar PFS and OS.[5,28] In the LRF CLL4 trial, TP53 mutations were significantly associated with poorer overall response rates (27 vs 83%; p < 0.001) and shorter PFS (5-year PFS: 5 vs 17%) and OS (5-year OS: 20 vs 59%), respectively (both p < 0.001). Results from clinical trials confirm the validity of TP53 abnormalities as a strong predictor of poor response and outcome also in the setting of immunochemotherapy such as FCR. In fact, the chance of achieving a complete remission by FCR is severely reduced by the presence of 17p13 deletion to only approximately 20%, with few durable remissions.[29,30]
There is some controversy about whether monoallelic TP53 abnormalities have the same poor prognostic effect as biallelic TP53 lesions, as well as whether all TP53 lesions mark poor outcome independent of mutation type and position in the protein. In fact, at variance of the GCLLSG CLL4 trial, cases from the LRF CLL4 trial harboring isolated TP53 mutation or deletion have longer PFS and OS than cases harboring biallelic TP53 inactivation. Also, a retrospective analysis from a population-based CLL cohort suggests that patients harboring truncating TP53 mutations or missense mutations outside the DNA-binding domain have a longer OS than cases harboring missense substitutions located in the TP53 DNA-binding motifs.
TP53 mutations lead to the accumulation of a TP53 protein with abnormally prolonged half-life, which can be detected by immunohistochemical or immunocytochemical analysis.[30,32] This notion has prompted the investigation of TP53 protein expression analysis as a surrogate assay for the identification of TP53 genetic defects. The main limitation of this approach is the substantial rate of false-negative results, which may be clinically harmful, thus restricting this TP53 expression analysis to the research scene.
Based on these data, genetic studies are the sole recommendation to detect TP53 defects in CLL.[33,34] 17p13 deletion is the sole cytogenetic abnormality for which testing by FISH is recommended in CLL patients requiring treatment. Because CLL with TP53 mutations carry a poor prognosis, current guidelines by the European Research Initiative on CLL warrant integration of TP53 mutation analysis into the evaluation of CLL patients before treatment initiation. CLL patients with indication for therapy and TP53 abnormalities, regardless of whether these are mutations or deletions, should be regarded as high-risk patients and considered for treatment approaches alternative to standard chemo-/chemoimmuno-therapy. These include drugs and regimens that may overcome the effect of TP53 such as alemtuzumab-based treatments, investigational agents and/or allogeneic stem cell transplant.[3,8,33–36]
Expert Rev Hematol. 2012;5(6):593-602. © 2012 Expert Reviews Ltd.