TP53 mutation profile in chronic lymphocytic leukemia: evidence for a disease specific profile from a comprehensive analysis of 268 mutations
Open Access
- 23 September 2010
- journal article
- research article
- Published by Springer Science and Business Media LLC in Leukemia
- Vol. 24 (12), 2072-2079
- https://doi.org/10.1038/leu.2010.208
Abstract
The TP53 mutation profile in chronic lymphocytic leukemia (CLL) and the correlation of TP53 mutations with allele status or associated molecular genetics are currently unknown. We performed a large mutation analysis of TP53 at four centers and characterized the pattern of TP53 mutations in CLL. We report on 268 mutations in 254 patients with CLL. Missense mutations appeared in 74% of cases compared with deletions and insertions (20%), nonsense (4%) and splice site (2%) mutations. The majority (243 of 268) of mutations were located in the DNA-binding domain. Transitions were found in 131 of 268 mutations, with only 41 occurring at methylated CpG sites (15%), suggesting that transitions at CpGs are uncommon. The codons most frequently mutated were at positions 175, 179, 248 and 273; in addition, we detected a common 2-nt deletion in the codon 209. Most mutations (199 of 259) were accompanied by deletion of the other allele (17p–). Interestingly, trisomy 12 (without 17p–) was only found in one of 60 cases with TP53 mutation (without 17p–) compared with 60 of 16 in the cohort without mutation (P=0.006). The mutational profile was not different in the cohorts with and without previous therapy, suggesting that the mechanism underlying the development of mutations may be similar, independent of treatment.Keywords
This publication has 35 references indexed in Scilit:
- Monoallelic and biallelic inactivation of TP53 gene in chronic lymphocytic leukemia: selection, impact on survival, and response to DNA damageBlood, 2009
- Detailed analysis of p53 pathway defects in fludarabine-refractory chronic lymphocytic leukemia (CLL): dissecting the contribution of 17p deletion, TP53 mutation, p53-p21 dysfunction, and miR34a in a prospective clinical trialBlood, 2009
- The Prognostic Value of TP53 Mutations in Chronic Lymphocytic Leukemia Is Independent of Del17p13: Implications for Overall Survival and ChemorefractorinessClinical Cancer Research, 2009
- Treatment resistance in chronic lymphocytic leukemia–the role of the p53 pathwayLeukemia & Lymphoma, 2009
- Monoallelic TP53 inactivation is associated with poor prognosis in chronic lymphocytic leukemia: results from a detailed genetic characterization with long-term follow-upBlood, 2008
- The detection of TP53 mutations in chronic lymphocytic leukemia independently predicts rapid disease progression and is highly correlated with a complex aberrant karyotypeLeukemia, 2008
- Structural Biology of the Tumor Suppressor p53Annual Review of Biochemistry, 2008
- Shaping Genetic Alterations in Human Cancer: The p53 Mutation ParadigmCancer Cell, 2007
- p53 alterations in human cancer: more questions than answersOncogene, 2007
- Inactivation of p53 and deletion of ATM in B-CLL patients in relation to IgVH mutation status and previous treatmentLeukemia, 2006