Monoallelic and biallelic inactivation of TP53 gene in chronic lymphocytic leukemia: selection, impact on survival and response to DNA damage. Blood [Blood] Journal article

Deletion of TP53 gene, under routine assessment by FISH analysis, connects with the worst prognosis in chronic lymphocytic leukemia (CLL). The presence of isolated TP53 mutation (without deletion) is associated with reduced survival in CLL patients. It is unclear how these abnormalities are selected and what their mutual proportion is. We have used methodologies with similar sensitivity for the detection of deletions (I-FISH) and mutations (yeast functional analysis) and analyzed a large consecutive series of 400 CLL patients; subset of p53-wt cases (n=132) was screened repeatedly during disease course. The most common type of TP53 inactivation, i.e. mutation accompanied by deletion of the remaining allele, occurred in 42 patients (10.5 %). Among additional defects, the frequency of the isolated TP53 mutation (n=20; 5 %) and the combination of two or more mutations on separate alleles (n=5; 1.3 %) greatly exceeded the sole deletion (n=3; 0.8 %). Twelve patients manifested defects during repeated investigation; in all circumstances the defects involved mutation and occurred after therapy. Monoallelic defects had a negative impact on survival and impaired in vitro response to fludarabine. Mutation analysis of the TP53 should be performed before each treatment initiation since novel defects may be selected by previous therapies.

Blood [Blood]