Monoallelic and biallelic inactivation of TP53 gene in chronic lymphocytic leukemia: selection, impact on survival, and response to DNA damage.
Deletion of TP53 gene, under routine assessment by fluorescence in situ hybridization 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 used methodologies with similar sensitivity for the detection of deletions (interphase fluorescence in situ hybridization) and mutations (yeast functional analysis) and analyzed a large consecutive series of 400 CLL patients; a subset of p53-wild-type cases (n = 132) was screened repeatedly during disease course. The most common type of TP53 inactivation, ie, 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 2 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 because novel defects may be selected by previous therapies.
Department of Internal Medicine-Hematooncology, University Hospital Brno and Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic.
Jitka
J
Malcikova
Jana
J
Smardova
Ludmila
L
Rocnova
Boris
B
Tichy
Petr
P
Kuglik
Vladimira
V
Vranova
Sona
S
Cejkova
Miluse
M
Svitakova
Hana
H
Skuhrova Francova
Yvona
Y
Brychtova
Michael
M
Doubek
Martin
M
Brejcha
Martin
M
Klabusay
Jiri
J
Mayer
Sarka
S
Pospisilova
Martin
M
Trbusek
D000970:Antineoplastic Agents / Q000627:therapeutic use; D015153:Blotting, Western; D004249:DNA Damage / Q000235:genetics*; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D020868:Gene Silencing; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014740:Vidarabine / Q000031:analogs & derivatives / Q000627:therapeutic use
D000970:Antineoplastic Agents; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D014740:Vidarabine; C024352:fludarabine