Volumen: 22 # Number : Numero Extraordinario 3er IBAM CLL 2018
Publication Date : Agosto Year: 2018
Mutations of TP53 in chronic lymphocytic leukemia.
Clinical impact and methodological considerations
Authors: Hassan R, Torres DC, Stanganelli C, Lima L, Segges P,Ferrerira G, Emmel V, Vera-Lozada G, de Souza Fernandes T,Campos Lima M, Abdelhay E, Slavutsky I
Abstract: TP53 mutations are detected in ~5% of chronic
lymphocytic leukemia (CLL) patients at diagnosis
and are associated with unfavorable outcome,
independent of the presence of 17p deletion. Most
of knowledge on molecular and clinical characteristics of TP53 mutation in CLL patients comes from developed countries. In this work, we aim to describe results of TP53 molecular screening in
a group of CLL patients from Brazil and Argentina.
We studied a group of 133 CLL patients (110
from Rio de Janeiro, Brazil and 23 from Buenos
Aires, Argentina). Detection of TP53 mutations
by Sanger sequencing disclosed a frequency of
22.56%; 8.7% at diagnosis, and 39% in pre-treatment/
progression samples (p<0.001; Fisher’s exact
test). Mutation frequency in 33 cases with del17p
was 42.4%. NGS analysis was reproducible, all mutations, even at diagnosis exhibited >70% VAF (variant allele frequency). TP53 mutations were not significantly associated to the immunoglobulin heavy
chain (IGVH) mutational status. Mutations were
associated to a shorter time to first treatment (p=
0.001; log-rank analysis). In cases needed to treat
between 0-12 months after diagnosis, the frequency
of TP53 mutation was 21.6%, compared with 6% in
patients needed to treat after 12 months and 0% in
non-treated patients. Hemoglobin levels <10 g/dL,
platelet count less than 100 × 109/L, lymphadenomegaly, an IGVH unmutated status, mutated TP53 and mutated NOTCH1 were associated with lower
overall survival in univariate analysis. In multivariate analysis, only thrombocytopenia and TP53 mutation status maintained an independent impact (HR 5.25; CI95% 2.13 – 12.94; p< 0.001). Although our study is limited by the small number of heterogeneously treated patients, we think that it is a contribution with sensible knowledge on a real-world CLL series outside the developed countries. Our results suggest that TP53 mutation screening could be useful at diagnosis in the fraction of cases with early treatment intent.
Key words: TP53,
mutations,
CLL,
diagnosis,
NGS.
Pages : 26-32
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