Recurrent mutations refine prognosis in chronic lymphocytic leukemia

• Published in: Leukemia Vol. 29; no. 2; pp. 329 - 336
• Main Authors: Baliakas, P, Hadzidimitriou, A, Sutton, L-A, Rossi, D, Minga, E, Villamor, N, Larrayoz, M, Kminkova, J, Agathangelidis, A, Davis, Z, Tausch, E, Stalika, E, Kantorova, B, Mansouri, L, Scarfò, L, Cortese, D, Navrkalova, V, Rose-Zerilli, M J J, Smedby, K E, Juliusson, G, Anagnostopoulos, A, Makris, A M, Navarro, A, Delgado, J, Oscier, D, Belessi, C, Stilgenbauer, S, Ghia, P, Pospisilova, S, Gaidano, G, Campo, E, Strefford, J C, Stamatopoulos, K, Rosenquist, R
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-02-2015; Nature Publishing Group
• Subjects: 631/208/737; 692/699/67/1990/283/1895; 692/700/1750; Aged; Agent Orange; Analysis; Cancer and Oncology; Cancer och onkologi; Cancer Research; Chromosome 11; Chronic lymphocytic leukemia; Clinical Medicine; Critical Care Medicine; Cytogenetics; Diagnosis; DNA Mutational Analysis; Europe; Female; Gene Deletion; Gene mutations; Genes; Genetic aspects; Health aspects; Hematology; Humans; Intensive; Internal Medicine; Klinisk medicin; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - diagnosis; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Lymphatic leukemia; Male; Medical and Health Sciences; Medical prognosis; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Middle Aged; Multivariate Analysis; Mutation; MyD88 protein; Oncology; original-article; p53 Protein; Phosphoproteins - genetics; Physiological aspects; Polymorphism, Single Nucleotide; Prognosis; Receptor, Notch1 - genetics; Recurrence; Ribonucleoprotein, U2 Small Nuclear - genetics; Risk factors; RNA Splicing Factors; Standardization; Time Factors; Trisomy; Tumor proteins; Tumor Suppressor Protein p53 - genetics; United Kingdom
• ISSN: 0887-6924; 1476-5551; 1476-5551
• DOI: 10.1038/leu.2014.196

Through the European Research Initiative on chronic lymphocytic leukemia (CLL) (ERIC), we screened 3490 patients with CLL for mutations within the
NOTCH1
(
n
=3334),
SF3B1
(
n
=2322),
TP53
(
n
=2309),
MYD88
(
n
=1080) and
BIRC3
(
n
=919) genes, mainly at diagnosis (75%) and before treatment (>90%).
BIRC3
mutations (2.5%) were associated with unmutated
IGHV
genes (U-CLL), del(11q) and trisomy 12, whereas
MYD88
mutations (2.2%) were exclusively found among M-CLL.
NOTCH1
,
SF3B1
and
TP53
exhibited variable frequencies and were mostly enriched within clinically aggressive cases. Interestingly, as the timespan between diagnosis and mutational screening increased, so too did the incidence of
SF3B1
mutations; no such increase was observed for
NOTCH1
mutations. Regarding the clinical impact,
NOTCH1
mutations,
SF3B1
mutations and
TP53
aberrations (deletion/mutation,
TP53ab
) correlated with shorter time-to-first-treatment (
P
<0.0001) in 889 treatment-naive Binet stage A cases. In multivariate analysis (
n
=774),
SF3B1
mutations and
TP53ab
along with del(11q) and U-CLL, but not
NOTCH1
mutations, retained independent significance. Importantly,
TP53ab
and
SF3B1
mutations had an adverse impact even in U-CLL. In conclusion, we support the clinical relevance of novel recurrent mutations in CLL, highlighting the adverse impact of
SF3B1
and
TP53
mutations, even independent of
IGHV
mutational status, thus underscoring the need for urgent standardization/harmonization of the detection methods.