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Br J Cancer. 2017 Jul 11;117(2):256-265. doi: 10.1038/bjc.2017.152. Epub 2017 May 30.

Mutations in TP53 and JAK2 are independent prognostic biomarkers in B-cell precursor acute lymphoblastic leukaemia.

Author information

1
IBSAL, IBMCC, University of Salamanca, CSIC, Cancer Research Center, Campus Miguel de Unamuno, Salamanca 37007, Spain.
2
School of Biological Sciences (GICBUPTC research group), Universidad Pedagógica y Tecnológica de Colombia (UPTC), Avenida Central del Norte 39-115, Tunja 150003, Colombia.
3
Molecular Biology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Calle Diego de León, 62, Madrid 28006, Spain.
4
Department of Hematology, Hospital 12 de Octubre, Avenida de Córdoba s/n, Madrid 28041, Spain.
5
Personalised Healthcare and Biomarkers, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Darwin Building, 310 Cambridge Science Park, Milton Road, Cambridge CB4 0WG, UK.
6
Department of Pediatric Oncohematology, Hospital Universitario Virgen de la Arrixaca, Ctra. Madrid-Cartagena, s/n, El Palmar, Murcia 30120, Spain.
7
Department of Hematology, Hospital Río Carrión, Av. Donantes de Sangre, s/n, Palencia 34005, Spain.
8
Department of Hematology, Hospital Virgen Blanca, Altos de Nava s/n, León 24071, Spain.
9
Department of Pediatrics, Hospital Universitario de Salamanca, Paseo de San Vicente, 88-182, Salamanca 37007, Spain.
10
Department of Hematology, Hospital Juan Ramón Jiménez, Ronda Exterior Norte, s/n, Huelva 21005, Spain.
11
Department of Hematology, Hospital de Jerez, Carr Madrid-Cádiz, Jerez de la Frontera 11407, Cádiz, Spain.
12
Department of Hematology, ICO-Hospital Germans Trias i Pujol, Instituto de Investigación Josep Carreras, (Can Ruti), Carretera de Canyet, s/n, Badalona, Barcelona 08916, Spain.
13
Hematology Laboratory, Institut de Recerca Pediátrica Hospital Sant Joan de Déu de Barcelona, Passeig de Sant Joan de Déu, 2, Esplugues de Llobregat, Barcelona 08950, Spain.
14
Pediatric Oncohematology, Hospital Universitario Infantil Niño Jesús, Instituto de Investigación Sanitaria Princesa (IIS-IP), Av. de Menéndez Pelayo, 65, Madrid 28009, Spain.
15
Pediatric Oncohematology, Hospital Vall d'Hebron, Passeig de la Vall d'Hebron, 119-129, Barcelona 0803, Spain.
16
Molecular Biology Lab, Clinical Analysis Service, Hospital Universitario y Politécnico de La Fe, Avinguda de Fernando Abril Martorell, 106, Valencia 46026, Spain.
17
Department of Hematology, Hospital Universitario de Salamanca, Paseo de San Vicente, 88-182, Salamanca 37007, Spain.

Abstract

BACKGROUND:

In B-cell precursor acute lymphoblastic leukaemia (B-ALL), the identification of additional genetic alterations associated with poor prognosis is still of importance. We determined the frequency and prognostic impact of somatic mutations in children and adult cases with B-ALL treated with Spanish PETHEMA and SEHOP protocols.

METHODS:

Mutational status of hotspot regions of TP53, JAK2, PAX5, LEF1, CRLF2 and IL7R genes was determined by next-generation deep sequencing in 340 B-ALL patients (211 children and 129 adults). The associations between mutation status and clinicopathological features at the time of diagnosis, treatment outcome and survival were assessed. Univariate and multivariate survival analyses were performed to identify independent prognostic factors associated with overall survival (OS), event-free survival (EFS) and relapse rate (RR).

RESULTS:

A mutation rate of 12.4% was identified. The frequency of adult mutations was higher (20.2% vs 7.6%, P=0.001). TP53 was the most frequently mutated gene (4.1%), followed by JAK2 (3.8%), CRLF2 (2.9%), PAX5 (2.4%), LEF1 (0.6%) and IL7R (0.3%). All mutations were observed in B-ALL without ETV6-RUNX1 (P=0.047) or BCR-ABL1 fusions (P<0.0001). In children, TP53mut was associated with lower OS (5-year OS: 50% vs 86%, P=0.002) and EFS rates (5-year EFS: 50% vs 78.3%, P=0.009) and higher RR (5-year RR: 33.3% vs 18.6% P=0.037), and was independently associated with higher RR (hazard ratio (HR)=4.5; P=0.04). In adults, TP53mut was associated with a lower OS (5-year OS: 0% vs 43.3%, P=0.019) and a higher RR (5-year RR: 100% vs 61.4%, P=0.029), whereas JAK2mut was associated with a lower EFS (5-year EFS: 0% vs 30.6%, P=0.035) and a higher RR (5-year RR: 100% vs 60.4%, P=0.002). TP53mut was an independent risk factor for shorter OS (HR=2.3; P=0.035) and, together with JAK2mut, also were independent markers of poor prognosis for RR (TP53mut: HR=5.9; P=0.027 and JAK2mut: HR=5.6; P=0.036).

CONCLUSIONS:

TP53mut and JAK2mut are potential biomarkers associated with poor prognosis in B-ALL patients.

PMID:
28557976
PMCID:
PMC5520505
DOI:
10.1038/bjc.2017.152
[Indexed for MEDLINE]
Free PMC Article

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