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. 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

Maribel Forero-Castro  1   2 , Cristina Robledo  1 , Rocío Benito  1 , Irene Bodega-Mayor  3 , Inmaculada Rapado  4 , María Hernández-Sánchez  1 , María Abáigar  1 , Jesús Maria Hernández-Sánchez  1 , Miguel Quijada-Álamo  1 , José María Sánchez-Pina  4 , Mónica Sala-Valdés  3 , Fernanda Araujo-Silva  3 , Alexander Kohlmann  5 , José Luis Fuster  6 , Maryam Arefi  7 , Natalia de Las Heras  8 , Susana Riesco  9 , Juan N Rodríguez  10 , Lourdes Hermosín  11 , Jordi Ribera  12 , Mireia Camos Guijosa  13 , Manuel Ramírez  14 , Cristina Díaz de Heredia Rubio  15 , Eva Barragán  16 , Joaquín Martínez  4 , José M Ribera  12 , Elena Fernández-Ruiz  3 , Jesús-María Hernández-Rivas  1   17
Affiliations

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

Maribel Forero-Castro et al. Br J Cancer. .

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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Kaplan–Meier curves for OS, EFS and RR of the whole cohort of children with B-ALL. (A–C) OS, EFS and RR in patients bearing TP53mut.
Figure 2
Figure 2
Kaplan–Meier curves for OS, EFS and RR of the whole cohort of adults with B-ALL. (A and B) OS and RR in patients bearing TP53mut. (C and D) EFS and RR in patients with JAK2mut.
See this image and copyright information in PMC

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