Mutations in TP53 and JAK2 are independent prognostic biomarkers in B-cell precursor acute lymphoblastic leukaemia
Por:
Forero-Castro, M, Robledo, C, Benito, R, Bodega-Mayor, I, Rapado, I, Hernandez-Sanchez, M, Abaigar, M, Hernandez-Sanchez, JM, Quijada-Alamo, M, Sanchez-Pina, JM, Sala-Valdes, M, Araujo-Silva, F, Kohlmann, A, Fuster, JL, Arefi, M, de las Heras, N, Riesco, S, Rodriguez, JN, Hermosin, L, Ribera, J, Guijosa, MC, Ramirez, M, Rubio, CDD, Barragan, E, Martinez, J, Ribera, JM, Fernandez-Ruiz, E and Hernandez-Rivas, JM
Publicada:
11 jul 2017
Resumen:
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 nextgeneration 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.
Filiaciones:
Forero-Castro, M:
Univ Salamanca, CSIC, Canc Res Ctr, IBSAL,IBMCC, Campus Miguel de Unamuno, Salamanca 37007, Spain
UPTC, GICBUPTC Res Grp, Sch Biol Sci, Ave Cent Norte 39-115, Tunja 150003, Colombia
Robledo, C:
Univ Salamanca, CSIC, Canc Res Ctr, IBSAL,IBMCC, Campus Miguel de Unamuno, Salamanca 37007, Spain
Benito, R:
Univ Salamanca, CSIC, Canc Res Ctr, IBSAL,IBMCC, Campus Miguel de Unamuno, Salamanca 37007, Spain
Bodega-Mayor, I:
Hosp Univ La Princesa, Mol Biol Unit, Inst Invest Sanitaria Princesa IIS IP, Calle Diego de Leon 62, Madrid 28006, Spain
Rapado, I:
Hosp 12 Octubre, Dept Hematol, Ave Cordoba S-N, E-28041 Madrid, Spain
Hernandez-Sanchez, M:
Univ Salamanca, CSIC, Canc Res Ctr, IBSAL,IBMCC, Campus Miguel de Unamuno, Salamanca 37007, Spain
Abaigar, M:
Univ Salamanca, CSIC, Canc Res Ctr, IBSAL,IBMCC, Campus Miguel de Unamuno, Salamanca 37007, Spain
Hernandez-Sanchez, JM:
Univ Salamanca, CSIC, Canc Res Ctr, IBSAL,IBMCC, Campus Miguel de Unamuno, Salamanca 37007, Spain
Quijada-Alamo, M:
Univ Salamanca, CSIC, Canc Res Ctr, IBSAL,IBMCC, Campus Miguel de Unamuno, Salamanca 37007, Spain
Sanchez-Pina, JM:
Hosp 12 Octubre, Dept Hematol, Ave Cordoba S-N, E-28041 Madrid, Spain
Sala-Valdes, M:
Hosp Univ La Princesa, Mol Biol Unit, Inst Invest Sanitaria Princesa IIS IP, Calle Diego de Leon 62, Madrid 28006, Spain
Araujo-Silva, F:
Hosp Univ La Princesa, Mol Biol Unit, Inst Invest Sanitaria Princesa IIS IP, Calle Diego de Leon 62, Madrid 28006, Spain
Kohlmann, A:
AstraZeneca, Innovat Med & Early Dev Biotech Unit, Personalised Healthcare & Biomarkers, Darwin Bldg,310 Cambridge Sci Pk,Milton Rd, Cambridge CB4 0WG, England
Fuster, JL:
Hosp Univ Virgen de la Arrixaca, Dept Pediat Oncohematol, Ctra Madrid Cartagena S-N, Murcia 30120, Spain
Arefi, M:
Hosp Rio Carrion, Dept Hematol, Av Donantes Sangre S-N, Palencia 34005, Spain
de las Heras, N:
Hosp Virgen Blanca, Dept Hematol, Altos De Nava S-N, Leon 24071, Spain
Riesco, S:
Hosp Univ Salamanca, Dept Pediat, Paseo San Vicente 88-182, Salamanca 37007, Spain
Rodriguez, JN:
Hosp Juan Ramon Jimenez, Dept Hematol, Ronda Exterior Norte S-N, Huelva 21005, Spain
Hermosin, L:
Hosp Jerez, Dept Hematol, Carr Madrid Cadiz, Cadiz 11407, Spain
:
ICO Hosp Germans Trias & Pujol, Inst Invest Josep Carreras, Dept Hematol, Carretera Canyet S-N, Barcelona 08916, Spain
Guijosa, MC:
Hosp St Joan de Deu Barcelona, Hematol Lab, Inst Recerca Pediat, Passeig St Joan de Deu 2, Barcelona 08950, Spain
Ramirez, M:
Hosp Univ Infantil Nino Jesus, Pediat Oncohematol, Inst Invest Sanitaria Princesa IIS IP, Av Menendez Pelayo 65, Madrid 28009, Spain
Rubio, CDD:
Hosp Valle De Hebron, Pediat Oncohematol, Passeig Vall dHebron 119-129, Barcelona 0803, Spain
Barragan, E:
Hosp Univ & Politecn La Fe, Mol Biol Lab, Clin Anal Serv, Avinguda Fernando Abril Martorell 106, Valencia 46026, Spain
Martinez, J:
Hosp 12 Octubre, Dept Hematol, Ave Cordoba S-N, E-28041 Madrid, Spain
:
ICO Hosp Germans Trias & Pujol, Inst Invest Josep Carreras, Dept Hematol, Carretera Canyet S-N, Barcelona 08916, Spain
Fernandez-Ruiz, E:
Hosp Univ La Princesa, Mol Biol Unit, Inst Invest Sanitaria Princesa IIS IP, Calle Diego de Leon 62, Madrid 28006, Spain
Hernandez-Rivas, JM:
Univ Salamanca, CSIC, Canc Res Ctr, IBSAL,IBMCC, Campus Miguel de Unamuno, Salamanca 37007, Spain
Hosp Univ Salamanca, Dept Hematol, Paseo San Vicente 88-182, Salamanca 37007, Spain
Green Published, hybrid
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