20 research outputs found
Frequency and clinical impact of CDKN2A/ARF/CDKN2B gene deletions as assessed by in-depth genetic analyses in adult T cell acute lymphoblastic leukemia
© The Author(s).Recurrent deletions of the CDKN2A/ARF/CDKN2B genes encoded at chromosome 9p21 have been described in both pediatric and adult acute lymphoblastic leukemia (ALL), but their prognostic value remains controversial, with limited data on adult T-ALL. Here, we investigated the presence of homozygous and heterozygous deletions of the CDKN2A/ARF and CDKN2B genes in 64 adult T-ALL patients enrolled in two consecutive trials from the Spanish PETHEMA group. Alterations in CDKN2A/ARF/CDKN2B were detected in 35/64 patients (55%). Most of them consisted of 9p21 losses involving homozygous deletions of the CDKNA/ARF gene (26/64), as confirmed by single nucleotide polymorphism (SNP) arrays and interphase fluorescence in situ hybridization (iFISH). Deletions involving the CDKN2A/ARF/CDKN2B locus correlated with a higher frequency of cortical T cell phenotype and a better clearance of minimal residual disease (MRD) after induction therapy. Moreover, the combination of an altered copy-number-value (CNV) involving the CDKN2A/ARF/CDKN2B gene locus and undetectable MRD (â€â0.01%) values allowed the identification of a subset of T-ALL with better overall survival in the absence of hematopoietic stem cell transplantation.This project was supported by the AsociaciĂłn Española Contra el CĂĄncer, AECC (project ref.: GC16173697BIGA), by CERCA Program/Generalitat de Catalunya, the Catalan Government: 2014-SGR225 (GRE), Obra Social âLa Caixaâ and by Celgene Spain. E. GenescĂ is the recipient of agrant from the Spanish Health Ministry (ISCIII, CA12/00468) and an unrestricted grant from Gilead.A. Gonzalez-Perez is supported by a Ramon y Cajal fellowship (RYC-2013-14554) of the Educational Ministry (Madrid, Spain). This work was also partially supported by FEDER funds from the ISCIII (PT13/0010/0026, CIBERONC (CB16/12/00284 and CB16/12/00400), Madrid, Spain)
Use of 1H and 31P HRMAS to evaluate the relationship between quantitative alterations in metabolite concentrations and tissue features in human brain tumour biopsies
[EN] Quantitative multinuclear high-resolution magic angle
spinning (HRMAS) was performed in order to determine
the tissue pH values of and the absolute metabolite concentrations
in 33 samples of human brain tumour tissue. Metabolite
concentrations were quantified by 1D 1
H and 31P HRMAS
using the electronic reference to in vivo concentrations
(ERETIC) synthetic signal. 1
Hâ1
H homonuclear and 1
Hâ31P
heteronuclear correlation experiments enabled the direct assessment
of the 1
Hâ31P spin systems for signals that suffered from
overlapping in the 1D 1
H spectra, and linked the information
present in the 1D 1
H and 31P spectra. Afterwards, the main
histological features were determined, and high heterogeneity
in the tumour content, necrotic content and nonaffected tissue
content was observed. The metabolite profiles obtained by
HRMAS showed characteristics typical of tumour tissues: rather
low levels of energetic molecules and increased concentrations
of protective metabolites. Nevertheless, these
characteristics were more strongly correlated with the total
amount of living tissue than with the tumour cell contents of
the samples alone, which could indicate that the sampling
conditions make a significant contribution aside from the effect
of tumour development in vivo. The use of methylene diphosphonic
acid as a chemical shift and concentration reference for
the 31P HRMAS spectra of tissues presented important drawbacks
due to its interaction with the tissue. Moreover, the pH
data obtained from 31P HRMAS enabled us to establish a
correlation between the pH and the distance between the
N(CH3)3 signals of phosphocholine and choline in 1
H spectra
of the tissue in these tumour samples.The authors acknowledge the SCSIE-University of Valencia Microscopy Service for the histological preparations. They also acknowledge Martial Piotto (Bruker BioSpin, France) for providing the ERETIC synthetic signal. Furthermore, they acknowledge financial support from the Spanish Government project SAF2007-6547, the Generalitat Valenciana project GVACOMP2009-303, and the E.U.'s VI Framework Programme via the project "Web accessible MR decision support system for brain tumor diagnosis and prognosis, incorporating in vivo and ex vivo genomic and metabolomic data" (FP6-2002-LSH 503094). CIBER-BBN is an initiative funded by the VI National R&D&D&i Plan 2008-2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions, and financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund.Esteve Moya, V.; Celda, B.; MartĂnez Bisbal, MC. (2012). Use of 1H and 31P HRMAS to evaluate the relationship between quantitative alterations in metabolite concentrations and tissue features in human brain tumour biopsies. 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Frequency and clinical impact of CDKN2A/ARF/CDKN2B gene deletions as assessed by in-depth genetic analyses in adult T cell acute lymphoblastic leukemia
Altres ajuts: This project was supported by the Asociación Española Contra el Cåncer, AECC (project ref.: GC16173697BIGA), Obra Social "La Caixa" and by Celgene Spain. A. Gonzalez-Perez is supported by a Ramon y Cajal fellowship (RYC-2013-14554) of the Educational Ministry (Madrid, Spain). This work was also partially supported by FEDER funds from CIBERONC (CB16/12/00284 and CB16/12/00400), Madrid, Spain).Recurrent deletions of the CDKN2A/ARF/CDKN2B genes encoded at chromosome 9p21 have been described in both pediatric and adult acute lymphoblastic leukemia (ALL), but their prognostic value remains controversial, with limited data on adult T-ALL. Here, we investigated the presence of homozygous and heterozygous deletions of the CDKN2A/ARF and CDKN2B genes in 64 adult T-ALL patients enrolled in two consecutive trials from the Spanish PETHEMA group. Alterations in CDKN2A/ARF/CDKN2B were detected in 35/64 patients (55%). Most of them consisted of 9p21 losses involving homozygous deletions of the CDKNA/ARF gene (26/64), as confirmed by single nucleotide polymorphism (SNP) arrays and interphase fluorescence in situ hybridization (iFISH). Deletions involving the CDKN2A/ARF/CDKN2B locus correlated with a higher frequency of cortical T cell phenotype and a better clearance of minimal residual disease (MRD) after induction therapy. Moreover, the combination of an altered copy-number-value (CNV) involving the CDKN2A/ARF/CDKN2B gene locus and undetectable MRD (†0.01%) values allowed the identification of a subset of T-ALL with better overall survival in the absence of hematopoietic stem cell transplantation
Molecular profiling refines minimal residual disease-based prognostic assessment in adults with Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia
Minimal residual disease (MRD) assessment is an essential tool in contemporary acute lymphoblastic leukemia (ALL) protocols, being used for therapeutic decisions such as hematopoietic stem cell transplantation in highârisk patients. However, a significant proportion of adult ALL patients with negative MRD still relapse suggesting that other factors (ie, molecular alterations) must be considered in order to identify those patients with high risk of disease progression. We have identified partial IKZF1 gene deletions and CDKN2A/B deletions as markers of disease recurrence and poor survival in a series of uniformly treated adolescent and adult Philadelphia chromosomeânegative Bâcell progenitor ALL patients treated according to the Programa Español de Tratamientos en HematologĂa protocols. Importantly, CDKN2A/B deletions showed independent significance of MRD at the end of induction, which points out the need for treatment intensification in these patients despite being MRDânegative after induction therapy.FundaciĂł Internacional Josep Carreras; Generalitat de Catalunya, Grant/Award Number: 2017 SGR 288 GRC; Instituto de Salud Carlos III; Ministerio de Salud Carlos III RTICCâFEDER, Grant/Award Numbers: RD12/0036/0029, RD/0036/044; Obra Social âLa Caixaâ; Sociedad Española de HematologĂa y Hemoterapia; Fondo de Investigaciones Sanitarias, Grant/Award Numbers: PI14/01971, PI10/0141
P1702: IMPACT OF CENTER CHARACTERISTICS AND MACROECONOMIC FACTORS ON THE OUTCOME OF ADULT PATIENTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA TREATED WITH PEDIATRIC-INSPIRED PROTOCOLS
The poor prognosis of low hypodiploidy in adults with B-cell precursor acute lymphoblastic leukaemia is restricted to older adults and elderly patients
The prognostic significance of lowâhypodiploidy has not been extensively evaluated in minimal residual disease (MRD)âoriented protocols for adult acute lymphoblastic leukaemia (ALL). We analysed the outcome of hypodiploid adult ALL patients treated within Programa Español de Tratamientos en HematologĂa (PETHEMA) protocols. The 5âyear cumulative incidence of relapse (CIR) of lowâhypodiploid Bâcell precursor (BCP)âALL was significantly higher than that of highâhypodiploids (52% vs. 12%, P = 0.013). Lowâhypodiploid BCPâALL patients aged â€35 years showed superior survival (71% vs. 21%, P = 0.026) and lower 5âyear CIR (17% vs. 66%, P = 0.090) than lowâhypodiploids aged >35 years. Older adults and elderly lowâhypodiploid BCPâALL patients show dismal prognosis although achieving an endâinduction good MRD response.This work was supported in part by grants from AsociaciĂłn Española Contra el CĂĄncer, AECC (GC16173697BIGA), Instituto de Salud Carlos III (PI14/01971 FI), 2017âSGR288 (GRC), CERCA Program from Generalitat de Catalunya and âLa Caixaâ Foundation
Frequency and clinical impact of CDKN2A/ARF/CDKN2B gene deletions as assessed by in-depth genetic analyses in adult T cell acute lymphoblastic leukemia
Abstract Recurrent deletions of the CDKN2A/ARF/CDKN2B genes encoded at chromosome 9p21 have been described in both pediatric and adult acute lymphoblastic leukemia (ALL), but their prognostic value remains controversial, with limited data on adult T-ALL. Here, we investigated the presence of homozygous and heterozygous deletions of the CDKN2A/ARF and CDKN2B genes in 64 adult T-ALL patients enrolled in two consecutive trials from the Spanish PETHEMA group. Alterations in CDKN2A/ARF/CDKN2B were detected in 35/64 patients (55%). Most of them consisted of 9p21 losses involving homozygous deletions of the CDKNA/ARF gene (26/64), as confirmed by single nucleotide polymorphism (SNP) arrays and interphase fluorescence in situ hybridization (iFISH). Deletions involving the CDKN2A/ARF/CDKN2B locus correlated with a higher frequency of cortical T cell phenotype and a better clearance of minimal residual disease (MRD) after induction therapy. Moreover, the combination of an altered copy-number-value (CNV) involving the CDKN2A/ARF/CDKN2B gene locus and undetectable MRD (â€â0.01%) values allowed the identification of a subset of T-ALL with better overall survival in the absence of hematopoietic stem cell transplantation