CDKN2A deletions in acute lymphoblastic leukemia of adolescents and young adults—An array CGH study

Usvasalo, Anu; Savola, Suvi; Räty, Riikka; Vettenranta, Kim; Harila‐Saari, Arja; Koistinen, Pirjo; Savolainen, Eeva‐Riitta; Elonen, Erkki; Saarinen‐Pihkala, Ulla M.; Knuutila, Sakari

doi:10.1016/j.leukres.2008.01.014

Cited by 61 publications

(56 citation statements)

References 29 publications

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“…Among them, deletions of various sizes involving chromosome 9p were detected in 46% of patients with the CDR involving the CDKN2A gene. 69 Similar deletions of 9p21 were observed in another study using high-resolution BAC CGH-A that also allowed for detection of gains in 1q23-qter in low-risk and 2p11.2 in high-risk disease. 70 In 2 other studies, intrachromosomal 21q amplifications involving RUNX1 were found.…”

Section: Implications Of Array-based Karyotyping In Hematologic Diseasessupporting

confidence: 55%

Whole genome scanning as a cytogenetic tool in hematologic malignancies

Maciejewski

Mufti

2008

Blood

125

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Over the years, methods of cytogenetic analysis evolved and became part of routine laboratory testing, providing valuable diagnostic and prognostic information in hematologic disorders. Karyotypic aberrations contribute to the understanding of the molecular pathogenesis of disease and thereby to rational application of therapeutic modalities. Most of the progress in this field stems from the application of metaphase cytogenetics (MC), but recently, novel molecular technologies have been introduced that complement MC and overcome many of the limitations of traditional cytogenetics, including a need for cell culture. Whole genome scanning using comparative genomic hybridization and single nucleotide polymorphism arrays (CGH-A; SNP-A) can be used for analysis of somatic or clonal unbalanced chromosomal defects. In SNP-A, the combination of copy number detection and genotyping enables diagnosis of copy-neutral loss of heterozygosity, a lesion that cannot be detected using MC but may have important pathogenetic implications. Overall, whole genome scanning arrays, despite the drawback of an inability to detect balanced translocations, allow for discovery of chromosomal defects in a higher proportion of patients with hematologic malignancies. Newly detected chromosomal aberrations, including somatic uniparental disomy, may lead to more precise prognostic schemes in many diseases. Routine cytogenetics diagnostics and its limitationsCytogenetic analysis has provided fundamental insights into the molecular pathogenesis of a variety of hematologic disorders. The discovery of the Philadelphia chromosome and other chromosomal aberrations paved the way for the characterization of molecular lesions that lead to phenotypic characteristics of a number of hematologic malignancies. Metaphase cytogenetics (MC) has proven an extremely valuable diagnostic tool, providing definite diagnoses, for example, in the case of balanced pathognomonic translocations in chronic myeloid leukemia (CML), acute promyelocytic leukemia (APL), or core binding factor acute myelogenous leukemias (AMLs). 1,2 Chromosomal aberrations support the cytomorphologic diagnosis and provide prognostic information, for example, in myelodysplastic syndromes (MDSs), [3][4][5] AML with unbalanced translocations, 6-10 multiple myeloma (MM), 11,12 and chronic lymphocytic leukemia (CLL). 13,14 Irrespective of their location, size, and corresponding phenotype, chromosomal defects also represent suitable markers of clonality suggestive of clonal dominance by the malignant clone or, in rare circumstances, of oligoclonality due to a profound depletion of stem cell reserves 15 (Figure 1). Such a scenario explains the occasional occurrence of chromosomal abnormalities in otherwise typical aplastic anemia (AA; M. Wlodarski, L. Gondek, C. L. O'Keefe, R. Tiu, A. Haddad, A. Risitano, J.P.M., manuscript submitted May 2008). Technical advantages and limitations of MCRoutine MC allows for detection of large clonal populations (Ͼ 10% of dividing cells), indicating the presence of sign...

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Section: Implications Of Array-based Karyotyping In Hematologic Diseasessupporting

confidence: 55%

Whole genome scanning as a cytogenetic tool in hematologic malignancies

Maciejewski

Mufti

2008

Blood

125

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“…The frequency of losses seen here was higher than that reported in some previous studies [40,41], although our findings agreed with others [17,42]. Six of the CDKN2A deletions appeared homozygous by array, while the remaining cases may reflect either heterozygosity or homozygosity in a subclone of cells, given the inherent non-cellular limitations of array technology.…”

Section: Discussionsupporting

confidence: 86%

CGH-based microarray detection of cryptic and novel copy number alterations and balanced translocations in cytogenetically abnormal cases of b-cell all

Schultz¹,

Tsuchiya²,

Furrow³

et al. 2013

Health

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Acute lymphoblastic leukemia (ALL) is the most common malignancy in children, with the majority of cases being of precursor B-cell phenoltype. Conventional cytogenetic analysis plays an important role in the diagnosis of B-cell ALL, identifying characteristic chromosomal abnormalities associated with a given prognosis therein facilitating optimized treatment. The more recent introduction of microarray technology to the analysis of B-cell ALL has afforded both higher resolution for the detection of known abnormalities and an ability to identify novel copy number abnormalities (CNAs) with potential clinical relevance. In the current study, microarray analysis was performed on 20 cytogenetically abnormal B-cell ALL cases (10 pediatric and 10 adult), while a novel microarray-based balancedtranslocation detection methodology (translocation CGH or tCGH) was applied to that subset of cases with a known or suspected recurrent balanced translocation. Standard microarray analysis identified that CNAs was not detected by previous conventional cytogenetics in 75% (15/20) cases. tCGH identified 9/9 (100%) balanced translocations defining BCR/ABL1 (x4), ETV6/RUNX1 (x3), and MLL/AFF1 (x2) breakpoints with high resolution. The results illustrate the improved molecular detail afforded by these technologies and a comparison of translocation breakpoints, CNAs and patient age offers new insights into tumor biology with potential prognostic significance.

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“…Iacobucci et al 13 reported that CDKN2A/B deletions had independent significance for lower disease-free survival in a series of 112 adult Ph-positive patients, but other authors did not show any prognostic impact. 27 No differences in outcomes were observed from a comparison of heterozygous and homozygous CDKN2A/B deletions, 12 and this suggests an important haplo-insufficiency effect 28 or concomitant inactivation of the remaining allele by epigenetic events. 29,30 Although our patients were treated within protocols, some limitations should be pointed out.…”

Section: Discussionmentioning

confidence: 96%

Prognostic significance of copy number alterations in adolescent and adult patients with precursor B acute lymphoblastic leukemia enrolled in PETHEMA protocols

Ribera

Morgades

Zamora

et al. 2015

Cancer

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; for the Spanish PETHEMA Group and the Spanish Society of Hematology BACKGROUND: Some copy number alterations (CNAs) have independent prognostic significance for adults with acute lymphoblastic leukemia (ALL). METHODS: This study analyzed via multiplex ligation-dependent probe amplification the frequency and prognostic impact of CNAs of 12 genetic regions in 142 adolescents and adults with de novo precursor B-cell ALL. RESULTS: The cyclindependent kinase inhibitor 2A/B (CDKN2A/B) deletion (59 of 142 or 42%) was the most frequent CNA, and it was followed by Ikaros family zinc finger 1 (IKZF1) losses (49 of 142 or 35%). IKZF1 deletions were more prevalent in Philadelphia chromosome (Ph)-positive ALL and were associated with advanced age and high white blood cell (WBC) counts. The multivariate analysis showed that advanced age and early B-cell factor 1 (EBF1) deletions were associated with chemotherapy resistance in both the whole series (hazard ratios, 0.949 and 0.135, respectively) and the Ph-negative subgroup (hazard ratios, 0.946 and 0.118, respectively). High WBC counts and focal IKZF1 deletions correlated with disease recurrence (hazard ratios, 1.005 and 1.869, respectively), whereas advanced age and CDKN2A/B losses influenced overall survival in both the whole series (hazard ratios, 1.038 and 2.545, respectively) and the Ph-negative subgroup (hazard ratios, 1.044 and 2.105, respectively). CONCLUSIONS: Deletions of EBF1, IKZF1, and CDKN2A/B have an independent adverse prognosis for adolescents and adults with B-precursor ALL, and this suggests that these CNAs should be included in the initial risk assessment of ALL. Cancer 2015;121:3809-17.

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CDKN2A deletions in acute lymphoblastic leukemia of adolescents and young adults—An array CGH study

Cited by 61 publications

References 29 publications

Whole genome scanning as a cytogenetic tool in hematologic malignancies

Whole genome scanning as a cytogenetic tool in hematologic malignancies

CGH-based microarray detection of cryptic and novel copy number alterations and balanced translocations in cytogenetically abnormal cases of b-cell all

Prognostic significance of copy number alterations in adolescent and adult patients with precursor B acute lymphoblastic leukemia enrolled in PETHEMA protocols

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