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2.
Genes Chromosomes Cancer ; 55(5): 480-91, 2016 May.
Article in English | MEDLINE | ID: mdl-26774012

ABSTRACT

Genetic profiling is important for disease evaluation and prediction of prognosis or responsiveness to therapy in neoplasia. Microarray technologies, including array comparative genomic hybridization and single-nucleotide polymorphism-detecting arrays, have in recent years been introduced into the diagnostic setting for specific types of haematological malignancies and solid tumours. It can be used as a complementary test or depending on the neoplasia investigated, also as a standalone test. However, comprehensive and readable presentation of frequently identified complex genomic profiles remains challenging. To assist diagnostic laboratories, standardization and minimum criteria for clinical interpretation and reporting of acquired genomic abnormalities detected through arrays in neoplastic disorders are presented.


Subject(s)
Hematologic Neoplasms/genetics , DNA Copy Number Variations , Guidelines as Topic , Humans , Oligonucleotide Array Sequence Analysis
3.
Leukemia ; 27(12): 2280-8, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23531517

ABSTRACT

Cytogenetic abnormalities and early response to treatment are the main prognostic factors in acute myeloid leukemia (AML). Recently, NUP98/NSD1 (t(5; 11)(q35; p15)), a cytogenetically cryptic fusion, was described as recurrent event in AML, characterized by dismal prognosis and HOXA/B gene overexpression. Using split-signal fluorescence in situ hybridization, other NUP98-rearranged pediatric AML cases were identified, including several acute megakaryoblastic leukemia (AMKL) cases with a cytogenetically cryptic fusion of NUP98 to JARID1A (t(11;15)(p15;q35)). In this study we screened 105 pediatric AMKL cases to analyze the frequency of NUP98/JARID1A and other recurrent genetic abnormalities. NUP98/JARID1A was identified in 11/105 patients (10.5%). Other abnormalities consisted of RBM15/MKL1 (n=16), CBFA2T3/GLIS2 (n=13) and MLL-rearrangements (n=13). Comparing NUP98/JARID1A-positive patients with other pediatric AMKL patients, no significant differences in sex, age and white blood cell count were found. NUP98/JARID1A was not an independent prognostic factor for 5-year overall (probability of overall survival (pOS)) or event-free survival (probability of event-free survival (pEFS)), although the 5-year pOS for the entire AMKL cohort was poor (42 ± 6%). Cases with RBM15/MLK1 fared significantly better in terms of pOS and pEFS, although this was not independent from other risk factors in multivariate analysis. NUP98/JARID1A cases were characterized by HOXA/B gene overexpression, which is a potential druggable pathway. In conclusion, NUP98/JARID1A is a novel recurrent genetic abnormality in pediatric AMKL.


Subject(s)
Gene Expression Profiling , Genes, Homeobox , Leukemia, Megakaryoblastic, Acute/genetics , Nuclear Pore Complex Proteins/genetics , Retinoblastoma-Binding Protein 2/genetics , Adolescent , Base Sequence , Child , Child, Preschool , Chromosomes, Human, Pair 11 , Chromosomes, Human, Pair 5 , Female , Humans , Infant , Infant, Newborn , Male , Molecular Sequence Data , Translocation, Genetic
4.
Br J Haematol ; 136(1): 96-105, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17129222

ABSTRACT

Diagnostic cytogenetic abnormalities are considered important prognostic factors in patients with acute myeloid leukaemia (AML). However, the prognostic assessments have mainly been derived from patients with AML aged <60 years. Two recent studies of AML patients of 60 years and older proposed prognostic classifications with distinct discrepancies. To further study the prognostic value of cytogenetic abnormalities in this patient population, we have evaluated cytogenetic abnormalities in a series of 293 untreated patients with AML aged 60 years and older, included in a randomised phase 3 trial, also in relation to patient characteristics and clinical outcome. The most frequently observed cytogenetic abnormality was trisomy 8 (+8), in 31 (11%) patients. Abnormalities, such as -5, 5q-, abn(17p) and abn(17q), were almost exclusively present in complex karyotypes. A relatively favourable outcome was only observed in five patients with core-binding factor abnormalities t(8;21) and inv(16)/del(16)/t(16;16). However, most of the other evaluated cytogenetic abnormalities, such as 5q-, -7, +8, abn(17p), abn(17q), and complex aberrations expressed a more adverse prognosis when compared with patients with AML aged 60 years and older with a normal karyotype. Large studies to confirm the prognosis of individual cytogenetic aberrations are warranted.


Subject(s)
Chromosome Aberrations , Genes, MDR , Leukemia, Myeloid/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 1 , Acute Disease , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cyclosporins/therapeutic use , Disease-Free Survival , Female , Humans , Immunosuppressive Agents/therapeutic use , In Situ Hybridization, Fluorescence , Leukemia, Myeloid/immunology , Leukemia, Myeloid/mortality , Leukocyte Count , Male , Middle Aged , Prognosis , Prospective Studies , Survival Analysis , Treatment Outcome
5.
Hematol J ; 4(1): 31-40, 2003.
Article in English | MEDLINE | ID: mdl-12692518

ABSTRACT

The CCAAT/enhancer binding protein alpha is an essential transcription factor for granulocytic differentiation. Recent studies reported N- and C-terminal CEBPA mutations in approximately 7% of acute myeloid leukaemia (AML) patients. C-terminal mutations are usually in-frame and occur in the basic-leucine zipper (bZIP) domain, resulting in deficient DNA binding. Using a rapid PCR approach, we screened for bZIP mutations and determined the prognostic value of these mutations in a cohort of 277 de novo AMLs. In addition, we set out to quantify CEBPA mRNA levels by 'real-time' PCR using TaqMan technology. In-frame insertions were observed in 12 (4.3%) cases. All cases with mutations carried an intermediate-risk karyotype and all but one belonged to M1 or M2 FAB class. Further sequence analysis revealed that CEBPA C-terminal mutations are associated with frameshift mutations in the N-terminus of CEBPA. These two mutations were always found in different alleles. Event-free survival (EFS) and overall survival (OS) of patients with CEBPA mutations were significantly increased (P=0.02 and 0.03, respectively) in comparison to the patients lacking these mutations. Mutations were associated with a significantly reduced hazard ratio for death (OS: HR=0.35, P=0.04) and failure (EFS: no CR, death in CR or relapse, HR=0.37, P=0.03). This favourable hazard ratio was maintained after adjustment for cytogenetic risk, FLT3-ITD and CEBPA expression levels in multivariable analysis. In contrast, low CEBPA expression in AML with intermediate-risk karyotype (n=6) seemed to be associated with poor prognosis (not significant). By including this newly developed PCR assay, we define a subgroup of good-risk patients within the heterogeneous intermediate-risk group of AML.


Subject(s)
CCAAT-Enhancer-Binding Protein-alpha/genetics , Gene Expression Regulation, Leukemic , Leukemia, Myeloid/genetics , Neoplasm Proteins/genetics , Acute Disease , Adolescent , Adult , Alleles , Amino Acid Sequence , Binding Sites , CCAAT-Enhancer-Binding Protein-alpha/biosynthesis , CCAAT-Enhancer-Binding Protein-alpha/deficiency , DNA Mutational Analysis , DNA, Complementary/genetics , DNA, Neoplasm/genetics , Disease-Free Survival , Female , Frameshift Mutation , Humans , Karyotyping , Leucine Zippers/genetics , Leukemia, Myeloid/metabolism , Leukemia, Myeloid/mortality , Life Tables , Male , Middle Aged , Molecular Sequence Data , Mutagenesis, Insertional , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/deficiency , Neoplastic Stem Cells/metabolism , Prognosis , Protein Structure, Tertiary , RNA, Messenger/biosynthesis , RNA, Neoplasm/biosynthesis , Remission Induction , Risk , Risk Factors , Sequence Alignment , Sequence Homology, Amino Acid , Survival Analysis
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