Prognostic information from cytogenetic analysis in chronic B- lymphocytic leukemia and leukemic immunocytoma

Fifty-five patients with a clonal expansion of B lymphocytes in the peripheral blood were studied. According to the Kiel classification, 22 patients had chronic lymphocytic leukemia (CLL), 29 had immunocytoma (IC), two had prolymphocytic leukemia, and one had centrocytic lymphoma; one was not subclassified. Cytogenetic studies after B cell mitogen stimulation showed that six patients had an extra chromosome 12 as the sole abnormality. Another ten patients had an extra chromosome 12 together with other abnormalities. One patient had dup(12). Fifteen patients showed clonal aberrations without +12. Eleven patients showed only normal metaphases, and 12 patients were not evaluated cytogenetically. The cytogenetic subgroup pattern did not distinguish between CLL and IC patients. There was no significant difference between the CLL and IC groups as regards clinical findings and prognosis. However, the cytogenetic typing proved to be of prognostic significance. Increasing numbers of chromosomal aberrations within the cell clone were significantly associated with a poorer prognosis, ie, with impairment of survival (P = .04) and therapy-free survival (P less than 10(-4]. Patients with complex karyotypes (at least clonal aberrations) showed the poorest survival (P = .007). Patients with +12 required treatment earlier than patients with a normal karyotype (P = .01) and patients with karyotypic changes other than +12 (P = .006). These latter differences were even more pronounced when only IC patients were considered (P = .005 and P = .002, respectively). A multivariate analysis revealed that +12 was as strong an indicator of poor survival as advanced Rai or Binet stages and a stronger predictor of therapy-demanding disease.

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Prognostic information from cytogenetic analysis in chronic B- lymphocytic leukemia and leukemic immunocytoma

Blood ◽

10.1182/blood.v65.1.134.134 ◽

1985 ◽

Vol 65 (1) ◽

pp. 134-141 ◽

Cited By ~ 92

Author(s):

G Juliusson ◽

KH Robert ◽

A Ost ◽

K Friberg ◽

P Biberfeld ◽

...

Keyword(s):

Cell Clone ◽

Extra Chromosome ◽

Prognostic Significance ◽

Normal Karyotype ◽

Clinical Findings ◽

Lymphocytic Leukemia ◽

Chromosome 12 ◽

Prognostic Information ◽

Prolymphocytic Leukemia ◽

Significant Difference

Abstract Fifty-five patients with a clonal expansion of B lymphocytes in the peripheral blood were studied. According to the Kiel classification, 22 patients had chronic lymphocytic leukemia (CLL), 29 had immunocytoma (IC), two had prolymphocytic leukemia, and one had centrocytic lymphoma; one was not subclassified. Cytogenetic studies after B cell mitogen stimulation showed that six patients had an extra chromosome 12 as the sole abnormality. Another ten patients had an extra chromosome 12 together with other abnormalities. One patient had dup(12). Fifteen patients showed clonal aberrations without +12. Eleven patients showed only normal metaphases, and 12 patients were not evaluated cytogenetically. The cytogenetic subgroup pattern did not distinguish between CLL and IC patients. There was no significant difference between the CLL and IC groups as regards clinical findings and prognosis. However, the cytogenetic typing proved to be of prognostic significance. Increasing numbers of chromosomal aberrations within the cell clone were significantly associated with a poorer prognosis, ie, with impairment of survival (P = .04) and therapy-free survival (P less than 10(-4]. Patients with complex karyotypes (at least clonal aberrations) showed the poorest survival (P = .007). Patients with +12 required treatment earlier than patients with a normal karyotype (P = .01) and patients with karyotypic changes other than +12 (P = .006). These latter differences were even more pronounced when only IC patients were considered (P = .005 and P = .002, respectively). A multivariate analysis revealed that +12 was as strong an indicator of poor survival as advanced Rai or Binet stages and a stronger predictor of therapy-demanding disease.

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Nonrandom chromosomal aberrations in chronic lymphocytic leukemia revealed by polyclonal B-cell-mitogen stimulation

Blood ◽

10.1182/blood.v56.4.640.bloodjournal564640 ◽

1980 ◽

Vol 56 (4) ◽

pp. 640-647 ◽

Cited By ~ 7

Author(s):

G Gahrton ◽

KH Robert ◽

K Friberg ◽

L Zech ◽

AG Bird

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Chromosomal Abnormalities ◽

Extra Chromosome ◽

Normal Karyotype ◽

Chromosome Analysis ◽

Peripheral Blood Lymphocytes ◽

Lymphocytic Leukemia ◽

Chromosome 12 ◽

Banding Technique ◽

Chromosome 11

Peripheral blood lymphocytes from 11 patients with chronic lymphocytic leukemia were stimulated by Epstein-Barr virus (EBV), lipopolysaccharide from Escherichia (LPS), and phytohemagglutinin (PHA). Chromosome analysis with the Q-banding technique after 5 days incubation revealed an extra chromosome 12 in 5 of the patients and a translocation between chromosome 11 and chromosome 14 in 1. Two patients had a deletion of chromosome 6, and only 3 patients had a normal karyotype. In most patients, the abnormalities were found in the majority of metaphases after stimulation with EBV, LPS, or both mitogens, while PHA revealed a normal karyotype, with the exception of a total of 4 metaphases in 3 patients. An extra chromosome 12 appears to be specifically associated with chronic lymphocytic leukemia. The frequency of chromosomal abnormalities in this disease appears to be much higher than has previously been thought.

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Nonrandom chromosomal aberrations in chronic lymphocytic leukemia revealed by polyclonal B-cell-mitogen stimulation

Blood ◽

10.1182/blood.v56.4.640.640 ◽

1980 ◽

Vol 56 (4) ◽

pp. 640-647 ◽

Cited By ~ 149

Author(s):

G Gahrton ◽

KH Robert ◽

K Friberg ◽

L Zech ◽

AG Bird

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Chromosomal Abnormalities ◽

Extra Chromosome ◽

Normal Karyotype ◽

Chromosome Analysis ◽

Peripheral Blood Lymphocytes ◽

Lymphocytic Leukemia ◽

Chromosome 12 ◽

Banding Technique ◽

Chromosome 11

Abstract Peripheral blood lymphocytes from 11 patients with chronic lymphocytic leukemia were stimulated by Epstein-Barr virus (EBV), lipopolysaccharide from Escherichia (LPS), and phytohemagglutinin (PHA). Chromosome analysis with the Q-banding technique after 5 days incubation revealed an extra chromosome 12 in 5 of the patients and a translocation between chromosome 11 and chromosome 14 in 1. Two patients had a deletion of chromosome 6, and only 3 patients had a normal karyotype. In most patients, the abnormalities were found in the majority of metaphases after stimulation with EBV, LPS, or both mitogens, while PHA revealed a normal karyotype, with the exception of a total of 4 metaphases in 3 patients. An extra chromosome 12 appears to be specifically associated with chronic lymphocytic leukemia. The frequency of chromosomal abnormalities in this disease appears to be much higher than has previously been thought.

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Detection of trisomy 12 in chronic lymphocytic leukemia by fluorescence in situ hybridization to interphase cells: a simple and sensitive method

Blood ◽

10.1182/blood.v79.7.1796.1796 ◽

1992 ◽

Vol 79 (7) ◽

pp. 1796-1801 ◽

Cited By ~ 109

Author(s):

J Anastasi ◽

MM Le Beau ◽

JW Vardiman ◽

AA Fernald ◽

RA Larson ◽

...

Keyword(s):

In Situ Hybridization ◽

Chronic Lymphocytic Leukemia ◽

Fluorescence In Situ Hybridization ◽

Cytogenetic Analysis ◽

Normal Karyotype ◽

Lymphocytic Leukemia ◽

Chromosome 12 ◽

Interphase Cells ◽

Trisomy 12

Abstract Trisomy 12 is the most common cytogenetic abnormality in chronic lymphocytic leukemia (CLL), and a number of studies have suggested that it may be an adverse prognostic indicator. We have evaluated the usefulness of fluorescence in situ hybridization with a chromosome 12- specific probe as a simple means for detecting trisomy 12 in interphase cells. Forty cases of B-cell CLL previously studied with conventional cytogenetic techniques were analyzed with a biotinylated probe to the centromeric region of chromosome 12. Thirty of these retrospective cases could be reevaluated with in situ hybridization. Our analysis showed three hybridization signals (ie, trisomy 12) in interphase cells from seven of seven cases found previously to have trisomy 12. Trisomy 12 was also detected in five additional cases: in one case thought to have a normal karyotype, in two cases that had been inadequate for routine cytogenetic analysis, and in two cases that had been found to have an abnormal karyotype without trisomy 12. In a prospective series of 20 newly accrued CLL cases, all cases were analyzed successfully by in situ hybridization and six (30%) showed trisomy 12. We were able to perform the analysis on routinely prepared and previously Wright- stained peripheral blood smears. We conclude that fluorescence in situ hybridization is a simple means for the detection of trisomy 12 in CLL. The technique is more sensitive than conventional cytogenetic analysis and would be a useful tool in clinical studies.

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Multiplex ligation-dependent probe amplification identifies copy number changes in normal and undetectable karyotype MDS patients

10.21203/rs.3.rs-32982/v2 ◽

2020 ◽

Author(s):

Jing Ma ◽

xiaofei Ai ◽

Jinhuan Wang ◽

Limin Xing ◽

Chen Tian ◽

...

Keyword(s):

Copy Number ◽

Chromosome Banding ◽

Chromosomal Abnormalities ◽

Normal Karyotype ◽

Prognostic Information ◽

Significant Difference ◽

Banding Analysis ◽

Chromosome Banding Analysis ◽

Copy Number Changes ◽

Dependent Probe

Abstract Background Chromosomal abnormalities play an important role in classification and prognostication of myelodysplastic syndromes (MDS) patients. However, more than 50% low risk MDS patients harbor a normal karyotype. Recently, multiplex ligation-dependent probe amplification (MLPA) has emerged as an effective and robust method for the detection of cytogenetic aberrations in MDS patients. Methods To characterize the subset of MDS with normal karyotype or failed chromosome banding analysis, we analyzed 144 patient samples with normal karyotype or undetectable through regular chromosome banding, which were subjected to parallel comparison via fluorescence in situ hybridization (FISH) and MLPA. Results MLPA identifies copy number changes in 16.7% of 144 MDS patients and we observed a significant difference in overall survival (OS) (median OS: undefined vs 27 months, p=0.0071) in patients with normal karyotype proved by MLPA, versus aberrant karyotype cohort as determined by MLPA. Interestingly, patients with undetectable karyotype via regular chromosome banding indicated inferior outcome. Conclusion Collectively, MDS patients with normal or undetectable karyotype via chromosome banding analysis can be further clarified by MLPA, providing more prognostic information that benefit for individualized therapy.

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Suppressed CEBPA Function Is Associated with Favorable Prognosis in Normal Karyotype AML Patients

Blood ◽

10.1182/blood.v112.11.2506.2506 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2506-2506

Author(s):

Jose Fos ◽

Nicola Bonadies ◽

Thomas Pabst ◽

Beatrice U Mueller

Keyword(s):

Transcription Factor ◽

De Novo ◽

Prognostic Significance ◽

Normal Karyotype ◽

Binding Activity ◽

Leukemic Cells ◽

Prognostic Information ◽

Independent Prognostic Marker ◽

Favorable Prognosis ◽

Dna Binding Activity

Abstract The myeloid transcription factor CEBPA is crucial for normal differentiation of granulocytes. In addition, genomic mutations and deregulated expression of CEBPA have been reported in specific subsets of patients with acute myeloid leukemia (AML). We here investigated the prognostic significance of CEBPA mRNA, CEBPA protein, and CEBPA function in 105 consecutive de novo AML patients with a particular focus on AML patients with a normal karyotype. We found that the DNA binding activity of CEBPA in normal karyotype AML patients as determined by an ELISA-based assay conferred significant prognostic information: normal karyotype AML patients with suppressed CEBPA function showed a better OS (p=0.0068) and DFS (p=0.0138) compared to patients with conserved CEBPA function. In addition, suppressed levels of the 42kDa CEBPA protein in these patients tended to predict favorable outcome, whereas differences in p30 CEBPA protein levels and in mRNA expression did not affect the outcome. Finally, AML patients with suppressed CEBPA function had more frequently FLT3-ITD and an unmutated nucleophosmin status identifying CEBPA function as an independent prognostic marker for normal karyotype AML. This is the first study comprehensively assessing CEBPA transcription factor function in leukemic cells from AML patients. Our data suggest that suppressed CEBPA function is associated with favorable prognosis in normal karyotype AML patients independently of other molecular markers, and we propose assessment of CEBPA binding activity to be integrated into clinical practice. Moreover, our results highlight the importance of posttranscriptional mechanisms of CEBPA modulation in AML.

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Clinical significance of ZAP-70 protein expression in B-cell chronic lymphocytic leukemia

Blood ◽

10.1182/blood-2005-12-4986 ◽

2006 ◽

Vol 108 (3) ◽

pp. 853-861 ◽

Cited By ~ 125

Author(s):

Maria Ilaria Del Principe ◽

Giovanni Del Poeta ◽

Francesco Buccisano ◽

Luca Maurillo ◽

Adriano Venditti ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Prognostic Significance ◽

Normal Karyotype ◽

Progression Free Survival ◽

Lymphocytic Leukemia ◽

Clinical Staging ◽

Mutational Status ◽

Staging Systems ◽

Cell Chronic Lymphocytic Leukemia

Abstract The clinical course of B-cell chronic lymphocytic leukemia (B-CLL) is variable, and novel biologic parameters need to be added to the clinical staging systems to predict an indolent or aggressive outcome. We investigated the 70-kDa zeta-associated protein (ZAP-70), CD38, soluble CD23 (sCD23), and cytogenetics in 289 patients with B-CLL. Both a shorter progression-free survival (PFS) and overall survival (OS) were observed in ZAP-70+ (P < .001), in CD38+ (P < .001) and in sCD23+ patients (P < .001 and P = .013, respectively). ZAP-70+CD38+ or ZAP-70+ patients with an unmutated IgVH status showed both a shorter PFS (P < .001) and OS (P < .001 and P < .001, respectively) as compared with ZAP-70–/CD38– or ZAP-70– patients with mutated IgVH genes. Discordant patients showed an intermediate outcome. Note, ZAP-70+ patients even if CD38– or mutated showed a shorter PFS, whereas ZAP-70– patients even if CD38+ or unmutated had a longer PFS. Furthermore, ZAP-70 positivity was associated with a shorter PFS both within normal karyotype (P < .001) and within the poor-risk cytogenetic subset (P = .02). The predictive value of ZAP-70 expression was confirmed in multivariate analysis. Thus, ZAP-70 protein determined by flow cytometry improves the prognostic significance of cytogenetics and appears to be a better predictor of outcomes than IgVH gene mutational status. On this line, we recommend and are also interested in conducting a prospective randomized trial of early intervention versus observation for ZAP-70+ patients.

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Detection of trisomy 12 in chronic lymphocytic leukemia by fluorescence in situ hybridization to interphase cells: a simple and sensitive method

Blood ◽

10.1182/blood.v79.7.1796.bloodjournal7971796 ◽

1992 ◽

Vol 79 (7) ◽

pp. 1796-1801 ◽

Cited By ~ 1

Author(s):

J Anastasi ◽

MM Le Beau ◽

JW Vardiman ◽

AA Fernald ◽

RA Larson ◽

...

Keyword(s):

In Situ Hybridization ◽

Chronic Lymphocytic Leukemia ◽

Fluorescence In Situ Hybridization ◽

Cytogenetic Analysis ◽

Normal Karyotype ◽

Lymphocytic Leukemia ◽

Chromosome 12 ◽

Interphase Cells ◽

Trisomy 12

Trisomy 12 is the most common cytogenetic abnormality in chronic lymphocytic leukemia (CLL), and a number of studies have suggested that it may be an adverse prognostic indicator. We have evaluated the usefulness of fluorescence in situ hybridization with a chromosome 12- specific probe as a simple means for detecting trisomy 12 in interphase cells. Forty cases of B-cell CLL previously studied with conventional cytogenetic techniques were analyzed with a biotinylated probe to the centromeric region of chromosome 12. Thirty of these retrospective cases could be reevaluated with in situ hybridization. Our analysis showed three hybridization signals (ie, trisomy 12) in interphase cells from seven of seven cases found previously to have trisomy 12. Trisomy 12 was also detected in five additional cases: in one case thought to have a normal karyotype, in two cases that had been inadequate for routine cytogenetic analysis, and in two cases that had been found to have an abnormal karyotype without trisomy 12. In a prospective series of 20 newly accrued CLL cases, all cases were analyzed successfully by in situ hybridization and six (30%) showed trisomy 12. We were able to perform the analysis on routinely prepared and previously Wright- stained peripheral blood smears. We conclude that fluorescence in situ hybridization is a simple means for the detection of trisomy 12 in CLL. The technique is more sensitive than conventional cytogenetic analysis and would be a useful tool in clinical studies.

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CLLU1 expression analysis adds prognostic information to risk prediction in chronic lymphocytic leukemia

Blood ◽

10.1182/blood-2006-11-054916 ◽

2007 ◽

Vol 109 (11) ◽

pp. 4973-4979 ◽

Cited By ~ 36

Author(s):

Pär Josefsson ◽

Christian H. Geisler ◽

Henrik Leffers ◽

Jørgen H. Petersen ◽

Mette K. Andersen ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Risk Prediction ◽

Expression Analysis ◽

Prognostic Significance ◽

Lymphocytic Leukemia ◽

Specific Gene ◽

Prognostic Information ◽

Expression Levels ◽

Mutational Status ◽

Igvh Mutational Status

AbstractWe recently identified a disease-specific gene CLLU1 in chronic lymphocytic leukemia (CLL) and also demonstrated that high CLLU1 expression levels predict poor clinical outcome. To validate this finding, we measured CLLU1 mRNA expression levels by real-time reverse transcriptase–polymerase chain reaction (RT-PCR) in 175 patients with CLL. Analyses of IgVH mutational status, ZAP-70 expression, CD38 expression, and chromosomal aberrations were also performed. High levels of CLLU1 expression were associated with shorter overall survival (P < .001), with a 7% increase in risk of early death by each doubling of the CLLU1 expression level. Stratification for age at diagnosis demonstrated a strong prognostic significance of CLLU1 expression in patients younger than 70 years (P < .001), but not in patients aged 70 or older (P = .61). The prognostic significance of IgVH mutational status and ZAP-70 expression had a similar age-dependent variation. Multivariate analysis in the younger age group showed that CLLU1 expression analysis added further prognostic information within all prognostic subgroups, with the exception of patients with unmutated IgVH CLL. Only CLLU1 expression and IgVH mutational status had independent predictive power. Thus, analysis of CLLU1 expression is highly applicable in risk prediction in CLL for patients of an age eligible for risk stratification.

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Omphaloceles Associated with Chromosomal Segmental Alterations Carry a Poor Prognosis

American Journal of Clinical Pathology ◽

10.1093/ajcp/aqaa161.052 ◽

2020 ◽

Vol 154 (Supplement_1) ◽

pp. S26-S27

Author(s):

H Zhou

Keyword(s):

Overall Survival ◽

Survival Rate ◽

Chromosomal Abnormalities ◽

Prognostic Significance ◽

Normal Karyotype ◽

Chromosomal Microarray ◽

Chromosomal Microarray Analysis ◽

Overall Survival Rate ◽

Significant Difference ◽

Worse Prognosis

Abstract Introduction/Objective Omphaloceles are frequently associated with chromosomal abnormalities, including aneuploidy and segmental alterations. High resolution chromosomal microarray analysis (CMA) can detect segmental alterations < 5 Mb, which is not detectable by G-banding. However, the prognostic significance of the segmental alteration in infant with omphalocele is not elucidated. Methods To identify omphalocele cases with genetic studies, a CoPath database search (1/2000 - 7/2017) was performed with key words “omphalocele” and “genetic”. From 1/2000 to 12/2008, only G-banding was performed. From 1/2009 to 7/2017, omphalocele cases were screened with karyotyping. Cases with normal karyotype were reflexed to CMA. Copy number gains/losses and corresponding genes were analyzed by the Affymetrix Chromosome Analysis Suite. Results Follow-up data are available in 75% (67/89) cases. There is no significant difference of the overall survival rate of male and female patients (80.5% vs 76.9%; χ 2, p = 0.7645). There are 16.9% (15/89) omphaloceles with aneuploidy, 10.1% (9/89) cases with segmental alterations by CMA, and 73.0% (65/89) cases with normal CMA and/or normal karyotype. Although patients with segmental alterations have a significantly higher survival rate than those with aneuploidy (44.4% vs 0%, χ2, p = 0.0119), their overall survival rate is significantly lower than infant with normal CMA and/or normal karyotype (44.4% vs 82.8%; χ2, p < 0.0001). Infants with segmental alterations carry a significantly worse prognosis than infants with normal genetic study. Conclusion To date, this is the first study of the prognostic significance of segmental alteration in infants with omphalocele. Our data demonstrated that omphaloceles with segmental alterations carry a significantly worse prognosis than those with normal CMA and/or karyotype. It is crucial to convey the prognosis to the parents with a fetus carrying segmental alterations; so the family could make an informed decision and get ready for an infant with special needs.

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