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1
Steidl, Christian, Rainer Schabla, Ulrich Germing, et al. "Sequential Cytogenetic Analyses of 577 Patients with Myelodysplastic Syndromes: Correlations between Initial Karyotype, Cytogenetic Dynamics, and Clinical Course." Blood 106, no. 11 (2005): 2531. http://dx.doi.org/10.1182/blood.v106.11.2531.2531.
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Abstract Myelodysplastic syndromes are dynamic diseases presenting with different clinical courses ranging from almost stable courses to rapid progression to acute myeloid leukemias. Karyotype is one of the most important prognostic factors and defines subgroups of favorable, intermediate and adverse prognosis. So far, comparably low attention has been payed on karyotypic changes occuring in sequential cytogentic examinations during the course of the disease. We retrospectively examined karyotypes of 577 patients with MDS or AML with previous history of MDS and at least two successfully performed metaphase analyses. The cytogenetic and clinical data was collected from 5 different centres of the “Kompetenznetz Akute und Chronische Leukaemien” (Duesseldorf, Duisburg, Freiburg, Goettingen, Vienna). Compared to the inital karyotype, karyotype evolution was defined as acquisition of additional aberrations, expansion of an aberrant clone by more than 20% or development of a completely aberrant karyotype after a former mosaic karyotype. According to these criteria, we found karyotype evolution in 155 cases (27%). 2–8 cytogenetic examinations have been performed per case. In 121 cases additional aberrations occured and in 34 cases the aberrant clone expanded in a subsequent analysis. In the group of patients with expansion of the aberrant clone the most frequent karyotypes were 5q- (9x) and +8 (7x). The most frequent aberrant karyotypes later acquiring additional aberrations were complex (22x) and karyotypes with two aberrations (11x), but in the vast majority of cases additional aberrations occurred on basis of a normal karyotype (70x). The most frequent additional aberrations were −7/7q- (23x), 5q- (11x) and +8 (11x). In the group of initially normal karyotypes patients with karyotype evolution had a shorter survivial (p<0.05). In summary, partial or complete momosomy 7 is the most frequent additional aberration in sequential cytogenetic analyses, indicating progression of disease. Due to their genetic instability complex karyotypes or karyotypes with 2 aberrations typically acquire additional anomalies in the course, whereas karyotypes with 5q- and +8 tend to have comparably stable courses. Furthermore, we show that also cases with a normal karyotype can harbour genetic instability as in 12% of all cases a normal karyotype evolved into an aberrant karyotype which was associated with a worse prognosis compared to stable normal karyotypes. Subgroup analyses are necessary to address correlations with therapy, time to AML progression, and the dependency on examination intervals.
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Pinar, Halit, Marshall Carpenter, Benjamin J. Martin, and Umadevi Tantravahi. "Utility of Fetal Karyotype in the Evaluation of Phenotypically Abnormal Stillbirths." Pediatric and Developmental Pathology 12, no. 3 (2009): 217–21. http://dx.doi.org/10.2350/07-07-0307.1.
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The objectives of this study are to test the hypothesis that stillbirths without aneuploidy-associated phenotypes have a low incidence of karyotypic abnormalities, similar among those with and without other anatomic defects. We employed a uniform postmortem protocol to examine fetuses and placentas in 962 consecutive stillbirths measuring ≥20 weeks in clinically determined gestational age submitted to the Women and Infants Hospital Division of Perinatal Pathology from 1990 through 2005. Classification of anatomic (macroscopic) abnormalities was based on a priori criteria. Anatomic fetal abnormalities were noted in 387 cases. Conventional karyotype analysis was successfully performed on 346 fetal tissue samples, 114 in anatomically normal and 232 in anatomically abnormal fetuses. The distribution of karyotypic abnormalities among cases with and without anatomic abnormalities was compared. Of the 962 stillbirths, 40% (387) had malformations. Tissue culture for karyotype analysis was attempted in 412 cases from both groups and failed in 66 cases (16%). At the 450 to 500-band resolution level, 60 of the remaining 346 karyotypes were abnormal. Of the 232 malformation cases with successful karyotyping, 59 had phenotypic attributes indicative of aneuploidy, all of which had later karyotype confirmation. Of the remaining 173 anomalous fetuses with karyotype analysis, only 1 demonstrated a karyotypic abnormality. All 114 karyotypes performed in stillbirths without anatomic abnormalities were normal. Among ≥20-week stillbirths, aneuploid karyotypes are uncommon except in fetuses with suspect phenotypes. The 95% probability estimates of karyotype abnormality in the phenotypically abnormal and normal stillbirths, 5.5% and 5.6%, respectively, do not differ. These data do not have sufficient power to detect a small difference in rates of karyotypic abnormalities between the 2 groups of ≥20-week stillbirths. However, this series indicates that this technology is uninformative among stillborn fetuses that lack aneuploidy phenotypes.
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Göhring, Gudrun, Kathrin Thomay, Caroline Fedder, Winfried Hofmann, Hans Heinrich Kreipe, and Brigitte Schlegelberger. "Telomere Shortening, TP53 Mutations and Deletions in Chronic Lymphocytic Leukemia Result in Increased Chromosomal Instability and Breakpoint Clustering in Heterochromatic Regions." Blood 128, no. 22 (2016): 3220. http://dx.doi.org/10.1182/blood.v128.22.3220.3220.
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Abstract Complex karyotypes are associated with a poor prognosis in chronic lymphocytic leukemia (CLL). Using mFISH, iFISHand T/C FISH we thoroughly characterized 59 CLL patients regarding parameters known to be involved in chromosomal instability: status of the genes ATM and TP53 and telomere length (10 patients with a normal karyotype, 10 patients with an isolated deletion 11q, 19 patients with a complex karyotype without a deletion 11q and 20 patients with a complex karyotype including a deletion 11q). Among the patients with a complex karyotype, 29 of 39 (74%) showed a karyotypic evolution or a composite karyotype expressing great karyotypic heterogeneity and high chromosomal instability. Deletion of TP53 and ATM, two master regulators of DNA repair, was mutually exclusive in all but one patient. Interestingly, a deletion in 11q, either isolated or in the complex context of a complex karyotype, was associated with a significantly diminished risk (p<0.05) of carrying a mutation in TP53. In patients with loss or mutation of TP53 chromosomal breakage occurred more frequently (p<0.01) in (near-) heterochromatic regions leading to dicentric chromosomes and whole arm translocations. Telomeres of aberrant cells were significantly shorter than those of cells with a normal karyotype from the same patient. Also, median telomere length in patients with complex karyotypes was significantly shorter than of healthy controls (p<0.05) and shorter than telomere length of all other cytogenetic cohorts. Furthermore, the median telomere length of patients carrying a TP53 mutation was significantly shorter than of patients without mutation (p<0.05). We conclude that telomere shortening in combination with loss of TP53 induces increased chromosomal instability with preferential involvement of (near-) heterochromatic regions. Figure 1 a-b) Results of the Cytogenetic Data Analysis System (CyDAS) evaluation of all integratedkaryotypicdata from R-banding,iFISHandmFISHanalyses for recurrent gains and losses (a) as well as for recurrent breakpoints (b) c-f) T/C FISH on metaphases (d,e) and T/C FISHkaryograms(f,g) of patient 46 with a complex karyotype. Depicted are a normal cell (d and f) and an aberrant cell (e and f) The fluorescence intensity correlating with telomere length is higher in the normal cell than in the aberrant cell indicating telomere shortening in the aberrant cell. g)Karyogramof patient 46 aftermulticolorfluorescence in situ hybridization (mFISH) demonstrating a complex karyotype with cryptic aberrations. h) Median telomere lengths (kilobases) of normal and aberrant metaphases in three patients with CLL.*statistically significant difference (p<0.05). i) Average telomere length (kilobases) of each chromosome arm of normal and aberrant metaphases of one patient. Figure 1. a-b) Results of the Cytogenetic Data Analysis System (CyDAS) evaluation of all integratedkaryotypicdata from R-banding,iFISHandmFISHanalyses for recurrent gains and losses (a) as well as for recurrent breakpoints (b). / c-f) T/C FISH on metaphases (d,e) and T/C FISHkaryograms(f,g) of patient 46 with a complex karyotype. Depicted are a normal cell (d and f) and an aberrant cell (e and f) The fluorescence intensity correlating with telomere length is higher in the normal cell than in the aberrant cell indicating telomere shortening in the aberrant cell. / g)Karyogramof patient 46 aftermulticolorfluorescence in situ hybridization (mFISH) demonstrating a complex karyotype with cryptic aberrations. / h) Median telomere lengths (kilobases) of normal and aberrant metaphases in three patients with CLL.*statistically significant difference (p<0.05). / i) Average telomere length (kilobases) of each chromosome arm of normal and aberrant metaphases of one patient. Disclosures No relevant conflicts of interest to declare.
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Feng, Qiutian, and Jian Huang. "Cytogenetic Abnormalities Lead to Poor Prognosis in Patients with Myelofibrosis, Especially Postessential Thrombocythemia Myelofibrosis and Postpolycythemia Vera Myelofibrosis: A Multicenter Retrospective Study." Blood 144, Supplement 1 (2024): 6638. https://doi.org/10.1182/blood-2024-205559.
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For patients with myelofibrosis (MF), personalized treatment planning based on disease risk stratification and symptom assessment is typically carried out. Some prognostic scoring systems applicable to overt Primary myelofibrosis(overt PMF) patients may not accurately categorize the prognosis of postessential thrombocythemia myelofibrosis (post-ET MF) and postpolycythemia vera myelofibrosis (post-PV MF) patients. Currently, the prognostic model for myelofibrosis secondary to postpolycythemia vera(PV) and thrombocythemia(ET) (MYSEC-PM) involves only clinical features and driver gene mutations, without stratified assessment of their cellular genetic characteristics. Here, we conducted a retrospective study of 338 MF patients in 6 hematooncology centers between 01 October 2013 and 30 November 2023. By analyzing the correlation and differences between the cellular genetic characteristics of patients with different types of MF and clinical factors, gene mutations, and survival prognosis, we aimed to provide guidance for clinical diagnosis, treatment, and prognosis assessment of different types of MF, especially post-ET MF and post-PV MF. Chromosomal results for 338 MF patients revealed 253 patients with a normal karyotype (74.9%) and 85 patients with an abnormal karyotype (25.1%). When comparing the distribution of abnormal karyotypes among the different types of MF, the most common abnormal karyotypes in overt PMF patients were +8 (4.2%) and -20/20q- (4.2%), followed by -13/13q- (3.8%). The most common abnormal karyotype in post-ET MF patients was trisomy 1 (8.1%), followed by +8 (4.8%). In post-PV MF patients, the most common abnormal karyotypes were -17 (5.0%) and -5/5q- (5.0%). We analyzed the impact of abnormal karyotypes on the survival prognosis of MF patients. In MF patients (including those with overt PMF, post-ET MF, and post-PV MF), abnormal karyotypes were associated with significantly shortened overall survival (OS) compared to normal karyotypes (P&lt;0.0001, P=0.0483, P&lt;0.0001). In overt PMF and post-ET MF patients, both monosomal karyotypes and complex karyotypes were associated with significantly shortened OS compared to normal karyotypes (P&lt;0.0001, P&lt;0.0001). In overt PMF patients, the isolated +8 karyotype was associated with shortened OS compared to normal karyotypes (P=0.0001). In post-ET MF patients with the +8 karyotype (3 cases), all with additional abnormal karyotypes, OS was significantly shortened compared to those with normal karyotypes (P=0.0010). In overt PMF patients with the 1q+ karyotype (7 cases), all with additional abnormal karyotypes, OS was significantly shortened compared to those with normal karyotypes (P=0.0002). In post-ET MF patients with an isolated 1q+ karyotype, OS was significantly shortened compared to those with normal karyotypes (P=0.0007). Analysis of the impact of other common abnormal karyotypes on the survival prognosis of overt PMF patients revealed that -13/13q-, -7/7q-, -11/11q-, +9, -12/12q-, -17, der(6), -5/5q-, and +19 abnormal karyotypes were associated with significantly shortened OS compared to normal karyotypes (P=0.0191, P＜0.0001, P=0.0030, P=0.0102, P=0.0014, P＜0.0001, P=0.0023, P＜0.0001, P=0.0021). In conclusion, abnormal karyotypes, complex karyotypes, and monosomal karyotypes were adverse prognostic factors in MF patients. Aberrations such as +8, -13/13q-, -7/7q-, -11/11q-, +9, -12/12q-, -17, der(6), -5/5q-, and +19 all indicated poor prognosis in overt PMF patients, and translocations/duplications of chromosomes 1 and +8 were associated with poor prognosis in post-ET MF patients. Acknowledgement: This research was funded by the Key R&D Program of Zhejiang, No. 2022C03137; Public Technology Application Research Program of Zhejiang, China, No. LGF21H080003; Zhejiang Medical Association Clinical Medical Research special fund project, No. 2022ZYC-D09. *Correspondence to: Jian Huang, M.D., Ph.D., Department of Hematology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang, China. E-mail: househuang@zju.edu.cn
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Zeng, Xiangzong, Min Dai, Yu Zhang, Lingling Zhou, Ya Zhou, and Qifa Liu. "Somatic Mutations Predict Poor Prognosis in Myelodysplastic Syndrome Patients with Normal Karyotypes." Blood 136, Supplement 1 (2020): 44–45. http://dx.doi.org/10.1182/blood-2020-138368.
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Purpose: Somatic mutations are common in myelodysplastic syndrome (MDS), but its risk stratification is mainly based on cytogenetics. This study was to explore the prognostic significance of somatic mutations in MDS patients with normal karyotypes. Patients and Methods: Three hundred and four patients with MDS were enrolled in this retrospective study. A genomic panel of 127 gene targets were detected by next-generation sequencing. Results: Two hundred and Eighty-one (92.4%) patients carried at least one somatic mutation, while cytogenetics identified abnormalities in 140 (46.1%) patients. The 5 most frequently mutated genes were TET2, ASXL1, EZH2, TET1, FAT1, and TET2, TP53, TET1, EP300, SF3B1 in the patients with normal karyotypes and aberrant karyotypes, respectively. When mutations detected in &gt;5% of the whole cohort, they were included in analysis and the results showed that the frequency of TET2, TP53, ASXL1, CD101, KDM6A, SH2B3 and IL-3RA mutations was different between two groups(all P&lt;0.05). ASXL1, CD101, KDM6A, SH2B3, IL-3RA mutations were more common in normal karyotype group, while TET2 and TP53 were more common in aberrant karyotype group. Multivariable analysis showed that age (HR 1.02; P=0.027), IPSS-R(HR 1.80; P&lt;0.0001), TP53(HR 2.36; P&lt;0.0001) and DNMT3A (HR 1.83, P=0.044) were the risk factors while allo-HSCT(HR 0.50; P=0.001) was a protect factor for OS in the whole cohort. For sub-group analysis, IPSS-R(HR 1.54; P=0.005; HR 1.80; P&lt;0.0001, respectively), TP53 mutation(HR 2.49; P=0.030; HR 2.13; P=0.005, respectively) and allo-HSCT(HR 0.52; P=0.040; HR 0.37; P&lt;0.0001, respectively) retained the prognostic significance in both the normal karyotype and aberrant karyotype group. FAT1(HR 2.32; P=0.019), DNMT3A(HR 3.32; P=0.006) and IL-7R(HR 4.35; P=0.002) mutations were unfavorable factors for OS only in the normal karyotype group. Conclusion: FAT1, IL-7R and DNMT3A mutations pretict poor prognosis in MDS patients with normal karyotypes. Key words: Somatic mutation, Next-generation sequencing, Prognosis, Myelodysplastic syndrome Disclosures No relevant conflicts of interest to declare.
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Xiao, Yajuan, Yuanlu Huang, Na Xu, et al. "Chromosomal Instability: A Probable Unfavorable Prognostic Factor For Patients Of Myeloidysplastic Syndromes." Blood 122, no. 21 (2013): 5243. http://dx.doi.org/10.1182/blood.v122.21.5243.5243.
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Abstract Objective Myelodysplastic syndromes (MDS) are a group of heterogeneous hematopoetic stem cell clonal disorders with a high frequency of karyotypic abnormalities (40-60%). Among karyotypic abnormalities, abnormal chromosome numbers (aneuploidy) occurs frequently. In aneuploidy, chromosomal instability (CIN) is defined as persistent mis-segregation of whole chromosomes and is caused by defects during mitosis with an odd number of chromosomes. CIN is associated with tumor heterogenesis, multidrug resistance and aggressiveness in solid tumor. Hence, we performed a one-center study on MDS patients to uncover the role of CIN in MDS clinical development. Method A total of 104 cases , 62 male and 42 female, aged from 15 years to 89 years, were tested by fluorescent in situ hybridization (FISH) and karyotypic analysis before any therapeutic intervention. According to the cytogenetic analysis of those two technology they were separated into 5 groups including: CIN, normal karyotype, complex karyotype excluding CIN, deletion chromosome 7 abnormality and other chromosomal abnormalities. All cases were followed up for a median of 19.5 months. Results Karyotyping and FISH identified 70 (67.3%) patients with abnormal karyotypes containing 32 cases of CIN, 9 cases of deletion chromosome 7 abnormality and 5 cases of complex karyotype excluding CIN. The median survival for CIN group was 13 months (incredible interval:6-20 months) compared with 23 months (incredible interval :20-27 months) in all cases, 44months in normal karyotype, 23 months in deletion chromosome 7 abnormality and 13 months in complex karyotype excluding CIN group (P=0.001 for log rank method). In CIN group, 11 cases transformed into acute leukemia with a incidence of 34% with no significant difference with total cases. And the length of time for leukemia transformation shows no significant difference between CIN group and total cases. Conclusion Chromosomal instability in MDS patients of the study revealed worst prognosis compared with other groups. This may suggest that chromosomal instability in MDS chromosomal abnormality confer a significant independent adverse impact on patients survival. However this effect might have no relation to leukemia transformation. Disclosures: No relevant conflicts of interest to declare.
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Almefty, Kaith K., Svetlana Pravdenkova, Jeffrey R. Sawyer, and Ossama Al-Mefty. "Impact of cytogenetic abnormalities on the management of skull base chordomas." Journal of Neurosurgery 110, no. 4 (2009): 715–24. http://dx.doi.org/10.3171/2008.9.jns08285.
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Object Cytogenetic studies of chordomas are scarce and show multiple changes involving different chromosomes. These abnormalities are implicated in the pathogenesis of chordoma, but the clinical significance of these changes is yet to be determined. In this study, the authors discuss the cytogenetic changes in a large series of skull base chordomas with long-term follow-up and focus on the impact of these changes on the prognosis, progression, and management of the disease. Methods The karyotypes of chordomas in 64 patients (36 men and 28 women) were studied in relation to survival and recurrence or progression over a mean follow-up period of 48 ± 37.5 months. The standard G-banding technique was used for karyotype analysis. Statistical analysis was performed with the Fisher exact test and ORs, and Kaplan-Meier curves were generated for survival and recurrence/progression of disease. Results Seventy-four percent of de novo chordomas had normal karyotypes and a 3% recurrence rate; there was a 45% recurrence rate in de novo tumors with abnormal karyotypes (p < 0.01). Recurrent tumors were associated with a high incidence of abnormal karyotype (75%). The OR for recurrence in lesions with an abnormal versus a normal karyotype was 12. Aberrations in chromosomes 3, 4, 12, 13, and 14 were associated with frequent recurrence and decreased survival time. Ninety-five percent of cases with progression involved chromosome 3 and/or 13. The median survival time was 4 months when both of these chromosomes had aberrations (p = 0.02). Conclusions Chordomas with normal karyotypes were associated with a low rate of recurrence and a long patient survival, and recurrent chordomas were associated with an abnormal karyotype, disease progression, and poor survival. De novo chordomas with normal karyotypes may be amenable to radical resection and adjunctive proton beam therapy. Recurrent and de novo chordomas with abnormal karyotypes were associated with complex cytogenetic abnormalities and a poor prognosis, particularly in the presence of aberrations underlying tumor progression in chromosomes 3, 4, 12, 13, and 14.
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Hasanova A.T. and Jafarova G.A. "Relationship of human heterochromatin and congenital malformations." Journal of Theoretical, Clinical and Experimental Morphology 2, no. 3-4 (2020): 54–56. http://dx.doi.org/10.28942/jtcem.v2i3-4.121.
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Aim. The variability of centromeric heterochromatin of the chromosome pairs 1,9 and 16 was studied in material pro- vided by the Cytogenetic Counselling Centre.
 Materials and methods. The size of bands 1q12, 9q12 and 16q11 was classified as normal, larger, very large, narrow and pericentric inversion. The karyotypes under study were divided into four groups: (I) from persons with abnormal karyotype and abnor-mal phenotype, ( I I ) from persons with abnormal phenotype and normal karyotype, (III) from healthy nearest relatives (parents and sibs) of persons with abnormal phenotype and karyotype, (I V ) from normal healthy persons with normal phenotype and karyotype without any congenital malformations in the family history.
 Results. A different variability of centromeric hetero-chromatin of chromosomes 1 , 9 and 16 was observed. Quite a low variability was found in chromosome 16, while chromosomes 9 and 1 showed a high degree of variability, which was more accentuated in chromosome 9 than in chromo-some 1 .
 Conclusions. In all four groups there was a similar pattern of variability with the only exception in the group of nearest relatives of children with abnormal phenotype and karyotype where an unusually narrow band 1q12 was more fre- quently detected.
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Guha, Debasree, and Sayan Banerjee. "Cyclopia syndrome with normal karyotype." Indian Journal of Medical Research 152, no. 7 (2020): 57. http://dx.doi.org/10.4103/ijmr.ijmr_1893_19.
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Beck, Richard J., and Noemi Andor. "Abstract 2486: Decoding tumor evolution through fitness landscapes of aneuploid cells." Cancer Research 85, no. 8_Supplement_1 (2025): 2486. https://doi.org/10.1158/1538-7445.am2025-2486.
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Abstract Aneuploidy, prevalent in most solid tumors, significantly alters cellular phenotype and fitness. Despite its critical role in tumor evolution, a detailed quantitative understanding of its evolutionary dynamics remains elusive. To address this gap, we developed ALFA-K, a novel method to infer the fitness landscape of chromosome-level karyotypes. Utilizing longitudinal single-cell karyotype data from evolving cell populations, our method estimates the fitness of thousands of karyotypes proximal to the input data in karyotype space, enabling predictions of unseen karyotypes. We validated our approach using both synthetic data from an agent-based model (ABM) and empirical data from in vitro and in vivo passaged cell lines. The empirical data comprised over 40, 000 sequenced cells across five cell lines, each sequenced longitudinally at 5-10 timepoints per lineage. Analysis of the fitted landscapes yielded several key insights: 1) WGD alters the distribution of fitness effects of copy number alterations (CNAs) (K.S. test: P&lt;10-). Specifically, karyotypes with WGD exhibit more mutations with positive selection coefficients compared to diploid karyotypes; 2) Mutations in cisplatin-treated lineages showed changes in fitness effects on average 2.3 times larger than those in untreated lineages (t-test: P&lt;2.2×10-1); 3) The fitness impact of a CNA varies depending on the parental karyotype; 4) The rate of chromosome missegregation can dictate the predominant karyotypes in an evolving population. To further investigate how the tumor microenvironment shapes karyotype evolution, we are integrating these inferred fitness landscapes into an existing spatial ABM. This modeling simulates the spatially heterogeneous tumor microenvironment and its influence on karyotypic selection and adaptation. By leveraging this ABM, we aim to capture the effects of spatial constraints—such as resource availability, competition, and cellular interactions—on the fitness and distribution of karyotypes. Complementing these simulations, we are developing a bioinformatics pipeline for spatial transcriptomics data from glioblastoma clinical samples. This dataset includes samples from various regions (normal, tumor, and tumor-infiltrating) across 31 samples from 19 patients, using 10X Visium with an average of 3, 100 spots per sample. The pipeline is designed to provide detailed information about the spatial organization of karyotypic diversity, elucidating how aneuploid karyotypes are distributed and interact within the tumor microenvironment. By integrating this spatially resolved data with the ABM, we aim to generate a comprehensive framework to explore how microenvironmental pressures in glioblastoma tumors shape the evolution of karyotypic diversity and drive the emergence of therapeutic resistance in patient-specific contexts. Citation Format: Richard J. Beck, Noemi Andor. Decoding tumor evolution through fitness landscapes of aneuploid cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2486.
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Rigolin, Gian Matteo, Francesca Cibien, Sara Martinelli, et al. "Chromosome aberrations detected by conventional karyotyping using novel mitogens in chronic lymphocytic leukemia with “normal” FISH: correlations with clinicobiologic parameters." Blood 119, no. 10 (2012): 2310–13. http://dx.doi.org/10.1182/blood-2011-11-395269.
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Abstract It is unclear whether karyotype aberrations that occur in regions uncovered by the standard fluorescence in situ hybridization (FISH) panel have prognostic relevance in chronic lymphocytic leukemia (CLL). We evaluated the significance of karyotypic aberrations in a learning cohort (LC; n = 64) and a validation cohort (VC; n = 84) of patients with chronic lymphocytic leukemia with “normal” FISH. An abnormal karyotype was found in 21.5% and 35.7% of cases in the LC and VC, respectively, and was associated with a lower immunophenotypic score (P = .030 in the LC, P = .035 in the VC), advanced stage (P = .040 in the VC), and need for treatment (P = .002 in the LC, P = < .0001 in the VC). The abnormal karyotype correlated with shorter time to first treatment and shorter survival in both the LC and the VC, representing the strongest prognostic parameter. In patients with chronic lymphocytic leukemia with normal FISH, karyotypic aberrations by conventional cytogenetics with novel mitogens identify a subset of cases with adverse prognostic features.
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McFadden, Patrick, Sarah Smithson, Robert Massaro, Jialing Huang, Gail T. Prado, and Wendy Shertz. "Monozygotic Twins Discordant for Trisomy 13." Pediatric and Developmental Pathology 20, no. 4 (2017): 340–47. http://dx.doi.org/10.1177/1093526616686471.
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Monozygotic twins with discordant karyotypes for trisomy 13 are rare. We report a case of a spontaneously conceived pregnancy who presented with first-trimester ultrasound finding of umbilical cord cyst and increased nuchal translucency in Twin A and no abnormalities in Twin B. Amniocentesis revealed 47,XY,+13 karyotype in Twin A and 46,XY karyotype in Twin B. Selective fetal reduction was performed for Twin A. Twin B was delivered at 32 weeks gestation with normal phenotype. Peripheral blood karyotype revealed 15% mosaicism for trisomy 13 and skin fibroblast revealed 46,XY karyotype. The surviving twin will be monitored for potential complication of uniparental disomy 13 and mosaic trisomy 13. This case reinforces the need for early ultrasound and nuchal translucency measurements, especially in twin gestations.
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Chauffaille, Maria de Lourdes L. F., Eliana Azevedo Marques, Jose Salvador Rodrigues de Oliveira, et al. "Detection of trisomy 12 by fluorescent in situ hybridization (FISH) in chronic lymphocytic leukemia." Genetics and Molecular Biology 23, no. 3 (2000): 531–33. http://dx.doi.org/10.1590/s1415-47572000000300005.
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Chronic lymphocytic leukemia (CLL) presents a varying incidence of karyotypic abnormalities whose detection is complicated by difficulties in obtaining mitosis for analysis in this type of mature lymphocyte disorder. Since the introduction of molecular cytogenetics (FISH = fluorescent in situ hybridization), applying centromeric probes for chromosome 12 has made it possible to detect a higher percentage of trisomy 12 cases. The objective of the present study was to detect trisomy 12 by FISH (alpha satellite probe) in 13 patients with CLL whose karyotypes by G-banding were either normal or inadequate. Using this method trisomy 12 was detected in three patients in a percentage of positive cells varying from 55.5% to 79%, showing that FISH is a sensitive and highly specific method for trisomy detection and should be routinely performed when the karyotype is normal.
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Cha, Yongjun, Kwang-Sung Ahn, Juwon Park, et al. "Whole Genome Association Study in Acute Myeloid Leukemia with a Normal Karyotype, Using a Single-Nucleotide Polymorphism (SNP) Analysis." Blood 110, no. 11 (2007): 4253. http://dx.doi.org/10.1182/blood.v110.11.4253.4253.
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Abstract As a result of numerous genetic aberrations, acute myeloid leukemia (AML) present with very heterogeneous clinical features. Moreover, structural and numerical chromosome aberrations currently comprise the most important basis for predicting these heterogeneous outcomes. However, 30 to 50 percent of AML patients have cytogenetically normal karyotypes. Though submicroscopic genetic alterations (such as NPM1, CEBPA, MLL-PTD) are increasingly being used for clinical purposes, additional markers with prognostic or predictive value are still lacking in this group. In this study, we performed a genome-wide, single-nucleotide polymorphism (SNP) study in order to identify novel genomic regions of interest in normal karyotype AML. 54 untreated AML patients with normal karyotypes were analyzed with an Illumina infinium 317K SNP chip assay. SNP genotype call rate was 99.8 percent, resulting in a resolution of 1 SNP/Mb. In a genome-wide SNP analysis, 317 SNP loci, having a significant difference between AML and normal control, were found. In addition, about 300 loci were also identified, showing a significant difference between patients who achieved CR and those who did not. Some of these were found to be related with drug metabolism and MDR family. Also we used the SNP assay to screen a loss of heterozygosity (LOH), suggesting possible involvement of tumor suppressor genes. In summary, 38 LOH regions larger than 1Mb were observed in 23 cases (43%) among 54 AML patients having normal karyotypes. Most (55%) of them were copy-neutral events and the most frequently identified alterations were located at 3p, 8p, 13q and 22q. 11 (29%) out of 38 LOH regions had overlapping parts among them. Some LOHs were correlated with response to chemotherapy. Various genetic changes were discovered by use of an SNP-based chip array in normal karyotype AML patients. Moreover, some of these were related with CR acquisition and drug metabolism. These results can be used to differentiate normal karyotype AML and warrant further study.
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Song, Mingzhu, Tun Zhang, Dongdong Yang, et al. "Chromosomal aberrations and prognostic analysis of secondary acute myeloid leukemia—a retrospective study." PeerJ 11 (May 15, 2023): e15333. http://dx.doi.org/10.7717/peerj.15333.
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Background Secondary acute myeloid leukemia (S-AML) patients generally have a poor prognosis, but the chromosomal aberrations of S-AML have been rarely reported. We aimed to explore the chromosomal aberrations and clinical significance in patients with S-AML. Patients and methods The clinical characteristics and karyotypes of 26 patients with S-AML were retrospectively analyzed. The overall survival (OS) was measured from the time of the patients’ transition to AML (i.e., at S-AML diagnosis). Results The study included 26 S-AML patients (13 males and 13 females), with a median age of 63 years (range, 20–77 years). They transformed from various hematologic malignancies or solid tumors; most of them were secondary to myelodysplastic syndrome (MDS). About 62% of the S-AML patients showed chromosomal aberrations. The serum lactate dehydrogenase (LDH) level in S-AML patients with abnormal karyotype was higher than those with normal karyotype. Apart from the differences in treatment regimens, S-AML patients with chromosomal aberrations had shorter OS (P < 0.05). Conclusion S-AML patients with abnormal karyotype have higher LDH levels and shorter OS than normal karyotype patients, and the OS of hypodiploidy was much shorter than hyperdiploid.
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Pullarkat, Vinod, Marilyn L. Slovak, Kenneth J. Kopecky, Stephen J. Forman, and Frederick R. Appelbaum. "Impact of cytogenetics on the outcome of adult acute lymphoblastic leukemia: results of Southwest Oncology Group 9400 study." Blood 111, no. 5 (2008): 2563–72. http://dx.doi.org/10.1182/blood-2007-10-116186.
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We examined the prognostic impact of cytogenetics on the outcome of 200 acute lymphoblastic leukemia (ALL) patients 15 to 65 years of age enrolled in Southwest Oncology Group (SWOG)–9400 study. Evaluable cytogenetics or fluorescence in situ hybridization studies were available in 140 (70%) patients. Four karyotype categories (normal [n = 31, 22%], t(9;22)/BCR/ABL1 [n = 36, 26%], other unfavorable [−7, +8, or 11q23 rearrangement, n = 19, 13%], and miscellaneous [n = 54, 39%]) and the biologically and clinically relevant ALL ploidy subgroups were prospectively defined. Overall survival (OS) decreased significantly with increasing age (P = .009) and varied with karyotype category (P < .001). OS was worst for t(9;22)/BCR/ABL1 followed by other unfavorable karyotypes, with hazard ratios (HR) of 3.45 (95% confidence interval [CI], 1.88-6.31) and 2.14 (95% CI, 1.04-4.04), respectively, compared with normal diploid group. OS of the miscellaneous group was similar to that of the normal diploid group (HR = 0.82; 95% CI, 0.44-1.53). Relapse-free survival (RFS) was not significantly associated with age (P = .30) but was heterogeneous among karyotype categories (P < .001) primarily because of poor RFS in t(9;22)/BCR/ABL1 (HR = 3.49; 95% CI, 1.80-6.75) compared with the normal diploid group. After accounting for the variation among karyotype groups, age was not a significant prognostic factor for OS or RFS, highlighting cytogenetics as the most important prognostic factor in adult ALL. This trial was registered at www.ClinicalTrials.gov as #NCT00002665.
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Bozkurt, Süreyya, Yahya Büyükaşık, Haluk Demiroğlu, et al. "Cytogenetic anomalies in Multiple Myeloma patients:A single center study." Genetics & Applications 3, no. 1 (2019): 51. http://dx.doi.org/10.31383/ga.vol3iss1pp51-56.
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Conventional karyotyping in the patients with Multiple myeloma (MM) is very important. Because chromosomal abnormalities which detected in these patients have diagnostic and prognostic value. In this retrospective study we aim to evaluate cytogenetic abnormalities in 133 MM patients which diagnosed at the Hematology Department of Hacettepe University. Samples were treated with trypsin and stained with Giemsa (GTG banding). 20 metaphases of each patient were examined and karyotypes were formed. Cytogenetic results of the patient’s bone marrow samples were not obtained in 19 patients, while in 116 patients karyotyping was performed. Among of these 116 patients showed that 80 patients had normal karyotpe while 34 patients had abnormal karyotypes. Both numerical and structural chromosomal anomalies were detected in patients with abnormal karyotype. Numerical and structural anomalies of chromosomes 1, 9, 16 and 13 were detected most frequently among these complex karyotypes. The anomalies we found in our patient group were consistent with the literature.
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Downie, Ben J., Harry P. Erba, Richard M. Stone, David A. Rizzieri, and James M. Foran. "Monosomal Karyotype Is Predictive of Poor Response to Therapy and Worse Overall Survival in Secondary Acute Myeloid Leukemia (sAML); Analysis of a Multi-Center Phase II Study of Amonafide and Cytarabine Induction Therapy." Blood 114, no. 22 (2009): 2076. http://dx.doi.org/10.1182/blood.v114.22.2076.2076.
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Abstract Abstract 2076 Poster Board II-53 Background Recently, further refinement of the “unfavorable” cytogenetic category in AML demonstrated that a “monosomal karyotype” (MK+) – defined as two or more distinct autosomal chromosome monosomies or one single autosomal monosomy in the presence of structural abnormalities – carries a markedly inferior prognosis to that of a “non-monosomal karyotype” (MK-) – defined as a group with various non-core binding factor (CBF) cytogenetic abnormalities but who are MK negative (J. Clin Onc 26:4791). This finding was based on data from patients predominantly with de novo AML. We analysed data from a phase II trial of patients with sAML to examine whether the monosomal karyotype is also predictive of poor outcome in sAML patients. Methods The karyotypes of pre-treatment blast cells from previously untreated sAML patients on a phase II study were reviewed to identify categories of core binding factor karyotype (CBF), normal karyotype (CN), MK+ and MK- (as defined above), and compared to clinical outcomes. Patients on the study all received induction therapy with amonafide 600 mg/m2/day IV days 1-5 and cytarabine 200 mg/m2/day IV days 1-7. Consolidation consisted of stem cell transplant (HSCT, n=10) or intermediate-dose (IDAC, n=13)/high-dose (HiDAC, n=7) cytarabine, depending on age and available HSCT donors. Results 88 patients were treated. 2/88 (2%) were CBF, 29/88 (33%) were CN, 16/88 (18%) were MK+ and 31/88 (35%) were MK-. Patients with CBF and the 10 patients with unknown karyotype at baseline were excluded from the analysis. CR+CRi rate by karyotypic group was 19/29 (66%) for CN, 11/31 (35%) for MK-, 2/16 (13%) for MK+ (CN vs MK- p&lt;0.05; CN vs MK+ p&lt;0.05; MK- vs MK+ p=0.09). Median duration of remission was 282 days for CN, 304 days for MK-, and not reached for the 2 MK+ patients who achieved CR (p=NS). Median overall survival: 304 days CN, 145 days MK- and 144 days MK+ (Log rank test for survival: CN vs MK- p=0.07; CN vs MK+ p&lt;0.05; MK- vs MK+ p=0.06). Conclusions In this study of 88 patients with secondary AML, a monosomal karyotype was predictive of inferior response to therapy compared with both a normal karyotype and a non-monosomal “unfavorable” karyotype. Importantly, the 2-year overall survival in the MK+ group was significantly inferior to that in the CN group. Of note durable complete remissions were observed in responders regardless of karyotype. Though the number of patients in this study is relatively small, to our knowledge this is the only prospectively defined study of sAML patients demonstrating a significantly adverse impact of monosomal karyotype as compared with other “unfavorable” karyotypes. Further data to address the prognostic and predictive significance of specific cytogenetic abnormalities in sAML will be obtained from a currently enrolling 450-patient phase III randomized trial of amonafide + cytarabine vs daunorubicin + cytarabine in patients with sAML (ACCEDE). Disclosures: Downie: Antisoma: Research Funding. Erba:Lilly: Research Funding; Antisoma: Research Funding; Wyeth: Research Funding; Cephalon: Honoraria, Research Funding; MGI Pharma: Honoraria; Pharmion: Honoraria; Celgene: Honoraria; BMS: Honoraria; Novartis: Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; Gemin-X: Research Funding; Kanisa: Research Funding. Stone:Celgene: Consultancy, Speakers Bureau; Merck: Consultancy; Genzyme: Consultancy; Eisai: Consultancy. Rizzieri:Antisoma: Research Funding. Foran:Antisoma: Research Funding.
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Terré, Christine, and Victoria Raggueneau. "Double insertion in normal karyotype CML." Blood 137, no. 17 (2021): 2418. http://dx.doi.org/10.1182/blood.2021010829.
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Mukhopadhyay, S., S. Biswas, and S. Vindla. "Familial cystic hygroma with normal karyotype." Journal of Obstetrics and Gynaecology 26, no. 8 (2006): 836. http://dx.doi.org/10.1080/01443610600994908.
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Gallagher, Robert E. "Dueling mutations in normal karyotype AML." Blood 106, no. 12 (2005): 3681–82. http://dx.doi.org/10.1182/blood-2005-08-3444.
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Mula, R., A. Goncé, M. Bennásar, et al. "Increased Nuchal Translucency and Normal Karyotype." Obstetrical & Gynecological Survey 67, no. 5 (2012): 279–80. http://dx.doi.org/10.1097/ogx.0b013e3182562cf0.
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Souka, Athena P., Constantin S. von Kaisenberg, Jonathan A. Hyett, Jiri D. Sonek, and Kypros H. Nicolaides. "Increased nuchal translucency with normal karyotype." American Journal of Obstetrics and Gynecology 192, no. 4 (2005): 1005–21. http://dx.doi.org/10.1016/j.ajog.2004.12.093.
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Nakamura, Hideo, Naoki Sadamori, Ippei Sasagawa, et al. "Acute nonlymphocytic leukemia with normal karyotype." Cancer Genetics and Cytogenetics 51, no. 1 (1991): 67–71. http://dx.doi.org/10.1016/0165-4608(91)90010-r.
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Loizeau, S., M. V. Senat, J. Ronne, S. Conderc, and Y. Ville. "P021: Nuchal anomalies with normal karyotype." Ultrasound in Obstetrics and Gynecology 22, S1 (2003): 76–77. http://dx.doi.org/10.1002/uog.481.
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Watson, William J., John M. Thorp, and John W. Seeds. "Familial cystic hygroma with normal karyotype." Prenatal Diagnosis 10, no. 1 (1990): 37–40. http://dx.doi.org/10.1002/pd.1970100107.
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Schnittger, Susanne, Torsten Haferlach, Petro E. Petrides, Wolfgang Kern, and Claudia Schoch. "JAK2 Mutation Screening and Chromosome Analysis Are Necessary for a Comprehensive Diagnostic Work up in CMPD: A Study on 469 Cases." Blood 106, no. 11 (2005): 4963. http://dx.doi.org/10.1182/blood.v106.11.4963.4963.
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Abstract The diagnosis of BCR-ABL negative chronic myeloproliferative disorders (CMPD) is still a challenge for the morphologist and clinician, mainly because of overlapping phenotypes of essential thrombocythemia (ET), polycythemia vera (PV), idiopathic myelofibrosis (IMF) and non-malignant reactive phenotypes. Recently, a new mutation in JAK2 leading to V617F exchange in exon 12 was described in these entities. Therefore, we developed a rapid and easy LightCycler based melting curve assay and screened 469 patients with various malignancies for the respective JAK2 mutation using cDNA prepared from mononucleated cells. All cases tested positive were confirmed by sequencing and without any exception all mutations were G to T exchanges at nucleotide 1849. In total, 61 cases with PV were analysed. 56 (91.8%) were mutated (see table). A karyotype was available in 36 cases. Of the JAK2- cases 4 had normal karyotypes and one 20q-. Of the JAK2+ cases 21 had normal karyotype; four (7.1%) had +9, one +8, one +22, one 20q-, and three showed a complex aberrant karyotype. Of the 47 analyzed ET 26 (55%) were mutated. Cytogenetics was available in 20 cases (9 JAK2-, 11 JAK2+). All JAK2- cases all had normal karyotypes. Of the JAK2+ 10 had a normal karyotype and one a t(9;13)(p24;q22) involving the JAK2 locus. Of the 25 IMF cases 14 (56%) were mutated. Karyotype was available in 17 cases (7 JAK2-, 10 JAK2+). All 7 JAK2- had normal karyotype. Of the 10 JAK2+ 6 had normal karyotype and four were aberrant (+9:n=2; 20q-: n=2). In addition, 2/7 cases (28.6%) with CMML were JAK2+. Furthermore, we analysed 89 BCR-ABL negative MPS that were not further specified. V617F was detectable in 43 patients (48.3%). At next 128 AML were analyzed (84 novo AML, 11 t-AML after a previous malignancy, 15 secondary to MDS, and 16 secondary to MPS (PV:n=7, ET:n=5, OMF:n=2). No V617F was detected in all cases with t-AML and s-AML after MDS. In contrast, in de novo AML 6/84 (7.1%) were JAK2+, of which 4 were proven homozygous. Surprisingly, 4 of these six cases had a +9. In AML secondary to a previous CMPD 11/16 (68.8 %) were JAK2+. Of these 2 had +9, one a normal karyotype and 12 a complex aberrant karyotype. These data suggest that acquisition of +9 may lead to progress or blast crisis in JAK2 mutated MPS and supports the gain of function mechanism of the mutation. In conclusion, more than half of all BCR-ABL-negative MPS harbour a V617F mutation. This helps in the differential diagnosis of MPS versus reactive disorders. V617F is more frequently associated with aberrant karyotype than wildtype JAK2. In addition, there is an increasing level of aberrant cytogenetics and mutation rate with respect to incidence and status from ET&lt;IMF&lt;PV indicating that these diseases might be overlapping or even a continuum. It demonstrates that the present classification is artificial and a new classification of “JAK2” positive diseases may be more adequate. In addition, the same mutation was observed in most cases of AML secondary to CMPD. It was also found in few cases with de novo AML and correlated with +9. JAK2V617F is a new and promising target for therapy as well as for molecular monitoring of therapy response in CMPD. Distribution of JAK2 mutation in various malignancies ET IMF PV MPS* CMML de novo AML AML after MPS *not further specified total 47 25 61 89 7 84 16 mutated (n=) 26 14 56 43 2 6 11 mutated (% of all) 55.0 % 56.0 % 91.8 % 48.3 % 28.6 % 7.1 % 68.8 % homozygous (n=) 3 9 33 19 1 4 7 homozygous (% of all) 6.4 % 36.0 % 54.1 % 21.3 % 14.3 % 4.8 % 43.8 %
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Mehta, S., S. Singh, and Wang Ning Ling. "Study on the Relativity between Cytogenetics and Cytomorphology and its Prognosis Significance in Children with Acute Myelogenous Leukemia." Journal of Gandaki Medical College-Nepal 10, no. 2 (2018): 35–41. http://dx.doi.org/10.3126/jgmcn.v10i2.20806.
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Objective: The main objective of this study was to retrospectively evaluate that the cytogenetic abnormalities is an important prognostic factor for the cure of acute myeloid leukemia (AML).Methods: This retrospective study enrolled newly diagnosed 70 cases (37 males and 33 females, aged 10.1 months to 14.5 years) of pediatric patients with AML during 2010 January - 2016 February from the Second Affiliated Hospital of Anhui Medical University. Excluding criteria were cases secondary to treatment-related MDS and AML. Samples were obtained from bone marrow cells in patients after treatment on the anterior superior iliac spine, blood diseases laboratory by direct culture or 24/48 hour short-term culture, G -banding technique for testing. Follow-up of 1 - 60 months, the analysis of treatment response rates of different karyotypes, distribution ratios in various subtypes, normal karyotype and abnormal karyotype. ISPSS17.0 software statistics was used for statistical analysis. Groups were compared using chi-square test; Survival rate was calculated by method of Kaplan Meier and survival difference between groups were compared with breslow test.Results: Among 70 cases, 42 cases were detected for chromosomal abnormalities (i.e. 60% of the total number of cases), M3 abnormal karyotype distortion rate of 78.5%, M2 abnormal karyotype aberrations 63.3%, M4 60.0%, M1 50%, M5 lowest 38.9 %, M7 nuclear aberrations highest rate was 100%. Total chromosomal aberration rate was 60%. Acute myeloid leukemia cases, t (8; 21) at most, there are 15 cases, and the presence of abnormal karyotype 86.7% in the original part of differentiated myeloid leukemia (M2); t (15; 17) has 11 cases, exists only in acute promyelocytic cell leukemia (M3). After treatment, the remission rate of t (8; 21) was 80%; the remission rate of t (15; 17) was 90%; the remission rate of other abnormal karyotype abnormalities was 50%; the remission rate of total abnormal karyotype was 71.4%. The event free survival rate was significantly different between normal karyotype, t (8; 21), t (15; 17) and other abnormal karyotype groups (P<0.05).Conclusions: Acute myeloid leukemia karyotype abnormalities among FAB subtypes are different; M3 is the highest rate of abnormal karyotype aberrations, M2, M4 medium, M5 minimum. t (15; 17) seen in acute promyelocytic leukemia (APL), prognosis is good; t (8; 21) is more common in M2, prognosis is good, also found in M4 and M5, worse prognosis; +8 Abnormalities found in AML M2, M3, M4, M5 and M6 subtypes, prognosis medium; inv (16) high white blood cells, low platelet poor prognosis, AML patients with normal karyotype prognosis medium. J-GMC-N | Volume 11 | Issue 01 | January-June 2018, Page: 35-41
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Usvasalo, Anu, Riikka Räty, Arja Harila-Saari, et al. "Acute Lymphoblastic Leukemia with “Normal” Karyotype is not without Genomic Aberrations." Blood 112, no. 11 (2008): 1491. http://dx.doi.org/10.1182/blood.v112.11.1491.1491.
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Abstract Development of cytogenetic methods has contributed to the understanding that ALL is not a homogenous disease. Detection of structural and numerical alterations in the chromosomes of lymphoblasts has identified several different ALL subgroups. G-banding reveals about 60–70% of these changes. The development of FISH and PCR methods has decreased the proportion of apparently normal karyotype to less than 20%. Still a part of ALL patients have no chromosomal aberrations detected with conventional cytogenetics. It seems likely, however, that ALL with a normal karyotype reflects rather our inadequate capability to detect all possible aberrations than a true normality of the lymphoblast genome. Microarray methods offer an effective tool to define novel cytogenetic changes in ALL. In our study characterizing and evaluating ALL in adolescents and young adults aged 10–25 years in Finland, we analyzed patients diagnosed during 1990–2007 (n=231). Eighty-nine patients had normal (n=80) or failed (n=9) karyotype at diagnosis. DNA from initial samples was available for 27 of these 89 patients. 26 patients had normal karyotypes, for one patient the karyotype analysis failed by G-banding at diagnosis. The key clinical characteristics of the 27 patients did not differ from the rest of the patients with normal or failed karyotype. Genomic DNA was extracted from diagnostic bone marrow samples. Digestion, labeling and hybridization of DNA was performed according to the Agilent protocol version 2.0 for 44K arrays. Labeled samples were hybridized against gender matched reference DNAs to Human Genome CGH 44B oligo microarray slides (Agilent Technologies Santa Clara, CA, USA). For data-analysis Agilent’s CGH Analytics software version 3.5 was used. The starting and ending points of the aberrations were confirmed by the ADM-2 algorithm with 10.0 threshold. The immunophenotype of the patients was as follows: T-cell ALL 8/27 patients, precursor B ALL 13/27, mixed lineage 5/27 (according to the European Group for the Immunological Characterization of Leukemias), not known 1/27. Seventeen patients had normal karyotype and no other marker for MRD follow-up, while 9 patients had either immunoglobulin and/or T-cell receptor gene rearrangement (n=8) or over-expression of Willms Tumor gene 1 (WT1) (n=1). In total 58 aberrations were detected in the 27 patient samples (1–7 aberrations per sample, mean 2.1) (Figure 1). Four samples (15%) did not show any aberration (two with immunoglobulin and/or T-cell receptor gene rearrangements). Losses were detected in 20/27 cases and gains in 10/27 cases. Cases with losses only were more frequent (n=13, 48%) than those with gains only (n=3, 11%). Losses were more numerous than gains (44/20 vs. 14/10). Single aberrations were seen in seven patients. Five of these were deletions affecting 9p21.3, two were gains in 21q. In the 27 cases, the most commonly detected aberrations were deletions involving 9p21.3 (n=10), 5/10 (50%) being T-ALL. In all the 10 cases the CDKN2A gene was affected. Other aberrations seen more than once were deletion of 6q (n=4), amplification of the terminal part of 21q (n=3), amplification of 1q (n=2), deletion of 12p (n=2), deletion in 12q23-q24 (n=2), deletion in 16q22 (n=2), deletion in 17q11 (n=2) and deletion in 22q11 (n=2). Nineteen relatively small aberrations (about 2 Mb or less in size) were detected in 15 cases and such deletion was found to be the only aberration in 4/15 cases. Our data indicate that a subgroup of ALL with fully normal cytogenetics may not exist. Microarray CGH shows a clear benefit in more detailed examination of the blast cell DNA. In 85% (23/27) of the patients with initially normal karyotypes we determined single or multiple aberrations with array CGH. Losses were more frequent than gains. Seven patients (26%) had only a single aberration, three of these being submicroscopic (&lt;200 kb).We conclude that microarray CGH enables to detect molecular-genetic changes also in ALL cases having a “normal” karyotype using conventional cytogenetics. We are getting closer to the point where normal molecular-genetic findings do not exist in leukemic lymphoblasts. Figure 1. DNA copy number alterations detected with array CGH in 27 adolescent ALL patients with initially normal or failed karyotype. Vertical lines to the left and right of each chromosome represents copy number losses and gains, respectively. Figure 1. DNA copy number alterations detected with array CGH in 27 adolescent ALL patients with initially normal or failed karyotype. Vertical lines to the left and right of each chromosome represents copy number losses and gains, respectively.
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Kaddouri-Kaddouri, Salma, Cintia Concepción-Lorenzo, Rubí N. Rodríguez-Díaz, et al. "Does female with chromosome translocation have a normal response to controlled ovarian hyperstimulation?" International Research Journal of Medicine and Medical Sciences 8, no. 4 (2020): 109–15. http://dx.doi.org/10.30918/irjmms.84.20.043.
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Patients with chromosomal translocation have been reported to have high risk of reproductive failure, lower ovarian response, recurrent pregnancy loss and implantation failure. The literature is not conclusive, and our objective is to study if female balanced translocation (BT) does affect the controlled ovarian stimulation (COS). We carried out a retrospective analysis of 3249 karyotypes between 2008 and 2016, including 2276 females and 973 males. 12 women (0.5%) with BT were compared with 93 control normal karyotype group (CN) in both female and male partner. An equivalent control group (EQc) of 12 patients was additionally selected to be accurate with the BT statistical contrast. Cycle, oocyte and embryo outcomes were analysed. We concluded that female BT carriers have no diminished response to COS than infertile females with normal karyotype. This is an important information for counselling couples previous to COS and preimplantational genetic testing (PGT). Keywords: Chromosomal translocation, reciprocal, Robertsonian, controlled ovarian stimulation.
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Mahjoubi, F., and N. Zolfagary. "A Partial Trisomy 2p(p21→pter) Derived from a Paternal t(2;4)(p21;q33) Karyotype." Balkan Journal of Medical Genetics 13, no. 1 (2010): 39–43. http://dx.doi.org/10.2478/v10034-010-0017-5.
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A Partial Trisomy 2p(p21→pter) Derived from a Paternal t(2;4)(p21;q33) KaryotypeWe describe a 7-year-old boy with additional material on 4q whose karyotype was 46, XY, der(4) t(2;4)(p21: q33). The father's karyotype was 46, XY, t(2;4)(p21;q33) and the mother's was normal. These results indicate that the extra material on 4q in the patient originated from the father's chromosome 2p. The patient had dysmorphic facial features, prominent ears, long fingers, developmental delay, speech delay and suffered from seizures.
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Göhring, Gudrun, Kyra Michalova, H. Berna Beverloo, et al. "Complex karyotype newly defined: the strongest prognostic factor in advanced childhood myelodysplastic syndrome." Blood 116, no. 19 (2010): 3766–69. http://dx.doi.org/10.1182/blood-2010-04-280313.
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Abstract To identify cytogenetic risk factors predicting outcome in children with advanced myelodysplastic syndrome, overall survival of 192 children prospectively enrolled in European Working Group of Myelodysplastic Syndrome in Childhood studies was evaluated with regard to karyotypic complexity. Structurally complex constitutes a new definition of complex karyotype characterized by more than or equal to 3 chromosomal aberrations, including at least one structural aberration. Five-year overall survival in patients with more than or equal to 3 clonal aberrations, which were not structurally complex, did not differ from that observed in patients with normal karyotype. Cox regression analysis revealed the presence of a monosomal and structurally complex karyotype to be strongly associated with poor prognosis (hazard ratio = 4.6, P < .01). Notably, a structurally complex karyotype without a monosomy was associated with a very short 2-year overall survival probability of only 14% (hazard ratio = 14.5; P < .01). The presence of a structurally complex karyotype was the strongest independent prognostic marker predicting poor outcome in children with advanced myelodysplastic syndrome.
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Mufti, Ghulam J., Steven D. Gore, Valeria Santini, et al. "Influence of Karyotype On Overall Survival in Patients with Higher-Risk Myelodysplastic Syndrome Treated with Azacitidine or a Conventional Care Regimen." Blood 114, no. 22 (2009): 1755. http://dx.doi.org/10.1182/blood.v114.22.1755.1755.
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Abstract Abstract 1755 Poster Board I-781 Background Karyotypic abnormalities are common in myelodysplastic syndromes (MDS), and specific chromosomal abnormalities are associated with poor prognosis. The phase III AZA-001 study (Lancet Oncol, 2009) showed azacitidine (AZA) prolonged overall survival (OS) regardless of IPSS cytogenetic risk category. This analysis assessed the effects of specific cytogenetic abnormalities on OS in patient (pt) subgroups treated with AZA or a conventional care regimen (CCR). Methods Pts with higher-risk MDS (FAB RAEB, RAEB-t, or CMML and IPSS Int-2 or High) were enrolled and randomized to receive AZA or CCR. CCR comprised 3 treatments: best supportive care only, low-dose ara-C, or induction chemotherapy. Erythropoietins were prohibited. OS was determined in subgroups of pts with del 5/5q-, del 7/7q-, or trisomy 8, each as part of a non-complex karyotype (<3 cytogenetic abnormalities) or as part of a complex karyotype (≥3 cytogenetic abnormalities). OS was also analyzed in pts with combinations of del 5/5q- and/or del 7/7q- as part of non-complex or complex karyotypes (Table). Pt karyotype was determined at baseline. OS was assessed using Kaplan-Meier methods. A stratified Cox proportional hazards regression model was used to estimate hazard ratios (HRs) and associated 95% confidence intervals (CI). Results A total of 358 pts were enrolled (AZA 179, CCR 179). Of them, 153 had normal karyotypes (AZA 77, CCR 76). Median OS in pts with normal karyotypes was not reached at 21.1 months with AZA vs 17.2 months (95%CI: 15.2 – 24.1 months) with CCR; HR = 0.63 (95%CI: 0.39 – 1.03). Of remaining pts, 136 had del 5/5q-, del 7/7q-, and/or trisomy 8 as part of a non-complex or complex karyotype. AZA was associated with longer OS vs CCR in all subgroups of pts with non-complex cytogenetics, with HRs ranging from 0.20 (95%CI: 0.06 – 0.65) to 0.51 (95%CI: 0.05 – 4.74) (Table). In both the AZA and CCR treatment groups, pts in all subgroups with non-complex karyotypes had substantially longer OS than pts with complex karyotypes. Pts with complex karyotypes in some subgroups had longer OS with AZA vs CCR: median OS in pts with del 5/5q-, del 5/5q- WITHOUT del 7/7q-, or trisomy 8 as part of a complex karyotype treated with AZA survived 5.1, 8.0, and 12.4 months longer, respectively, than their counterparts who received CCR. HRs with AZA vs CCR in pts with complex cytogenetics ranged from 0.42 (95%CI: 0.10 – 1.69) to 0.55 (95%CI: 0.29 – 1.05). Conclusions These findings support earlier data showing effectiveness of AZA in higher-risk MDS pts with complex or non-complex karyotypes. Major gains in OS were obtained with AZA vs CCR (12-18 months longer OS with AZA) for the following categories: del 7/7q- (non-complex), del 7/7q- WITHOUT del 5/5q- (non-complex), and trisomy 8 (non-complex and complex). Pts with trisomy 8 treated with AZA experienced a 3-fold increase in median OS compared with similar pts who received CCR. Longer OS (AZA 15.3 vs CCR 7.3 months) was also obtained for pts with del5/5q- WITHOUT del7/7q- as part of a complex karyotype. The worse cytogenetic categories, del 7/7q- and del 5/5q- AND del 7/7q-, both with complex karyotype, were associated with the poorest OS regardless of treatment. Pt subgroups in this post hoc analysis were small and heterogeneous; confirmation of these findings in larger pt samples is warranted. Disclosures Mufti: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gore:Celgene: Consultancy, Equity Ownership, Research Funding; Johnson & Johnson: Research Funding. Santini:Celgene: Honoraria. Fenaux:Celgene: Honoraria, Research Funding; Ortho Biotech: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Epicept: Honoraria, Research Funding. Skikne:Celgene: Employment, Equity Ownership. Hellstrom-Lindberg:Celgene: Research Funding. Seymour:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Beach:Celgene: Employment, Equity Ownership. Backstrom:Celgene: Employment, Equity Ownership. Fernando:Celgene: Employment, Equity Ownership.
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Tilak, Preetha, Sonia Dhawan, and Sayee Rajangam. "Congenital Heart Defects and Non-Cardiac Malformations in Patients with Normal Karyotype." Indian Journal of Anatomy 7, no. 1 (2018): 7–11. http://dx.doi.org/10.21088/ija.2320.0022.7118.1.
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Chauffaille, Maria de Lourdes Lopes Ferrari, Vicente Coutinho, Mihoko Yamamoto, and José Kerbauy. "Combined method for simultaneous morphology, immunophenotype and karyotype (MAC) in leukemias." Sao Paulo Medical Journal 115, no. 1 (1997): 1336–42. http://dx.doi.org/10.1590/s1516-31801997000100004.
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In the present study, a combined method (CM) for attaining simultaneous identification of leukemic cell morphology, karyotype and immunophenotype has been evaluated in 21 patients with acute leukemia and 1 with CML in blast crisis were studied for morphology, citochemistry, immunophenotype and karyotype. Karyotype was performed in a bone marrow sample by using conventional techniques. In each case, direct method (DM) and/or three cultures were tried. The CM consisted in separating a small part of the material resulting from any of the cultures or DM, preparing slides through cytospin and immunophenotyping through APAAP method using the same monoclonal antibodies (MoAb) as for diagnosis. In 14 cases, the metaphases proved positive to the MoAb: in 4, the cells with abnormality had their origin defined; in other 4 the karyotype was normal preventing any identification; 6 cases had minimal abnormalities not visible through CM; and in two cases abnormal karyotypes were detected only in the cultures with GM-CSF. This study showed that CM is feasible in cases where evident numerical or structural chromosomal abnormalties are present.
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Balleisen, Sebastian, Hildebrand Barbara, Royer-Prokora Brigitte, et al. "Cytogenetic Remission Status after Induction Chemotherapy for AML and High-Risk MDS Predicts Long-Term Outcome." Blood 104, no. 11 (2004): 3009. http://dx.doi.org/10.1182/blood.v104.11.3009.3009.
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Abstract Cytogenetic findings at diagnosis have an important impact on prognosis in AML and MDS. Therefore, treatment is commonly stratified according to karyotype. Another important prognostic factor is remission status after induction chemotherapy. However, the diagnosis of remission, and the resulting treatment decisions, are usually not based on cytogenetic findings, but rely on peripheral blood counts and bone marrow blast cell counts. We analysed the prognostic impact of cytogenetic remission status in 115 patients with abnormal karyotype who received induction chemotherapy because of AML (n=102) or MDS (n=13). Initial karyotypes were as follows: 14x t(15;17), 9x t(8;21), 5x inv(16), 55 intermediate-risk, and 32 complex karyotypes. The following induction protocols were used: 38x TAD, 4x HAM, 25x Ida-Ara, 36x ICE, and 3x other protocols. Eleven patients received induction chemotherapy plus ATRA. 23 patients underwent allogeneic transplantation after induction therapy, either as late consolidation in cytologic remission (CR), or as standard treatment in high-risk patients. 78 patients achieved CR, 21 achieved partial remission (PR), and 16 patients were non-responders (NR). There were 26 patients who reached cytological CR but still showed an abnormal karyotype after induction. 17 of these 26 patients had been classified as standard-risk and therefore did not receive intensified consolidation. In 59 patients, a normal karyotype was found after induction therapy. 24 of 28 patients belonging to low-risk cytogenetics (t15;17, t8/21, or inv16) achieved cytogenetic complete remission (CCR). The CCR rate was much lower in patients with intermediate-risk cytogenetics (24/55) and patients with complex karyotypes (11/32). Median survival in the group achieving CCR was 40 months, as compared to 11 months in patients with persistence of abnormal karyotype after induction (p<0,00005). The difference remained highly significant when calculated only for patients with complex or intermediate-risk karyotypes (median survival 29 vs 11 months). Conclusions: Cytogenetic analysis after induction chemotherapy is useful to detect residual disease and therefore provides meaningful information in addition to cytology. Achieving cytogenetic remission after induction therapy is strongly correlated with a better long-term outcome. Patients with a persisting abnormal karyotype must be regarded as high-risk patients who should receive intensified treatment.
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Chen, Jianhong, Qun Fang, Baojiang Chen, Yi Zhou, and Yanmin Luo. "Study on the Imprinting Status of Insulin-Like Growth Factor II (IGF-II) Gene in Villus during 6–10 Gestational Weeks." Obstetrics and Gynecology International 2010 (2010): 1–4. http://dx.doi.org/10.1155/2010/965905.
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Objective. To compare the difference of imprinting status of insulin-like growth factor II (IGF-II) gene in villus between normal embryo development group and abnormal embryo development group and to investigate the relationship between karyotype and the imprinting status of IGF-II gene.Methods. A total of 85 pregnant women with singleton pregnancy were divided into two groups: one with abnormal embryo development (n=38) and the other with normal embryo development (n=47). Apa I polymorphism of IGF-II gene in chorionic villus was assayed with reverse transcriptase polymerase chain reaction (RT-PCR) and restriction fragment length polymorphism (RFLP). The relationship between chromosomal abnormal karyotype and IGF-II gene imprinting status was analyzed by primary cell culture and G-banding chromosomal karyotype analysis.Results. IGF-II imprinting loss rate was higher in the abnormal embryo development group than the normal embryo development group (44.7% versus 31.6%), but without significant difference (P>.05). The percentage of abnormal chromosomes of chorionic villus in the abnormal embryo development group was 42.5%, in which IGF-II imprinting loss rate reached 64.7%. No abnormal karyotypes were found in the normal embryo development group. However, there was significant difference in IGF-II imprinting loss rate between two groups (P>.05).Conclusion. During weeks 6–10 of gestation, abnormal embryonic development is correlated with chromosomal abnormalities. The imprinting status of IGF-II gene played important roles in embryonic development, and imprinting loss might be related to chromosomal abnormalities.
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Borys, Dariusz, and Jerome B. Taxy. "Congenital Diaphragmatic Hernia and Chromosomal Anomalies: Autopsy Study." Pediatric and Developmental Pathology 7, no. 1 (2004): 35–38. http://dx.doi.org/10.1007/s10024-003-2133-7.
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In a 10-year review of autopsy records from Lutheran General Hospital (1992–2002), 13 cases of congenital diaphragmatic hernia (CDH) were found. The fetuses ranged between 21 and 35 wk of gestation. Four were born alive and five were diagnosed prenatally. The defect was left-sided in 11 cases. Cytogenetic study revealed five cases with normal karyotype and three cases with complex karyotypes. In five cases, no karyotype was performed. The three complex karyotypes were: 46,XX,del(8)(p23.1), 47,XX,+i(12)(p10)[6]/46XX[14] (Pallister-Killian syndrome), and 47,XY,+der(22)t(11:22) (q23.3:q11.2). The unbalanced translocation of chromosomes 11 and 22 in congenital diaphragmatic hernia has not been previously described. Three fetuses had heart abnormalities, including one which was associated with the 8p deletion. The other two had no karyotype study. Neither in this study, nor in the literature, is there a consistent or prevailing association between a specific chromosomal anomaly and CDH. The embryologic closure of the diaphragmatic leaflets may be mediated by a nonstructural chromosomal defect, more than one gene, and/or may be related to abnormalities not currently detectable.
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Bilardo, C. M., M. A. Muller, and E. Pajkrt. "OC041: Increased nuchal translucency with normal karyotype." Ultrasound in Obstetrics and Gynecology 22, S1 (2003): 11–12. http://dx.doi.org/10.1002/uog.255.
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Nam, S., and Y. Lee. "P07.11: Increased nuchal translucency with normal karyotype." Ultrasound in Obstetrics & Gynecology 38, S1 (2011): 193. http://dx.doi.org/10.1002/uog.9701.
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Haferlach, Claudia, Manja Meggendorfer, Wolfgang Kern, Susanne Schnittger, and Torsten Haferlach. "Characterization of CMML with Normal Karyotype in Comparison to CMML with Aberrant Karyotype." Blood 126, no. 23 (2015): 1674. http://dx.doi.org/10.1182/blood.v126.23.1674.1674.
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Abstract Background: CMML is a myelodysplastic/myeloproliferative neoplasm with distinct morphological and genetic features. Based on differences in blast count CMML is divided into CMML-1 (<1% blasts in the peripheral blood (pB) and <10% in the bone marrow (BM)) and CMML-2 (5-19% blasts in pB, 10-19% in BM or presence of Auer rods). Clonal cytogenetic abnormalities are detected in only 20-40% of patients by chromosome banding analysis (CBA) while >90% of patients harbor at least one molecular mutation. The most frequent cytogenetic abnormalities include abnormalities of chromosome 7, trisomy 8 and complex karyotype. The genes most frequently mutated in CMML are TET2, ASXL1 and SRSF2. Aims: 1. Evaluate the frequency of submicroscopic gains and losses of chromosomal material as well as copy neutral loss of heterozygosity (CN-LOH) in CMML with normal karyotype in chromosome banding analysis (CBA). 2. Analyze the association of these lesions with molecular mutations and impact on survival. Patients and Methods: 69 patients with CMML-1 and 31 with CMML-2 and normal karyotype by CBA were evaluated by array CGH (SurePrint G3 ISCA CGH+SNP, Agilent, Waldbronn, Germany). 32 patients were female, 68 male, median age was 75 years (range: 50-89 years). These were compared to 41 cases with aberrant karyotype by CBA. Patients were screened for mutations (mut) in ASXL1, CBL, DNMT3A, EZH2, JAK2 V617F, KITD 816, KRAS, NRAS, RUNX1, SETBP1, SF3B1, SRSF2, TET2, and U2AF1. Results: In 35 cases (35%) with normal karyotype by CBA 46 abnormalities were detected by array CGH (CGHpos). These were 6 gains, 17 losses and 23 CN-LOH. No recurrent gain was observed, while recurrent losses of 4q24 (n=2, including TET2) and of 13q14 (n=2) were identified. CN-LOH was recurrently observed on 4q (n=6, including TET2), 11q (n=5, including CBL), 17q (n=4) and 7q (n=2). Mutations were identified at the following frequencies: TET2: 77% (74/96), SRSF2: 56% (54/97), ASXL1: 48% (46/96), RUNX1: 20% (20/98), CBL: 15% (15/97), KRAS: 12% (12/97), JAK2 V617F: 10% (10/98). The following genes were mutated in <10%: NRAS, SETBP1, EZH2, U2AF1, KIT D816, SF3B1, DNMT3A. 85 patients were analysed for all mutations. In median 3 mutations were identified per patient (range 0-6), while only in 1 patient no mutation was detected. 4/5 (80%) cases with 11q CN-LOH harbored a CBL mut and 7/8 (88%) cases with CN-LOH 4q or 4q24 deletion harbored a TET2 mut, indicating that these two gene mutations might contribute in homozygous manner to pathogenesis. NRAS mut were significantly less frequent in CMML CGHpos compared to CGHneg (0% vs 14.3%, p=0.024). Mutations in ASXL1 and RUNX1 frequently occurred together: 35% of ASXL1 mut cases also carried a RUNX1 mut as compared to 8% of ASXL1 wild-type cases (p=0.002). All 7 SETBP1 mut cases also carried an ASXL1 mut (p=0.04) Patients with CGHneg (n=65) and CGHpos (n=35) were compared to 41 cases with aberrant karyotype by CBA. While TET2 mut were detected at comparable frequencies in CGHneg and CGHpos patients (80% and 71%) they were significantly less frequent in CMML with aberrant karyotype (54%, p=0.021). On the other hand SETBP1 mut were more frequent in CMML with aberrant karyotype as compared to CGHpos and CGHneg (21%, 7%, 9%, p=0.08). A distinct mutation profile was identified in 9 patients with monosomy 7 who showed ASXL1 mut in 78%, SETBP1 mut in 75%, CBL mut in 33% and TET2 mut in only 22%. In CMML-2 RUNX1 mut were more frequent than in CMML-1 (33% vs 12%. p=0.008). No differences in overall survival (OS) were observed between patients with CGHneg, CGHpos and aberrant karyotype. However, Cox regression analyses revealed a negative impact on OS for ASXL1 mut (relative risk (RR): 2.4, p=0.027), RUNX 1mut (RR: 2.5, p=0.025) and CMML-2 (RR: 2.2, p=0.02). Conclusions: 1. 35% of CMML cases with normal karyotype based on chromosome banding analysis harbor abnormalities detectable by array CGH. 2. Prognosis in CMML is determined by the molecular mutation profile, cytogenetic abnormalities play a minor role. 3. Mutations in ASXL1 and RUNX1 are associated with a negative impact on survival. 4. The poor prognosis described for monosomy 7 seems to be due to a high frequency of ASXL1 und SETBP1 mutations. 5. Inferior outcome in CMML-2 might be due to a higher frequency of RUNX1 mutations. 6. In CMML a molecular work up including screening for mutations in ASXL1 and RUNX1 provides more relevant prognostic information than chromosome banding analysis and/or array CGH. Disclosures Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.
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Dr., Sujithaa Nagarajan, Suma H. Y. Dr., and Latha Chaturvedula Dr. "Assessment of Chromosomal Abnormalities in Couples with Recurrent Pregnancy Loss." International Journal of Research and Review 6, no. 3 (2019): 147–54. https://doi.org/10.5281/zenodo.3987939.
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Previous studies have demonstrated the type of chromosomal abnormalities found among couples with recurrent pregnancy loss. But a majority of the couples show a normal karyotype. The present study was undertaken to inquire the nature of cytogenetic abnormalities by routine karyotyping and c-banding whenever required, among couples with recurrent pregnancy loss and to compare it with fertile couples. Among couples, women with the history of two or more than two spontaneous abortions ≤ 24 weeks of gestation were included and couples with the history of Diabetes mellitus, thyroid disorders and hypertension, etc. were excluded. The lymphocytes were cultured as per the standard protocol and metaphase spreads stained by GTG banding technique. The presence of chromosomal aberrations was analyzed by semi-automated karyotyping software (Ikaros). In the present study, abnormal karyotypes were found in 3 cases. All the controls had a normal karyotype.
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Victor, Ekundare Olugbemi, Fagbuaro Omotayo, and Adeniran Idowu Isaac. "Preliminary cytogenetic study of <em style="mso-bidi-font-style: normal;">Ctenopoma kingsleyae</em> from Esa-Odo water reservoir, Osun State, Nigeria." Journal of Science of the University of Kelaniya 17, no. 1 (2024): 9–13. http://dx.doi.org/10.4038/josuk.v17i1.8100.
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Ctenopoma kingsleyae belongs to the family Anabantidae covers a wide geographic region. It has been morphologically described by a number of authors, yet it is lacking in adequate cytogenetic information, which is a setback to understanding its karyotypic evolution. This study, therefore, describes the karyotype of C. kingsleyae (n = 10) from Esa-Odo, Reservoir, Osun State, Nigeria. Metaphase chromosome spread was obtained from the gills of fish after intraperitoneal injection with 0.05% colchicines. Slides prepared were stained with Giemsa stain, images of metaphase spread were taken digitally and a karyogram was prepared. The study revealed a karyotypic formula of 2n = 48t with uniarmed chromosomes. This study has provided needful information on C. kingsleyae karyotype and will serve as the basis for further study on its evolution, genetic resource management and production.
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Gupta, Vikas, Carol Brooker, Jennifer A. Tooze, et al. "Clinical Relevance of Cytogenetics Abnormalities in Adult Patients with Acquired Aplastic Anaemia." Blood 106, no. 11 (2005): 3748. http://dx.doi.org/10.1182/blood.v106.11.3748.3748.
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Abstract The clinical relevance of cytogenetics abnormalities in aplastic anaemia (AA) patients at time of diagnosis is unclear. We evaluated the clinical course of 81 AA patients with successful cytogenetics at diagnosis and treated with immunosuppressive therapy (IST) from January 1993 to March 2004. A cytogenetic study was considered to be successful if there were a minimum of 15 evaluable metaphases in the absence of a clonal abnormality. Response to IST, survival and later clonal complications in patients with an abnormal karyotype (n=10) was compared to those with a normal karyotype (n=71). The cytogenetic abnormalities at diagnosis consisted of trisomy 6 (n=2), trisomy 8 (n=2), trisomy 15 (n=2), monosomy 7 (n=1), add(10) (n=1), t(3;11) (n=1) and t(4;6) (n=1). Four out of five evaluable patients with a trisomy responded to a first or subsequent course of IST. One patient with monosomy 7 achieved a complete response and later developed haemolytic PNH but with no recurrence of the monosomy 7. None of the patients with a non-numerical karyotypic abnormality responded to IST. No significant differences in 4-year event-free survival (EFS) (54% vs. 30%, p=0.15), overall survival (OS) (84% vs. 80%, p=0.33) or later clonal disorders (PNH, MDS and AML) were observed between the patients with a normal karyotype and those with an abnormal karyotype. Advanced age (≥60 years) was the only independent poor prognostic factor for survival in a multivariate analysis. Among the patients with a normal karyotype (n=71), 6 patients later developed a clonal cytogenetic abnormality with a cumulative risk of 10% at 4 years. These abnormalities were trisomy 15 (n=2), trisomy 6(n=1), monosomy 7 (n=2) and t(13;15) (n=1). None of the three patients who acquired trisomies developed any clinically significant problem, while acquisition of monosomy 7 was associated with a transformation to MDS/AML. Our data show that AA patients with a trisomy cytogenetic clone at diagnosis show a similar response to IST, evolution to later clonal abnormalities and survival, compared to those AA patients with a normal karyotype.
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Rozell, Shaina A., Biruk Mengistu, Naseema Gangat, et al. "The Effect of Number of Metaphases Studied and Abnormal Metaphase Percentage On Cytogenetic Risk Stratification in Primary Myelofibrosis." Blood 120, no. 21 (2012): 1742. http://dx.doi.org/10.1182/blood.v120.21.1742.1742.
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Abstract Abstract 1742 Background Karyotype is one of the most potent and reproducible risk factors for both overall (OS) and leukemia-free (LFS) survival in primary myelofibrosis (PMF) (Blood 2011;118:4595). It is currently not clear if the number of metaphases studied or the abnormal metaphase percentage alters this prognostic impact. Methods: An updated Mayo Clinic database of karyotypically- and DIPSS-plus-annotated patients with PMF was used to identify a consecutive series of patients and their cytogenetic information obtained at time of referral was centrally re-reviewed. Cytogenetic results were interpreted and reported according to the International System for Human Cytogenetic Nomenclature; abnormal karyotype was defined by the presence of at least 2 metaphases with structural abnormalities or monosomy or 3 metaphases with polysomy, regardless of number of metaphases examined. For this particular study, the presence of less than 20 evaluable metaphases did not disqualify patients. “Very high risk” karyotype included monosomal karyotype, inv(3) or i(17q) abnormalities (Blood 2011;118:4595). “unfavorable” karyotype included complex or any sole or two abnormalities that included +8, −7/7q-, -5/5q-, inv(3), i(17q), 12p-, or 11q23 rearrangement (Blood 2011;118:4595). All other cytogenetic abnormalities were considered “favorable” Results: A total of 590 patients (median age 65 years; range 19–89 years) including 424 (72%) males. The DIPSS-plus (JCO 2011;29:392) risk distribution was 40% high, 39% intermediate-2, 12% intermediate-1 and 9% low. Cytogenetic findings included 17 (3%) very high risk, 69 (12%) unfavorable, 165 (28%) favorable and 339 (57%) normal karyotypes. The number of bone marrow metaphases studied to report these cytogenetic findings were ≥20 in 468 (79%) patients, 11 to 19 in 71 (12%) patients and ≤10 in 51 (9%) patients; the proportion of cases studied with ≥20 metaphases were 53% for very high risk, 74% for unfavorable, 83% for favorable and 80% for normal karyotype (p=0.006). Among patients with abnormal karyotype, the abnormal metaphase percentage was ≥75% in 148 (59%) patients, 50 to 74% in 36 (15%) patients, 26 to 49% in 27 (11%) patients and ≤25% in 38 (15%) patients; the proportion of patients with ≥75% was 59% for very high risk, 67% for unfavorable and 56% for favorable karyotypes (p=0.70). As expected, OS was significantly different among very high risk, unfavorable, favorable and normal karyotype patients with respective median survivals of 8, 23, 41 and 57 months (p<0.0001). The number of metaphases studied (p=0.62) or the abnormal metaphase percentage (p=0.12), by themselves, did not affect survival. Similarly, the survival difference among the aforementioned cytogenetic risk groups was equally apparent when patients with ≥20 metaphases studied (n=468; P<0.0001) and those with <20 metaphases studied (n=122; p<0.0001) were separately analyzed. Analysis of patients with very high risk or unfavorable karyotype (n=86) revealed no significant effect of abnormal metaphase percentage on survival (Figure; p=0.80). A similar scenario was demonstrated for patients with favorable karyotype (Figure; p=0.24). Conclusions: Neither the number of metaphases examined nor the abnormal metaphase percentage appear to influence the currently recognized cytogenetic risk stratification in PMF. The current study has implications for both clinical practice and clinical research involving cytogenetic prognostication in hematological malignancies. Disclosures: No relevant conflicts of interest to declare.
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Rigolin, Gian Matteo, Francesca Cibien, Sara Martinelli, et al. "Chromosome Aberrations by Conventional Karyotyping in Chronic Lymphocytic Leukemia Carrying No Aberration by Fluorescence in Situ Hybridization: Correlation with Prognostic Parameters and Clinical Features." Blood 118, no. 21 (2011): 1459. http://dx.doi.org/10.1182/blood.v118.21.1459.1459.
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Abstract Abstract 1459 Background. Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease. Adverse prognostic parameters include stage, CD38 and/or ZAP70 expression, the unmutated configuration of the variable region of the Ig heavy chain gene (IGHV) and the presence of specific chromosome aberrations. Using fluorescence in situ hybridization (FISH) with probes detecting trisomy 12 and deletions at 13q14, 11q22–23/ATM and 17p13/p53, approximately 60–80% of the cases carry an abnormality. Patients without FISH aberrations (“normal” FISH) have a relatively favourable outcome. Improved mitotic stimulation using oligonucleotide (odn) and interleukin-2 (IL-2) can detect karyotype aberrations in chromosome regions not covered by the classical 4-probe panel. This study was designed to assess whether the presence of karyotypic aberrations in CLL patients with “normal” FISH may have a correlation with established clinical and prognostic parameters. Methods. Eighty-four patients with “normal” FISH results referred to our laboratory between 2007 and June 2011 were included in the present report. These patients represent consecutive CLL cases diagnosed and treated, according to the NCI criteria, at 4 GIMEMA CLL group centres between 2006 and 2011. Indications for treatment included advanced stage (Binet C) or disease progression. The Matutes immunophenotypic score was calculated giving 1 point to CD5+, CD23+, CD22weak+, sIg weak+ and FMC7- and only patients with a score ≥3 (i.e. typical CLL) were included. The coexpression of the CD38 and CD19 antigens and ZAP-70 was tested on fresh PB cells with a 20% cut-off for positivity. IGVH genes were amplified from genomic DNA and sequenced according to standard methods and the cut-off of 98% homology to the germline sequence was chosen to discriminate between mutated (<98% homology) and unmutated (≥98% homology) cases, as reported previously. FISH studies were performed using probes for the following regions 13q14, 12q13; 11q22/ATM; 17p13/TP53. Conventional cytogenetic analysis using immunostimulatory CpG-oligonucleotide DSP30 plus IL2 (2μmol/L TibMolBiol / IL2 100U/mL Stem Cell Technologies Inc) was performed on the same samples that had been used for FISH studies. At least 20 metaphases were karyotyped. Stage, time to first treatment (TTFT) were obtained by review of clinical records at each centre. Results. An abnormal karyotype was found in 30/84 cases (35,7%) with “normal” FISH. The chromosome aberrations affected regions not covered by the 4-probe panel used by FISH. Recurring aberrations were: interstitial deletions of 14q and of 7q in 5 and 3 cases, respectively; 14q32 translocations in 2 cases, balanced and unbalanced structural changes in 1 case each. A complex karyotype with 3 or more aberrations was found in 12 patients. The correlations between karyotype and clinicobiological parameters are shown in tables 1 and 2.Table 1:Correlation between karyotype and salient clinicobiologic parametersParameterNormal karyotype (54 cases)Abnormal karyotype (30 cases)p (Fischer's exact test)Binet Stage A/B/C45/9/020/7/30.04Matutes score3/4/54/24/257/6/120.035CD38pos/neg11/4112/180.079ZAP-70 pos/neg16/3115/110.083IGHV Unmutated/ Mutated4/208/80.037Table 2:Factors affectingTTFT in univariate snalysisNumber of casesMedian TTFT months (se)pKaryotype Normal Abnormal50 34Not reached at 54 months 18 months (6.7)<0.0001Binet stage AB-C65 19Not reached at 54 months 12 months (2.1)0.0006IGHV Unmutated Mutated12 2815 months (2.5) Not reached at 54 months0.0007 At multivariate analysis, the following factors were independently predictive of shorter TTFT: advanced disease Binet stage (p=0.049, Hazard Ratio 2.39 [se: 1.06]), and abnormal karyotype (p<0.001, Hazard ratio 6.8 [se: 3.28]). IGHV mutations were not included in the TTFT analysis, because the data were not available for all patients. Conclusions. Conventional karyotyping using odn + IL-2 as mitogens is an effective method for the detection of chromosome aberrations in approximately 1/3 of patients with “normal” FISH on a conventional 4-probe panel. Recurrent aberrations include interstitial deletions at 14q and 7q. The current data show that, in CLL patients with “normal” FISH, conventional cytogenetic analysis using odn + IL-2 identifies a subset of cases with adverse clinical and prognostic features. Disclosures: Rizzotto: CELGENE CORPORATION: Research Funding. Cuneo:Roche: Consultancy, Speakers Bureau.
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Smadja, Nicole Véronique, Christian Bastard, Christophe Brigaudeau, Dominique Leroux, and Christophe Fruchart. "Hypodiploidy is a major prognostic factor in multiple myeloma." Blood 98, no. 7 (2001): 2229–38. http://dx.doi.org/10.1182/blood.v98.7.2229.
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Conventional karyotypes performed before any treatment in 208 patients with multiple myeloma were reviewed by the Groupe Français de Cytogénétique Hématologique. A total of 138 patients displayed complex chromosomal abnormalities (CCAs). According to the chromosome number pattern, a first group of 75 patients had a hyperdiploid karyotype. A second group of 63 patients referred to as the hypodiploid group had either pseudodiploid, hypodiploid, or near-tetraploid karyotypes. Of 159 treated patients available for survival analysis, 116 had an abnormal karyotype. The comparison of overall survival (OS) between hyperdiploid and hypodiploid patients showed a highly significant difference (median OS 33.8 vs 12.6 months, respectively, P &lt; .001). The presence of 14q32 rearrangements (36 of 116 patients) worsened the prognosis (median OS 17.6 vs 29.9 months, P &lt; .02). The presence of chromosome 13q abnormalities (13qA, 63 patients) did not modify OS in CCA patients (median OS 20.6 vs 27.8 months,P &lt; .59). However, taking into account the whole series including normal karyotypes, 13qA (63 of 159 patients) had a significant impact on OS (median 20.6 vs 37.1 months,P &lt; .04). In the same way, the presence of a hypodiploid karyotype (52 of 159 patients) had a strong prognostic value (OS 12.8 vs 44.5 months, P &lt; .000 01). A multivariate analysis including stage, β2-microglobulin, bone marrow plasmocytosis, treatment type, 13qA, and hyperdiploidy and hypodiploidy showed that a hypodiploid karyotype was the first independent factor for OS (P &lt; .001), followed by treatment approach. These results confirm that the chromosome number pattern of malignant plasma cells is a very powerful prognostic factor in newly diagnosed multiple myeloma patients.
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Hirpara, Ankit, Mathew Bloomfield, and Peter Duesberg. "Speciation Theory of Carcinogenesis Explains Karyotypic Individuality and Long Latencies of Cancers." Genes 9, no. 8 (2018): 402. http://dx.doi.org/10.3390/genes9080402.
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It has been known for over 100 years that cancers have individual karyotypes and arise only years to decades after initiating carcinogens. However, there is still no coherent theory to explain these definitive characteristics of cancer. The prevailing mutation theory holds that cancers are late because the primary cell must accumulate 3–8 causative mutations to become carcinogenic and that mutations, which induce chromosomal instability (CIN), generate the individual karyotypes of cancers. However, since there is still no proven set of mutations that transforms a normal to a cancer cell, we have recently advanced the theory that carcinogenesis is a form of speciation. This theory predicts carcinogens initiate cancer by inducing aneuploidy, which automatically unbalances thousands of genes and thus catalyzes chain-reactions of progressive aneuploidizations. Over time, these aneuploidizations have two endpoints, either non-viable karyotypes or very rarely karyotypes of new autonomous and immortal cancers. Cancer karyotypes are immortalized despite destabilizing congenital aneuploidy by clonal selections for autonomy—similar to those of conventional species. This theory predicts that the very low probability of converting the karyotype of a normal cell to that of a new autonomous cancer species by random aneuploidizations is the reason for the karyotypic individuality of new cancers and for the long latencies from carcinogens to cancers. In testing this theory, we observed: (1) Addition of mutagenic and non-mutagenic carcinogens to normal human and rat cells generated progressive aneuploidizations months before neoplastic transformation. (2) Sub-cloning of a neoplastic rat clone revealed heritable individual karyotypes, rather than the non-heritable karyotypes predicted by the CIN theory. (3) Analyses of neoplastic and preneoplastic karyotypes unexpectedly identified karyotypes with sets of 3–11 new marker chromosomes without detectable intermediates, consistent with single-step origins. We conclude that the speciation theory explains logically the long latencies from carcinogen exposure and the individuality of cancers. In addition, the theory supports the single-step origins of cancers, because karyotypic autonomy is all-or-nothing. Accordingly, we propose that preneoplastic aneuploidy and clonal neoplastic karyotypes provide more reliable therapeutic indications than current analyses of thousands of mutations.
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Haferlach, Claudia, Cristina Mecucci, Susanne Schnittger, et al. "AML with mutated NPM1 carrying a normal or aberrant karyotype show overlapping biologic, pathologic, immunophenotypic, and prognostic features." Blood 114, no. 14 (2009): 3024–32. http://dx.doi.org/10.1182/blood-2009-01-197871.
Full textAbstract:
Acute myeloid leukemia (AML) with mutated NPM1 usually carries normal karyotype (NK), but it may harbor chromosomal aberrations whose significance remains unclear. We addressed this question in 631 AML patients with mutated/cytoplasmic NPM1. An abnormal karyotype (AK) was present in 93 of 631 cases (14.7%), the most frequent abnormalities being +8, +4, −Y, del(9q), +21. Chromosome aberrations in NPM1-mutated AML were similar to, but occurred less frequently than additional chromosome changes found in other AML with recurrent cytogenetic abnormalities according to WHO classification. Four of the 31 NPM1-mutated AML patients karyotyped at different time points had NK at diagnosis but AK at relapse: del(9q) (n = 2), t(2;11) (n = 1), inv(12) (n = 1). NPM1-mutated AML with NK or AK showed overlapping morphologic, immunophenotypic (CD34 negativity), and gene expression profile (down-regulation of CD34 and up-regulation of HOX genes). No difference in survival was observed among NPM1-mutated AML patients independently of whether they carried a NK or an AK, the NPM1-mutated/FLT3-ITD negative cases showing the better prognosis. Findings in our patients point to chromosomal aberrations as secondary events, reinforce the concept that NPM1 mutation is a founder genetic lesion, and indicate that NPM1-mutated AML should be clinically handled as one entity, irrespective of the karyotype.
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Haase, Detlef, Ulrich Germing, Julie Schanz, et al. "New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients." Blood 110, no. 13 (2007): 4385–95. http://dx.doi.org/10.1182/blood-2007-03-082404.
Full textAbstract:
We have generated a large, unique database that includes morphologic, clinical, cytogenetic, and follow-up data from 2124 patients with myelodysplastic syndromes (MDSs) at 4 institutions in Austria and 4 in Germany. Cytogenetic analyses were successfully performed in 2072 (97.6%) patients, revealing clonal abnormalities in 1084 (52.3%) patients. Numeric and structural chromosomal abnormalities were documented for each patient and subdivided further according to the number of additional abnormalities. Thus, 684 different cytogenetic categories were identified. The impact of the karyotype on the natural course of the disease was studied in 1286 patients treated with supportive care only. Median survival was 53.4 months for patients with normal karyotypes (n = 612) and 8.7 months for those with complex anomalies (n = 166). A total of 13 rare abnormalities were identified with good (+1/+1q, t(1q), t(7q), del(9q), del(12p), chromosome 15 anomalies, t(17q), monosomy 21, trisomy 21, and −X), intermediate (del(11q), chromosome 19 anomalies), or poor (t(5q)) prognostic impact, respectively. The prognostic relevance of additional abnormalities varied considerably depending on the chromosomes affected. For all World Health Organization (WHO) and French-American-British (FAB) classification system subtypes, the karyotype provided additional prognostic information. Our analyses offer new insights into the prognostic significance of rare chromosomal abnormalities and specific karyotypic combinations in MDS.