Loss of Heterozygosity and Microsatellite Instability at theMLL Locus Are Common in Childhood Acute Leukemia, but not in Infant Acute Leukemia

Blood ◽  
1999 ◽  
Vol 94 (1) ◽  
pp. 283-290 ◽  
Author(s):  
Julie C. Webb ◽  
Irina Golovleva ◽  
Alan H. Simpkins ◽  
Helena Kempski ◽  
Brian Reeves ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Microsatellite Instability ◽  
Loss Of Heterozygosity ◽  
Chromosomal Abnormalities ◽  
Polymerase Chain Reaction Analysis ◽  
Polymorphic Markers ◽  
Mll Gene ◽  
Group A ◽  
Group B ◽  
Childhood Acute Leukemia

Rearrangements involving the MLL gene at chromosome 11q23 are associated with leukemia and are present in up to 70% of infant leukemias. Loss of heterozygosity (LOH) has been shown for anonymous polymorphic markers at 11q23 in adult leukemias. To study LOH at theMLL locus, we have identified two new polymorphic microsatellite markers: a GAA repeat (mllGAAn) in intron 6 of theMLL gene and a GA (mllGAn) repeat in the 5′ flanking region of the gene, approximately 2 kb upstream of the translation initiation codon. The heterozygosity index of mllGAAn is 0.54, which renders it useful for analyzing LOH. We screened two groups of leukemia patients to study LOH at the mllGAAn marker. Group A (n = 18) was selected on the basis of presentation before 18 months. Cytogenetic and reverse transcription-polymerase chain reaction analysis showed that 9 of these 18 children had translocations involving MLL. No LOH was observed. Group B (n = 36) were randomly selected children who had presented with leukemia between 1993 and 1994. Cytogenetic analysis of this group showed a variety of different chromosomal abnormalities. LOH was shown in 9 of 20 individuals (45%) who were informative. Microsatellite instability (MSI) was demonstrated in 1 of 18 individuals in group A and 5 of 36 individuals (13.9%) in group B. MSI and LOH were observed simultaneously in three individuals. Loss of an allele was confirmed in one individual by fluorescence in situ hybridization. Individuals with MSI or LOH at mllGAAn were selected for analysis at anonymous polymorphic markers D11S1364 and D11S1356, which flank the MLL gene. No LOH or MSI was observed at these markers in those individuals who were informative. These results show that LOH at the MLL gene locus is a common event during leukemogenesis. Furthermore, the presence of MSI at this locus suggests that the region is a hotspot for genetic instability.

scholarly journals Can Co-enzyme Q10 improve the chances of conception after the age of 35?

2017 ◽  
Vol 6 (7) ◽  
pp. 2729
Author(s):  
Eman Ali Abd El Fattah
Keyword(s):  
Chromosomal Abnormalities ◽  
Normal Pregnancy ◽  
Metabolic Energy ◽  
Secondary Outcome ◽  
Slowing Down ◽  
Ovulation Stimulation ◽  
Before And After ◽  
History Of ◽  
Group A ◽  
Group B

Background: ovarian follicular quality diminishes with age, Free radicals and oxidative stress begin to accumulate in cells, aging or slowing down the metabolic energy production centers in the cell- the mitochondria. When the mitochondria cannot generate a certain amount of energy, it slows growth and proper development of the follicle making it more prone to DNA damage, including chromosomal abnormalities resulting in poor fertilization patterns, and early miscarriage. Co-enzyme Q10 (CoQ10) is a major cellular antioxidant. its tissue levels gradually decrease with age. We attempt to evaluate its protective effect on ROS-induced ovarian damage, which is one of the most important and widely accepted patho- mechanisms underlying cell ageing.Methods: 40 Participants   from El Shatby hospital infertility clinic 35 to 38 years old, with history of bad response to ovulation stimulation, were divided into two equal groups (group A given (CoQ10) 3mg|kg body weight for three cycles prior to stimulation Serum anti- mullarian hormone level was measured before and after CoQ10 administration, group B= twenty cases as control). Participants were given gonadotrophins (150 IU to 375 IU). Follicular growth was monitored by trans- vaginal ultra- sonography and serum estradiol level (E2). Ovulation trigger was achieved using 10,000 IU of human chorionic gonadotrophin.Results: The primary outcome was occurrence of normal pregnancy; secondary outcome was good response to stimulation (at least one mature follicle 18-22mm).Conclusions: CoQ10 has no significant effect on response to ovulation stimulation or on pregnancy rates.

The Histone Deacetylase Inhibitor Depsipeptide Has Differential Activity in Specific Cytogenetic Subsets of Acute Myeloid Leukemia (AML).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 264-264 ◽  
Author(s):  
Olatoyosi M. Odenike ◽  
Serhan Alkan ◽  
Dorie Sher ◽  
John E. Godwin ◽  
Dezheng Huo ◽  
...  
Keyword(s):  
Histone Deacetylase Inhibitor ◽  
Histone Deacetylases ◽  
Target Genes ◽  
Mononuclear Cells ◽  
Chromosomal Abnormalities ◽  
Dna Hypermethylation ◽  
Deacetylase Inhibitor ◽  
Group A ◽  
Group B ◽  
Bone Marrow Blasts

Abstract Recruitment of histone deacetylases and DNA hypermethylation of promoter regions of specific genes are two mechanisms of transcriptional repression and gene silencing which have been linked, and are implicated in differentiation block in AML. We hypothesized that the histone deacetylase inhibitor (HDI) depsipeptide could result in transcriptional de-repression, upregulation of specific target genes and differentiation of the leukemic clone in AML. Eighteen patients (pts), median age 60 years (range 25–77) with relapsed or refractory AML were enrolled on a multicenter Phase II study of depsipeptide in AML. Patients were stratified into 2 groups on study entry: Group A (n=14) included patients without specific chromosomal abnormalities known to recruit histone deacetylases. Group B (n=4) included patients with chromosomal aberrations such as the t(8;21), inv 16 and t(15;17) known to recruit histone deacetylases. Depsipeptide was administered intravenously at a dose of 18mg/m2/d on days 1, 8 and 15 of a 28 day cycle. Peripheral blood mononuclear cells were obtained prior to (hour 0), and after 4 (hr 4) and 24 hrs (hr 24), on days 1 and 8 of the first cycle of therapy for evaluation of histone acetylation by flow cytometry, and gene re-expression by REAL-time RT-PCR. Target genes of interest include MDR1, a target of HDI mediated upregulation, and p15INK4B (p15), a target of DNA hypermethylation in AML. MDR1 and p15 copy numbers are expressed as a normalized quotient of MDR1 and p15, respectively, to the housekeeping gene ABL. The drug has been well tolerated. The most common adverse effects noted included grade 1/2 nausea, vomiting and fatigue. No objective evidence of response (CR or PR) or other evidence of antileukemic activity has been seen in group A. In contrast, 2 of 4 pts (50%) in Group B, have had a disappearance of bone marrow blasts (blast percentage < 5%) in the setting of a normocellular marrow, with concomitant recovery of near-normal hematopoiesis following 1 and 2 cycles of therapy respectively. This anti-leukemic effect was short-lived, with both pts developing an increase in bone marrow blasts within 30 days of the initial response. Both of these patients also had translocations involving the AML1 gene {1 had t(8;21) and the other had a novel translocation t(4;21)}. Interestingly both of these responding pts and one other pt (75%) in cohort B demonstrated an increase in H3 acetylation at 4 and/or 24 hrs, in contrast to 4 of 14 pts (28%) in cohort A. There was an overall mean increase of 41% in MDR1 expression at hr 4 on days 1 and 8 (p=0.04). p15 expression was also upregulated at hr 4 on days 1 and 8 (91% mean increase, p=0.01). We conclude that the HDI, depsipeptide, may have anti-leukemic activity in specific cytogenetic subsets of AML known to recruit histone deacetylases, and this is associated with a concomitant increase in histone acetylation. In addition, upregulation of specific target genes occurred in patient derived mononuclear cells, following depsipeptide treatment. The study remains open to accrual for pts with specific chromosomal abnormalities known to recruit histone deacetylases.

Identification of Numerical Chromosomal Changes Detected by Interphase Fluorescence In Situ Hybridization in High-Grade Prostate Intraepithelial Neoplasia as a Predictor of Carcinoma

2002 ◽  
Vol 126 (2) ◽  
pp. 165-169
Author(s):  
Jaudah Al-Maghrabi ◽  
Lada Vorobyova ◽  
A. Toi ◽  
William Chapman ◽  
Maria Zielenska ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
Chromosomal Abnormalities ◽  
Intraepithelial Neoplasia ◽  
High Grade ◽  
Prostate Intraepithelial Neoplasia ◽  
Group A ◽  
Chromosomal Changes ◽  
Group B

Abstract Context.—High-grade prostate intraepithelial neoplasia (HPIN) is the most likely precursor of prostate cancer. The condition of many patients with a diagnosis of HPIN in prostate needle core biopsy could, if left untreated, progress to invasive cancer. Currently there is no available clinical, immunohistochemical, or morphologic criteria that are predictive of this progression. Objective.—To determine whether chromosomal instability in these precursor lesions could increase their predictive value for cancer detection. Design.—Dual-color interphase fluorescence in situ hybridization analysis was performed on archived prostate needle core biopsies from 54 patients with initial diagnosis of isolated HPIN and follow-up of 3 years or more. We used commercially available centromere probes for chromosomes 4, 7, 8, and 10. We had interpretable results in 44 patients as follows: (1) group A: 24 HPIN patients with persistent HPIN and/or benign lesions in the follow-up biopsies, and (2) group B: 20 HPIN patients with progression to prostate carcinoma. Results.—Twenty-five percent of the patients in group B displayed numeric chromosomal aberrations. Only 8.3% of the patients from group A had chromosomal abnormalities (P = .1). The observed overall chromosomal changes in HPIN were higher than those in normal or hyperplastic epithelium, with a statistically significant difference (P < .05). All aberrations were detected in the form of chromosomal gain. Overall, the commonest aberration was gain of chromosome 8, followed by gains of chromosomes 7 and 10. Conclusion.—These results indicated that although no single numeric chromosomal abnormality could be assigned as a predictor of HPIN progression to carcinoma, the overall level of numeric chromosomal abnormalities shows a trend of elevation in HPIN patients whose condition subsequently progressed to carcinoma.

Survival Benefit with Decitabine Compared to Historical Experience with Intensive Chemotherapy in Patients with Higher Risk Myelodysplastic Syndrome (MDS).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2652-2652
Author(s):  
Elias Jabbour ◽  
Hagop M. Kantarjian ◽  
Jorge Cortes ◽  
William G. Wierda ◽  
Alessandra Ferrajoli ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Survival Benefit ◽  
Chromosomal Abnormalities ◽  
Independent Effect ◽  
Poor Performance Status ◽  
Study Group ◽  
Intensive Chemotherapy ◽  
Historical Experience ◽  
Group A ◽  
Group B

Abstract Background Decitabine is a hypomethylating agent, approved by the FDA for treating MDS. Intensive chemotherapy is one treatment option in higher risk MDS. The comparative efficacy of these two strategies, decitabine vs. intensive chemotherapy, has not been evaluated. Study Aims Compare the results of decitabine in MDS with contemporary historical experience with intensive chemotherapy (as used in AML) in patients with higher risk MDS. Study Group and Treatment The study group treated with decitabine included 115 patients with higher risk MDS treated on our decitabine frontline study. (Kantarjian, Blood 2006; First Edition Online). The contemporary historical experience included two cohorts: Group A: 115 patients receiving intensive chemotherapy from 1995–2005 and matched for age, IPSS and cytogenetics; and Group B: All 376 patients treated with intensive chemotherapy from 1995–2005 with similar entry criteria as the decitabine study. Patients received decitabine 20 mg/m2 IV/D x 5 every four weeks. Response was evaluated by the modified IWG criteria (Cheson, Blood 108:419, 2006) In comparing decitabine to Group B, a multivariate analysis was conducted to assess the independent effect of decitabine vs. intensive chemotherapy. Results 115 patients were treated with decitabine; median age 64 years (range 37–89 years). IPSS risk groups: intermediate-1 17%, intermediate-2 30%, high 15%, not assessable 39%. Decitabine was given for a median of 7 courses (range 1 to 23); number of decitabine courses 3 or more in 81/89 patients (91%) followed on study for at least 6 months. Hemoglobin <10 g/dL in 76%; thrombocytopenia <100 x 109/L in 72%; ANC <1.0 x 109/L in 47%; chromosomal abnormalities in 63%; prior therapy for MDS in 54%; marrow blast 5% or more in 79%. Overall, 80 patients (70%) achieved IWG response: CR 40 (35%), PR 2 (2%), marrow CR +/− other hematologic improvements (HI) 26 (23%), other HI 12 (10%). Median remission duration was 20 months; median survival was 21 months. The CR rates by AML criteria (Cheson JCO21:4642, 2003) were 43% with decitabine and 46% with intensive chemotherapy in Group A, and 52% with intensive chemotherapy in Group B. Mortality at 6 weeks was 3% with decitabine vs. 12% with intensive chemotherapy (p=0.002); the 3-month mortality was 7% with decitabine vs. 22% with intensive chemotherapy. The survival was better with decitabine versus intensive chemotherapy in Group A (median 22 month vs. 11 month; estimated 2-year survival rate 47% vs. 25%, p<0.001). A multivariate analysis for survival in all 491 patients receiving decitabine or intensive chemotherapy (Group B) identified the following to be independent adverse factors for survival: abnormal cytogenetics, older age, anemia, thrombocytopenia, and poor performance status. Entering decitabine vs. intensive chemotherapy after accounting for the effect of other prognostic factors selected decitabine as an independent favorable prognostic factor for survival (pvalue 0.002; hazard risk 0.76). Conclusions Compared with intensive chemotherapy decitabine is associated with a survival benefit in higher risk MDS.

scholarly journals Risk stratification–directed donor lymphocyte infusion could reduce relapse of standard-risk acute leukemia patients after allogeneic hematopoietic stem cell transplantation

Blood ◽  
2012 ◽  
Vol 119 (14) ◽  
pp. 3256-3262 ◽  
Author(s):  
Chen-Hua Yan ◽  
Dai-Hong Liu ◽  
Kai-Yan Liu ◽  
Lan-Ping Xu ◽  
Yan-Rong Liu ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Acute Leukemia ◽  
Low Dose ◽  
Disease Free Survival ◽  
Donor Lymphocyte Infusion ◽  
Hematopoietic Stem ◽  
Group A ◽  
Group B ◽  
The Impact ◽  
Standard Risk

Abstract We studied the impact of risk stratification–directed interventions for minimal residual disease (MRD) on relapse and disease-free survival (DFS) prospectively in 814 subjects with standard-risk acute leukemia receiving allotransplantation in first or second complete remission. A total of 709 subjects were MRD− after transplantation (Group A); 105 subjects were MRD+, 49 received low-dose IL-2 (Group B), and 56 received modified donor lymphocyte infusion (DLI) with or without low-dose IL-2 (Group C). Posttransplantation immune suppression for GVHD was also modified based on MRD state. The cumulative risk of relapse was significantly less and DFS was significantly better in subjects in Group C than in subjects in Group B (P = .001 and P = .002, respectively), but was not different from subjects in Group A (P = .269 and P = .688, respectively). Multivariate analyses confirmed that MRD state and modified DLI were significantly correlated with relapse (P = .000, odds ratio [OR] = 0.255 and P = .000, OR = 0.269) and DFS (P = .001, OR = 0.511 and P = .006, OR = 0.436, respectively). These data suggest that risk stratification–directed interventions with modified DLI in patients with standard-risk acute leukemia who are MRD+ after transplantation may improve transplantation outcomes.

Should Hematopoietic Stem Cell Transplantation in First Complete Remission Be Restricted to High-Risk Patients in Childhood Acute Myeloid Leukemia?.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1094-1094
Author(s):  
Hideki Muramatsu ◽  
Nobuhiro Nishio ◽  
Asahito Hama ◽  
Hiroshi Yagasaki ◽  
Yoshiyuki Takahashi ◽  
...  
Keyword(s):  
High Risk ◽  
Myeloid Leukemia ◽  
Chromosomal Abnormalities ◽  
Low Risk ◽  
Hematopoietic Stem ◽  
High Risk Patients ◽  
Risk Patients ◽  
Group A ◽  
Group B ◽  
First Complete Remission

Abstract Hematopoietic stem cell transplantation (HSCT) has been used as an effective consolidation therapy for children with acute myeloid leukemia (AML) in first complete remission (CR). Although it is effective in relapse prevention, often it causes severe late sequelae, such as short stature and infertility. There is a recent trend to restrict the use of HSCT in first CR for high-risk patients. However, there is no study comparing which strategy is better, risk-adapted or general recommendation for HSCT in AML children in first CR. In our institutes, all such children in first CR were recommended either allogeneic or autologous HSCT until 1997. After 1998, patients were classified into three risk-groups. Low-risk patients (t(8;21) and inv(16)) were not recommended to undergo HSCT. High-risk patients (−7, 5q-, Ph1, t(16;21) and remission failure) were recommended to undergo HSCT. Intermediate-risk (other karyotypes) patients received HSCT in first CR if a suitable donor was available. In this study, we retrospectively compared the prognosis of 66 patients who were diagnosed with de novo AML between 1991 and 1997 (group A; n=37) and between 1998 and 2003 (group B; n=29). AML with Down syndrome and AML-M3 were excluded. The median (range) age was five (0–15) years. FAB classifications were M0 (n = 1), M1 (n = 10), M2 (n = 22), M4 (n = 6), M4E (n = 5), M5 (n = 14), M6 (n = 0), and M7 (n = 8). Chromosome analysis data were t(8;21) (n = 18), inv(16) (n = 4), 11q23 (n = 10), other abnormalities (n = 14), normal karyotype (n = 14), and unknown (n = 6). Induction chemotherapy comprised VP-16, cytarabine, and mitoxantrone. Sixty-three of 66 patients (95.5%) achieved CR. HSCT in first CR was done in 24 patients (64.9%) in group A and seven patients (24.1%) in group B (p = 0.0044). Age, sex, WBC count at diagnosis, FAB classification and chromosomal abnormalities did not differ between the two groups. Fourteen (five in group A and nine in group B) patients relapsed. Six (three in group A and three in group B) of them were salvaged by HSCT. Both 5-year event-free survival (EFS) and overall survival (OS) were statistically higher in group A than in group B (5-year EFS: 83.8 ± 6.1% versus 62.1 ± 9.0%, p = 0.0404; 5-year OS: 91.6 ± 4.7% versus 71.6 ± 8.5%, p = 0.0364). Although intensified chemotherapy without HSCT for low-risk AML patients is desirable to avoid the late complications of HSCT, our analysis showed that the introduction of risk-stratified treatment strategy significantly worsened the chances of EFS and OS. Our risk stratification based on chromosomal abnormalities only may be insufficient to identify low-risk AML children. Development of more sophisticated risk classification, including molecular markers, may be required to identify true low-risk patients who should avoid HSCT in first CR.

Gemtuzumab Ozogamicin In Refractory Childhood Acute Myeloid Leukemia.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1075-1075 ◽  
Author(s):  
Dirk Reinhardt ◽  
Christian M. Zwaan ◽  
Annette Sander ◽  
Christine Neuhoff ◽  
Gertjan J. Kaspers ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Children And Adolescents ◽  
Fatal Outcome ◽  
Gemtuzumab Ozogamicin ◽  
Cell Transplant ◽  
Group A ◽  
Childhood Aml ◽  
Group B ◽  
Refractory Aml

Abstract Abstract 1075 Introduction: Gemtuzumab ozogamicin, a CD33 linked calicheamicin, has been used in children with refractory AML since some years. In a phase I/II study, the treatment feasibility and moderate toxicity of the compound have been demonstrated (Zwaan et al. British Journal of Haematology, 2010). Here we report the treatment results of 62 children and adolescents with refractory AML after at least two intensive regimens (n=62; male n=40; female n=22) and/or allogeneic stem cell transplant (n=9). Twenty-eight children received GO-monotherapy (7.5mg/m2 day 1 and day 15; group A)*, in 34 children GO 3mg/m2 was combined with cytarabine (500mg/m2/d 96h continuous infusion; group B). The median age at initial diagnosis was 10 years (range 0.2 to 21 years). Nine children had secondary AML following a previous malignant disease and in 4 cases an acute leukemia of ambigious lineage (ALAL) had been diagnosed. The morphological subtypes were AML FAB M0 n=4; M1/M2 n=17 M3 n =1; M4/M5 n=25; M4Eo n=1; M6/M7 n=9, undifferentiated (AUL)/acute leukemia of ambiguous lineage (ALAL) n=5. In cytogenetics, most patients had a normal karyotype (n=16; including 7 with FLT3-ITD) followed by MLL-rearrangements (n=14), numerical aberrations (n=7; including FLT3-ITD n=2), others aberrations (n=10; FLT3-ITD n=1), complex karyotype (n=3) and BCR/ABL positive AML (n=1). Favorable translocations [t(8;21), inv 16, t(15;17)] were diagnosed in 4 patients. In 7 patients no cytogenetic results were available. Results: Five children suffered acute anaphylactic reaction during or short after infusion (CTC grade III n=3, grade IV n=2). Severe, long lasting myelosuppression has been observed in almost all patients. While the frequency of severe infection during myelosuppression was moderate, side effects such as mucositis have rarely been reported. A vena occlusive-disease (VOD)-like syndrome was observed in 5 children after alloSCT, in two cases with fatal outcome. An overall response (CR, CRp, PR) has been documented in 32 children (group A n=10/28, 36%; group B n=22/34, 65%). A higher response rate has been observed in children with AML FAB M1/2 with auer rods (n=18 response n=12, 67%) and AML with favorable aberrations (n=3/4). Six out of 10 children with FLT3-ITD positive AML responded to GO whereas patients with AUL/ALAL (n=9; response n=1, 11%) and AML FAB M6/7 (n=10; response n=3, 30%) showed a poorer response. Thirty-five patients received allogeneic SCT following GO treatment, 30 of the responders and 5 patients without GO response. In total 13 children are alive. Out of the responders 11 children or adolescents are still in complete remission (follow-up 2.7 years, 0.5 to 8.2 yrs.). Again children with AML FAB M1/2 and/or favorable cytogenetics had the best prognosis (7 /19 children alive, 37%). By contrast, none of the children with AML FAB M6/7, AUL or ALAL survived. Out of the 30 patients who did not respond to GO, following alloSCT 2 children are alive, however, the follow-up of 0.5 years (0.3 to 0.9 yrs) is very short. In conclusion, in this particular poor group of heavily pretreated children and adolescents with multiple relapsed, refractory AML, GO seems to improve the prognosis in some children and enables further treatment e.g. alloSCT. Based on the specific needs of children it is of importance that clinical trials continue in childhood AML to identify the appropriate patient group and schedule of GO combined with chemotherapy. * Seven patients out of this group were eligible for the International AML 2001/02 study “Salvage of refractory childhood AML with Mylotarg, Zwaan et al. BJH, 2010. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Chromosomal Abnormality in Fetuses with Isolated Antenatal Hydronephrosis: Update for Prenatal Diagnosis and Genetic Counseling

2020 ◽  
Author(s):  
Xiaoyan Zhou ◽  
Yan Wang ◽  
Lulu Meng ◽  
Jianxin Tan ◽  
Fengchang Qiao ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
Chromosomal Abnormalities ◽  
Genetic Diagnosis ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Detection Rates ◽  
Antenatal Hydronephrosis ◽  
Prenatal Genetic Diagnosis ◽  
Group A ◽  
Group B

Abstract Background: The prenatal finding of fetuses with antenatal hydronephrosis (ANH) gives a significant dilemma for the clinicians. Which patients require invasive prenatal diagnosis? Though previous literatures have recommended the use of chromosomal microarray analysis (CMA)for fetuses with CAKUT, the cutoff value for CMA have no current consensus on fetuses with ANH. In this article, we aimed to detect chromosomal abnormalities in fetuses with isolated severe ANH (anterior-posterior renal pelvic diameter (APRPD) ≥ 10mm) by CMA, summarized the literatures and proposed recommendations for the prenatal genetic diagnosis according to APRPD.Methods: Fetuses (n=84) with isolated severe ANH (APRPD ≥ 10mm) were evaluated by CMA. According to APRPD measurements at second trimester, we classified the cases into two groups: (1) Group A: cases with APRPD of 10–15 mm(N=57); (2) Group B: cases with APRPD ≥ 15 mm(N=27).The prenatal and postnatal outcomes were assessed by ultrasonic examination and telephone follow-up.Results: Overall, one case with 18 trisomy was identified. Clinically significant copy number variants (pathogenic or likely pathogenic CNVs) were identified in 11.9% (10/84) cases, including 3.5% (3/84) of pathogenic CNVs. The detection rates were 5.2% (3/57), 25.9% (7/27) for group A and group B, respectively. There was statistically significant differences in the frequency of clinic significant CNVs in the two groups (p＜0.05). Conclusion: CMA is valuable in prenatal genetic diagnosis of fetuses with severe ANH（APRPD ≥ 10mm）, regardless of whether other ultrasonic abnormalities were observed. This cohort should be followed up during the pregnancy.

Age-Associated Difference in Gene Expression of Pediatric Myelo-Monocytic and MLL-Rearranged AML.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3164-3164
Author(s):  
Aoi Jo ◽  
Ichiro Tsukimoto ◽  
Eiichi Ishii ◽  
Norio Asou ◽  
Takashi Igarashi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Signature ◽  
Genetic Alterations ◽  
Myelogenous Leukemia ◽  
Striking Difference ◽  
Gene Rearrangements ◽  
Large Set ◽  
Mll Gene ◽  
Group A ◽  
Group B

Abstract Acute myelogenous leukemia (AML) is a heterogeneous disease with a variety of genetic alterations including the MLL gene rearrangement. Microarray-based gene expression profiling has been applied to diagnose AML patients and to explore their underlying molecular pathology. In this study, we focused on pediatric myelo-monocytic leukemia and analyzed 40 pediatric AML patients with FAB M4 and M5 subtypes [excluding inv(16) and t(8;21) cases] using Affymetrix HG-U133plus2.0 microarray. Patients consisted of 14 infants (<1 year old) and 26 children (>=1 year old), and 23 patients possessed MLL gene rearrangements. Unsupervised analysis revealed that 10 of the 14 infants display very distinct gene expression and large set of genes were over-expressed among the infants. Among these highly expressed genes, ZFHX1B, ARHGAP26 (GRAF), and FOXO3A (AF6) were included. With the use of these distinctively expressed genes, we were able to divide the 40 pediatric patients into three subgroups: 10 infants with very high expression as Group A, 2 infants and 10 children with medium expression as Group B, and 2 infants and 16 children with low expression as Group C. The average age of Group A was 0.3 year old, Group B was 3.1 years old, and Group C was 6.6 years old. All subgroups included MLL gene rearrangements as well as normal and other complex karyotypes. FAB subtypes were equally distributed among each subgroup. The comparison of the outcomes among the subgroups showed a striking difference where Group C presented extremely poor outcome (3-year EFS 28%). Genes specifically over-expressed among Group C included poor prognostic factors such as WT1 and KIT. In addition, we found that gene expression signature of MLL rearrangement was different among the subgroups as well. For example, EVI1, SOCS2 and MEF2C were up-regulated in MLL-rearranged AML of Group C but not in the others. HOXA9 and HOXA10 were regulated independently of MLL-rearrangement in pediatric myelo-monocytic AML. These results suggest that age is an important factor contributing to the biology of pediatric myelo-monocytic AML and sub-grouping procedures can provide proper stratification so that the poor prognostic subgroup can be distinguished to receive suitable therapy.

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