Concurrent copy number variations on chromosome 8 and 22 combined with mutation at FGA locus revealed in a parentage testing case

2015 ◽  
Vol 19 ◽  
pp. 81-85 ◽  
Author(s):  
Yaran Yang ◽  
He Ren ◽  
Wei Chen ◽  
Bingbing Xie ◽  
Yan Wang ◽  
...  
2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 495-495 ◽  
Author(s):  
Armin Soave ◽  
Heidi Schwarzenbach ◽  
Malte Vetterlein ◽  
Jessica Rührup ◽  
Oliver Engel ◽  
...  

495 Background: To investigate detection and oncological impact of circulating tumor cells (CTC) in bladder cancer patients with presence of copy number variations (CNV) of circulating cell-free DNA (cfDNA) treated with radical cystectomy (RC). Methods: Secondary analysis of 85 bladder cancer patients, who were prospectively enrolled and treated with RC at our institution between 2011 and 2014. Blood samples were obtained preoperatively. For CTC analysis, blood was analyzed with the CellSearch system (Janssen). cfDNA was extracted from serum using the PME DNA Extraction kit (Analytik Jena). Multiplex ligation-dependent probe amplification (MLPA) was carried out to identify CNV of cfDNA. In a single reaction MLPA allows analyzing CNV in 43 chromosomal regions containing 37 genes. Results: MLPA was suitable for characterization of CNV in 72 patients (84.7%). Data on CTC was available for 45 of these patients (62.5%). In total, 7 patients (15.6%) had CTC with a median CTC count of one (IQR: 1-3). In 21 patients (46.7%), one to 6 deleted or amplified chromosomal regions were detected with a median CNV count of 2 (IQR: 1-2). Overall, most changes were located in the genes CDH1, RIPK2 and ZFHX3 in 8 patients (17.8%), 6 patients (13.3%) and 5 patients (11.1%). Chromosomal aberrations were most frequently found on chromosome 8 in 8 patients (17.8%). Overall, presence of CTC was not associated with CNV status. However, presence of CTC was associated with copy number losses in miR-15a (p = 0.011). Patients with CTC had reduced recurrence-free survival (RFS) compared to patients without CTC (p = 0.012). In combined Kaplan-Meier analysis, patients with CTC plus presence of CNV had reduced cancer-specific survival (CSS) and RFS compared to patients without CTC but with presence of CNV (p≤0.035). In addition, patients with CTC plus presence of CNV had reduced RFS compared to patients without CTC and without presence of CNV (p = 0.028). Conclusions: CTC and CNV of various genes are detectable in peripheral blood of bladder cancer patients. The presence of CTC seems to be associated with CNV of specific genes. CTC have a negative impact on survival in patients with and without presence of CNV.


2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 11013-11013 ◽  
Author(s):  
Julia Beck ◽  
Ekkehard Schütz ◽  
Howard B. Urnovitz ◽  
Adel Tabchy ◽  
William M. Mitchell ◽  
...  

11013 Background: Massive parallel sequencing provides high numbers of cell-free nucleic acid serum DNA sequences (cfDNA) that can detect trace amounts of tumor derived chromosomal imbalances and copy number variations (CNVs) in patients with cancer. The aim of this study was to determine if there is a difference between the cfDNA CNVs from patients with breast cancer (BrCa) compared to healthy controls. Methods: DNA extracted from serum samples of 225 BrCa (Stage 1 to 4) and 205 gender and age-matched healthy controls (HC) was amplified using random primers, tagged with a unique molecular identifier per sample, sequenced on an Illumina HiSeq system and aligned to the human genome (Build 37). Hits were counted in sliding 1Mbp interval regions and normalized. Using a Random-Resampling procedure, a model was established to distinguish BrCa from HC using the copy number variations (CNV) and cross validated. Results: From 1,100 rounds of random resampling (50/50), a set of 31 regions was selected, based on the frequency of occurrence in the models. Using 20 random sets of a 10-fold cross validation, the selected regions were found to be highly significant discriminators between BrCa and HC (p<10-5). When using a final linear model with 16 regions the AUC of a diagnostic ROC curve was found to be 0.895 for all samples, for Stage I and II the AUC was 0.86 compared to 0.93 for the higher stages. The final model included three regions from chromosome 8 and 1 and two regions from chromosome 15, the remaining regions were found as one per chromosome. Conclusions: Using comparative massive parallel sequencing of cfDNA from cancer patients vs. controls, we were able to show that a 16-region model based on CNV, is useful to distinguish patients with breast cancer from matched controls. Genomic instabilities that are shed into the circulation from breast cancer may play a role in screening, monitoring or as companion diagnostic tests in breast cancer.


Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2426
Author(s):  
Pankita H. Pandya ◽  
Lijun Cheng ◽  
M. Reza Saadatzadeh ◽  
Khadijeh Bijangi-Vishehsaraei ◽  
Shan Tang ◽  
...  

Osteosarcoma (OS) patients exhibit poor overall survival, partly due to copy number variations (CNVs) resulting in dysregulated gene expression and therapeutic resistance. To identify actionable prognostic signatures of poor overall survival, we employed a systems biology approach using public databases to integrate CNVs, gene expression, and survival outcomes in pediatric, adolescent, and young adult OS patients. Chromosome 8 was a hotspot for poor prognostic signatures. The MYC-RAD21 copy number gain (8q24) correlated with increased gene expression and poor overall survival in 90% of the patients (n = 85). MYC and RAD21 play a role in replication-stress, which is a therapeutically actionable network. We prioritized replication-stress regulators, bromodomain and extra-terminal proteins (BETs), and CHK1, in order to test the hypothesis that the inhibition of BET + CHK1 in MYC-RAD21+ pediatric OS models would be efficacious and safe. We demonstrate that MYC-RAD21+ pediatric OS cell lines were sensitive to the inhibition of BET (BETi) and CHK1 (CHK1i) at clinically achievable concentrations. While the potentiation of CHK1i-mediated effects by BETi was BET-BRD4-dependent, MYC expression was BET-BRD4-independent. In MYC-RAD21+ pediatric OS xenografts, BETi + CHK1i significantly decreased tumor growth, increased survival, and was well tolerated. Therefore, targeting replication stress is a promising strategy to pursue as a therapeutic option for this devastating disease.


Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3242-3242
Author(s):  
Marjolein Blink ◽  
Marry M van den Heuvel-Eibrink ◽  
Brian Balgobind ◽  
Iris H.I.M. Hollink ◽  
Valerie de Haas ◽  
...  

Abstract Abstract 3242 Poster Board III-179 Pediatric acute myeloid leukemia (AML) is a heterogenous disease, with current therapy resulting in cure rates of approximately 60%. The prognosis depends on cytogenetics and early response to therapy. Recently, Radtke et al. (PNAS 2009) reported that (by using single-nucleotide-polymorphism microarrays and candidate resequencing) de novo AML is characterized by a low frequency of copy number variations (CNVs), with a mean of 2.38 somatic CNVs per case. This is in contrast to pediatric acute lymphoblastic leukemia (ALL), with an average of 6 per case (Mullighan et al, Leukemia 2009). The only exception in AML was acute megakaryocytic leukaemia (AMKL, n=9 cases), which is characterized by a high number of CNVs (average of 9.33). Of these 9 AMKL cases, only one patient had a GATA1-mutation, typical of Myeloid Leukemia in Down syndrome (ML-DS). Most ML-DS cases are classified as AMKL, and can be preceded by a pre-leukemic clone in newborns (transient leukaemia- TL), which in approximately 80% resolves spontaneously. Treatment outcome for non Down syndrome AMKL is poor, whereas Down AMKL has a good prognosis. We performed array-based comparative genomic hybridization (Array-CGH) to detect copy number variations (CNV) in Down syndrome related leukemias, with the aim to study whether progression from TL to ML-DS is associated with clonal evolution. We also compared the data obtained with array-CGH from DS patients with two other subgroups of non-DS pediatric AML, i.e. MLL-rearranged AML, and cytogenetically normal AML (CN-AML). This may provide insight in differences in genomic stability between these subgroups. For this analysis, 66 MLL-rearranged AML, 41 CN-AML, 7 TL and 14 ML-DS samples taken at initial diagnosis were available. TL and ML-DS samples were unpaired. Genomic aberrations were scored as a minimum of three (44K arrays, Agilent) and as a minimum of five (105K arrays, Agilent) adjacent probes deviating beyond the threshold of ∼0.5. Results are given in table 1 and 2 below. Copy number variations in different subgroups of pediatric AML in percentages of the total number of samples Subgroup Amplification Deletion Total CNV MLL-rearranged AML n = 66 38% 55% 71% CN-AML n =41 7% 34% 37% TL n = 7 29% 57% 57% ML-DS n =14 64% 93% 100% Copy number variations in different subgroups of pediatric AML, expressed per case Subgroup Amplification Deletion Total CNV MLL-rearranged AML n = 66 0.67 0.64 1.36 CN-AML n =41 0.07 0.46 0.54 TL n = 7 0.43 2.00 2.43 ML-DS n =14 1.86 2.93 4.79 ML-DS patients had a significantly higher frequency of samples with CNVs compared to TL-patients (100% vs. 57%; p=0.026). Most amplifications were (sub)chromosomal (e.g. extra copies of chromosome 8, 11 and 21), whereas the deletions were mostly focal. Except for the (sub)chromosomal amplifications, the other aberrations were mostly found in single cases. Overall, deletions were more common than amplifications. When we analyzed the number of CNVs per case, ML-DS patients had a trend to have a higher number of CNVs per patient (p=0.06) than TL-patients. When the TL and ML-DS patients were taken together and compared to the other non-DS AML-subgroups taken together, there was a significantly higher number of patients with copy variations (86% vs. 58%; p=0.013) in the Down leukemia group. Also, the number of CNV per case was significantly higher in the Down syndrome patients compared to the non-DS AML subgroups (p=< 0.001). In conclusion, we observed significantly less patients with CNVs and less CNVs per patient in MLL- rearranged and CN-AML compared to Down syndrome related leukemia. This suggests that the Down syndrome related leukemias are more genetically unstable when compared with their non-DS controls. Our data are consistent with the findings in AMKL in non-Down syndrome patients as reported by Radtke et al, and may suggest that genomic instability is a general phenomenon of AMKL. This is noteworthy because ML-DS and non-DS AMKL differ in various other aspects. The mechanisms behind the genetically more instable character of the AMKL subgroup is still unclear, and requires further study. Within the Down syndrome patients, there was a statistically significant increase in patients with CNVs in ML-DS compared to TL, and a trend for more CNVs per patient, suggestive of clonal evolution. Disclosures No relevant conflicts of interest to declare.


F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1033
Author(s):  
Isha Pandey ◽  
Ramandeep Kaur ◽  
Amit Kumar Subudhi ◽  
P.A Boopathi ◽  
Raja C. Mugasimangalam ◽  
...  

Background: There are several techniques to analyse copy number variation in both research and clinical settings, such as whole genome amplification (sWGA), SNP arrays and one of the most commonly used techniques, array based comparative genomic hybridization (aCGH). In the latter, copy number comparison is obtained between differentially labelled target and reference DNAs by measuring ratio of fluorescence intensity of probes indicating loss or gain in the chromosomal region. Methods: Here we carry out a comparative analysis between two Plasmodium falciparum parasite isolates (Pf-isolate-2 and Pf-isolate-1) causing malaria using array CGH. The array contains approximately 418,577, 60mer custom-designed probes with an average probe spacing of 56 bp. The significant major variations (amplifications and deletions) copy number variations (CNV) in Pf-isolate-2 (Pf-2) in comparison with Pf-isolate-1 (Pf-1), are reported. Results: CNVs have been seen in all the chromosomes in Pf-2, most of the deletions have been seen mostly in sub-telomeric and telomeric regions of the chromosomes that comprises of variant surface antigen family genes. Apart from the subtelomeric regions other parts of the chromosomes have also shown CNVs. Novel variations ,  like continuous amplification of 28kb region (249817-278491) of chromosome-8, which covers for 3 genes two of which codes for conserved Plasmodium proteins with unknown function (MAL8P1.139, PF08_0122) and tRNA pseudouridine synthase, putative (PF08_0123). Amplifications in regions harboring genes like GTP cyclohydrolase I (GCH-1, PFL1155W) and ribosomal protein, L24, putative (PFL1150C) of chromosome 12 were seen. Conclusion: Other than known variations reported earlier, some novel variations have also been seen in the chromosomes of Pf-2. This is an experimental case study reporting major amplifications and deletions in Pf-isolate-2 in comparison with Pf-isolate-1 using a tiling array based comparative genomic hybridization approach.


Author(s):  
Е.А. Фонова ◽  
Е.Н. Толмачева ◽  
А.А. Кашеварова ◽  
М.Е. Лопаткина ◽  
К.А. Павлова ◽  
...  

Смещение инактивации Х-хромосомы может быть следствием и маркером нарушения клеточной пролиферации при вариациях числа копий ДНК на Х-хромосоме. Х-сцепленные CNV выявляются как у женщин с невынашиванием беременности и смещением инактивации Х-хромосомы (с частотой 33,3%), так и у пациентов с умственной отсталостью и смещением инактивацией у их матерей (с частотой 40%). A skewed X-chromosome inactivation can be a consequence and a marker of impaired cell proliferation in the presence of copy number variations (CNV) on the X chromosome. X-linked CNVs are detected in women with miscarriages and a skewed X-chromosome inactivation (with a frequency of 33.3%), as well as in patients with intellectual disability and skewed X-chromosome inactivation in their mothers (with a frequency of 40%).


2021 ◽  
Vol 11 (1) ◽  
pp. 33
Author(s):  
Nayoung Han ◽  
Jung Mi Oh ◽  
In-Wha Kim

For predicting phenotypes and executing precision medicine, combination analysis of single nucleotide variants (SNVs) genotyping with copy number variations (CNVs) is required. The aim of this study was to discover SNVs or common copy CNVs and examine the combined frequencies of SNVs and CNVs in pharmacogenes using the Korean genome and epidemiology study (KoGES), a consortium project. The genotypes (N = 72,299) and CNV data (N = 1000) were provided by the Korean National Institute of Health, Korea Centers for Disease Control and Prevention. The allele frequencies of SNVs, CNVs, and combined SNVs with CNVs were calculated and haplotype analysis was performed. CYP2D6 rs1065852 (c.100C>T, p.P34S) was the most common variant allele (48.23%). A total of 8454 haplotype blocks in 18 pharmacogenes were estimated. DMD ranked the highest in frequency for gene gain (64.52%), while TPMT ranked the highest in frequency for gene loss (51.80%). Copy number gain of CYP4F2 was observed in 22 subjects; 13 of those subjects were carriers with CYP4F2*3 gain. In the case of TPMT, approximately one-half of the participants (N = 308) had loss of the TPMT*1*1 diplotype. The frequencies of SNVs and CNVs in pharmacogenes were determined using the Korean cohort-based genome-wide association study.


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