Examination of copy number variations of CHST9 in multiple types of hematologic malignancies

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%).

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Comprehensive Analyses of Copy Number Variations In DNA Repair Genes Reveal the Role of Poly(ADP-Ribose) Polymerase in Longevity in Trees

SSRN Electronic Journal ◽

10.2139/ssrn.3751787 ◽

2020 ◽

Author(s):

Yuta Aoyagi Blue ◽

Junko Kusumi ◽

Akiko Satake

Keyword(s):

Dna Repair ◽

Copy Number ◽

Copy Number Variations ◽

Dna Repair Genes ◽

Repair Genes

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Combination of Genome-Wide Polymorphisms and Copy Number Variations of Pharmacogenes in Koreans

Journal of Personalized Medicine ◽

10.3390/jpm11010033 ◽

2021 ◽

Vol 11 (1) ◽

pp. 33

Author(s):

Nayoung Han ◽

Jung Mi Oh ◽

In-Wha Kim

Keyword(s):

Copy Number ◽

Genome Wide Association Study ◽

Copy Number Gain ◽

Copy Number Variations ◽

Gene Gain ◽

Single Nucleotide Variants ◽

Single Nucleotide ◽

Haplotype Blocks ◽

Genome Wide ◽

Control And Prevention

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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Performance of In Silico Prediction Tools for the Detection of Germline Copy Number Variations in Cancer Predisposition Genes in 4208 Female Index Patients with Familial Breast and Ovarian Cancer

Cancers ◽

10.3390/cancers13010118 ◽

2021 ◽

Vol 13 (1) ◽

pp. 118

Author(s):

Louisa Lepkes ◽

Mohamad Kayali ◽

Britta Blümcke ◽

Jonas Weber ◽

Malwina Suszynska ◽

...

Keyword(s):

Ovarian Cancer ◽

In Silico ◽

Copy Number ◽

Gc Content ◽

Copy Number Variations ◽

Cancer Predisposition ◽

Predictive Values ◽

Prediction Tools ◽

Predisposition Genes ◽

Female Index

The identification of germline copy number variants (CNVs) by targeted next-generation sequencing (NGS) frequently relies on in silico CNV prediction tools with unknown sensitivities. We investigated the performances of four in silico CNV prediction tools, including one commercial (Sophia Genetics DDM) and three non-commercial tools (ExomeDepth, GATK gCNV, panelcn.MOPS) in 17 cancer predisposition genes in 4208 female index patients with familial breast and/or ovarian cancer (BC/OC). CNV predictions were verified via multiplex ligation-dependent probe amplification. We identified 77 CNVs in 76 out of 4208 patients (1.81%); 33 CNVs were identified in genes other than BRCA1/2, mostly in ATM, CHEK2, and RAD51C and less frequently in BARD1, MLH1, MSH2, PALB2, PMS2, RAD51D, and TP53. The Sophia Genetics DDM software showed the highest sensitivity; six CNVs were missed by at least one of the non-commercial tools. The positive predictive values ranged from 5.9% (74/1249) for panelcn.MOPS to 79.1% (72/91) for ExomeDepth. Verification of in silico predicted CNVs is required due to high frequencies of false positive predictions, particularly affecting target regions at the extremes of the GC content or target length distributions. CNV detection should not be restricted to BRCA1/2 due to the relevant proportion of CNVs in further BC/OC predisposition genes.

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Cell-free DNA copy number variations predict efficacy of immune checkpoint inhibitor-based therapy in hepatobiliary cancers

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001942 ◽

2021 ◽

Vol 9 (5) ◽

pp. e001942

Author(s):

Xu Yang ◽

Ying Hu ◽

Keyan Yang ◽

Dongxu Wang ◽

Jianzhen Lin ◽

...

Keyword(s):

Combination Therapy ◽

Clinical Outcome ◽

Risk Score ◽

Immune Checkpoint ◽

Copy Number ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Copy Number Variations ◽

Risk Scores ◽

Free Dna

BackgroundThis study was designed to screen potential biomarkers in plasma cell-free DNA (cfDNA) for predicting the clinical outcome of immune checkpoint inhibitor (ICI)-based therapy in advanced hepatobiliary cancers.MethodsThree cohorts including 187 patients with hepatobiliary cancers were recruited from clinical trials at the Peking Union Medical College Hospital. Forty-three patients received combination therapy of programmed cell death protein 1 (PD-1) inhibitor with lenvatinib (ICI cohort 1), 108 patients received ICI-based therapy (ICI cohort 2) and 36 patients received non-ICI therapy (non-ICI cohort). The plasma cfDNA and blood cell DNA mutation profiles were assessed to identify efficacy biomarkers by a cancer gene-targeted next-generation sequencing panel.ResultsBased on the copy number variations (CNVs) in plasma cfDNA, the CNV risk score model was constructed to predict survival by using the least absolute shrinkage and selection operator Cox regression methods. The results of the two independent ICI-based therapy cohorts showed that patients with lower CNV risk scores had longer overall survival (OS) and progression-free survival (PFS) than those with high CNV risk scores (log-rank p<0.01). In the non-ICI cohort, the CNV risk score was not associated with PFS or OS. Furthermore, the results indicated that 53% of patients with low CNV risk scores achieved durable clinical benefit; in contrast, 88% of patients with high CNV risk scores could not benefit from combination therapy (p<0.05).ConclusionsThe CNVs in plasma cfDNA could predict the clinical outcome of the combination therapy of PD-1 inhibitor with lenvatinib and other ICI-based therapies in hepatobiliary cancers.

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Application of Copy Number Variation Sequencing in Genetic Analysis of Miscarriages in Early and Middle Pregnancy

Cytogenetic and Genome Research ◽

10.1159/000512801 ◽

2020 ◽

Vol 160 (11-12) ◽

pp. 634-642

Author(s):

Shiqiang Luo ◽

Xingyuan Chen ◽

Tizhen Yan ◽

Jiaolian Ya ◽

Zehui Xu ◽

...

Keyword(s):

Copy Number Variation ◽

High Throughput ◽

Copy Number ◽

High Throughput Sequencing ◽

Chromosomal Abnormalities ◽

Pregnancy Termination ◽

Mendelian Inheritance ◽

Copy Number Variations ◽

Abnormal Chromosome ◽

Number Variation

High-throughput sequencing based on copy number variation (CNV-seq) is commonly used to detect chromosomal abnormalities. This study identifies chromosomal abnormalities in aborted embryos/fetuses in early and middle pregnancy and explores the application value of CNV-seq in determining the causes of pregnancy termination. High-throughput sequencing was used to detect chromosome copy number variations (CNVs) in 116 aborted embryos in early and middle pregnancy. The detection data were compared with the Database of Genomic Variants (DGV), the Database of Chromosomal Imbalance and Phenotype in Humans using Ensemble Resources (DECIPHER), and the Online Mendelian Inheritance in Man (OMIM) database to determine the CNV type and the clinical significance. High-throughput sequencing results were successfully obtained in 109 out of 116 specimens, with a detection success rate of 93.97%. In brief, there were 64 cases with abnormal chromosome numbers and 23 cases with CNVs, in which 10 were pathogenic mutations and 13 were variants of uncertain significance. An abnormal chromosome number is the most important reason for embryo termination in early and middle pregnancy, followed by pathogenic chromosome CNVs. CNV-seq can quickly and accurately detect chromosome abnormalities and identify microdeletion and microduplication CNVs that cannot be detected by conventional chromosome analysis, which is convenient and efficient for genetic etiology diagnosis in miscarriage.

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Expanded noninvasive prenatal testing for fetal aneuploidy and copy number variations and parental willingness for invasive diagnosis in a cohort of 18,516 cases

BMC Medical Genomics ◽

10.1186/s12920-021-00955-6 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Yunsheng Ge ◽

Jia Li ◽

Jianlong Zhuang ◽

Jian Zhang ◽

Yanru Huang ◽

...

Keyword(s):

Prenatal Diagnosis ◽

High Risk ◽

Pregnant Women ◽

Copy Number ◽

Prenatal Testing ◽

Copy Number Variations ◽

Trisomy 13 ◽

Noninvasive Prenatal Testing ◽

Predictive Values ◽

Parental Willingness

Abstract Background Noninvasive prenatal testing (NIPT) has been wildly used to screen for common aneuplodies. In recent years, the test has been expanded to detect rare autosomal aneuploidies (RATs) and copy number variations (CNVs). This study was performed to investigate the performance of expanded noninvasive prenatal testing (expanded NIPT) in screening for common trisomies, sex chromosomal aneuploidies (SCAs), rare autosomal aneuploidies (RATs), and copy number variations (CNVs) and parental willingness for invasive prenatal diagnosis in a Chinese prenatal diagnosis center. Methods A total of 24,702 pregnant women were retrospectively analyzed at the Women and Children’s Hospital from January 2013 to April 2019, among which expanded NIPT had been successfully conducted in 24,702 pregnant women. The high-risk expanded NIPT results were validated by karyotype analysis and chromosomal microarray analysis. All the tested pregnant women were followed up for pregnancy outcomes. Results Of the 24,702 cases, successful follow-up was conducted in 98.77% (401/446) of cases with common trisomies and SCAs, 91.95% (80/87) of RAT and CNV cases, and 76.25% (18,429/24,169) of cases with low-risk screening results. The sensitivity of expanded NIPT was 100% (95% confidence interval[CI], 97.38–100%), 96.67%(95%CI, 82.78–99.92%), and 100%(95%CI, 66.37–100.00%), and the specificity was 99.92%(95%CI, 99.87–99.96%), 99.96%(95%CI, 99.91–99.98%), and 99.88% (95%CI, 99.82–99.93%) for the detection of trisomies 21, 18, and 13, respectively. Expanded NIPT detected 45,X, 47,XXX, 47,XXY, XYY syndrome, RATs, and CNVs with positive predictive values of 25.49%, 75%, 94.12%, 76.19%, 6.45%, and 50%, respectively. The women carrying fetuses with Trisomy 21/Trisomy 18/Trisomy 13 underwent invasive prenatal diagnosis and terminated their pregnancies at higher rates than those at high risk for SCAs, RATs, and CNVs. Conclusions Our study demonstrates that the expanded NIPT detects fetal trisomies 21, 18, and 13 with high sensitivity and specificity. The accuracy of detecting SCAs, RATs, and CNVs is still relatively poor and needs to be improved. With a high-risk expanded NIPT result, the women at high risk for common trisomies are more likely to undergo invasive prenatal diagnosis procedures and terminate their pregnancies than those with unusual chromosome abnormalities.

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