copy number variations
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2024 ◽  
Vol 84 ◽  
Author(s):  
M. Ahmad ◽  
Y. Hameed ◽  
M. Khan ◽  
M Usman ◽  
A. Rehman ◽  
...  

Abstract Cancer is a fatal malignancy and its increasing worldwide prevalence demands the discovery of more sensitive and reliable molecular biomarkers. To investigate the GINS1 expression level and its prognostic value in distinct human cancers using a series of multi-layered in silico approach may help to establish it as a potential shared diagnostic and prognostic biomarker of different cancer subtypes. The GINS1 mRNA, protein expression, and promoter methylation were analyzed using UALCAN and Human Protein Atlas (HPA), while mRNA expression was further validated via GENT2. The potential prognostic values of GINS1 were evaluated through KM plotter. Then, cBioPortal was utilized to examine the GINS1-related genetic mutations and copy number variations (CNVs), while pathway enrichment analysis was performed using DAVID. Moreover, a correlational analysis between GINS1 expression and CD8+ T immune cells and a the construction of gene-drug interaction network was performed using TIMER, CDT, and Cytoscape. The GINS1 was found down-regulated in a single subtypes of human cancer while commonly up-regulated in 23 different other subtypes. The up-regulation of GINS1 was significantly correlated with the poor overall survival (OS) of Liver Hepatocellular Carcinoma (LIHC), Lung Adenocarcinoma (LUAD), and Kidney renal clear cell carcinoma (KIRC). The GINS1 was also found up-regulated in LIHC, LUAD, and KIRC patients of different clinicopathological features. Pathways enrichment analysis revealed the involvement of GINS1 in two diverse pathways, while few interesting correlations were also documented between GINS1 expression and its promoter methylation level, CD8+ T immune cells level, and CNVs. Moreover, we also predicted few drugs that could be used in the treatment of LIHC, LUAD, and KIRC by regulating the GINS1 expression. The expression profiling of GINS1 in the current study has suggested it a novel shared diagnostic and prognostic biomarker of LIHC, LUAD, and KIRC.


Diagnostics ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 207
Author(s):  
Luke Mansard ◽  
Christel Vaché ◽  
Julie Bianchi ◽  
Corinne Baudoin ◽  
Isabelle Perthus ◽  
...  

GSDME, also known as DFNA5, is a gene implicated in autosomal dominant nonsyndromic hearing loss (ADNSHL), affecting, at first, the high frequencies with a subsequent progression over all frequencies. To date, all the GSDME pathogenic variants associated with deafness lead to skipping of exon 8. In two families with apparent ADNSHL, massively parallel sequencing (MPS) integrating a coverage-based method for detection of copy number variations (CNVs) was applied, and it identified the first two causal GSDME structural variants affecting exon 8. The deleterious impact of the c.991-60_1095del variant, which includes the acceptor splice site sequence of exon 8, was confirmed by the study of the proband’s transcripts. The second mutational event is a complex rearrangement that deletes almost all of the exon 8 sequence. This study increases the mutational spectrum of the GSDME gene and highlights the crucial importance of MPS data for the detection of GSDME exon 8 deletions, even though the identification of a causal single-exon CNV by MPS analysis is still challenging.


2022 ◽  
Vol 11 (2) ◽  
pp. 372
Author(s):  
Thomas Harasim ◽  
Teresa Neuhann ◽  
Anne Behnecke ◽  
Miriam Stampfer ◽  
Elke Holinski-Feder ◽  
...  

Objective: Amniocentesis, chorionic villi sampling and first trimester combined testing are able to screen for common trisomies 13, 18, and 21 and other atypical chromosomal anomalies (ACA). The most frequent atypical aberrations reported are rare autosomal aneuploidies (RAA) and copy number variations (CNV), which are deletions or duplications of various sizes. We evaluated the clinical outcome of non-invasive prenatal testing (NIPT) results positive for RAA and large CNVs to determine the clinical significance of these abnormal results. Methods: Genome-wide NIPT was performed on 3664 eligible patient samples at a single genetics center. For patients with positive NIPT reports, the prescribing physician was asked retrospectively to provide clinical follow-up information using a standardized questionnaire. Results: RAAs and CNVs (>7 Mb) were detected in 0.5%, and 0.2% of tested cases, respectively. Follow up on pregnancies with an NIPT-positive result for RAA revealed signs of placental insufficiency or intra-uterine death in 50% of the cases and normal outcome at the time of birth in the other 50% of cases. We showed that CNV testing by NIPT allows for the detection of unbalanced translocations and relevant maternal health conditions. Conclusion: NIPT for aneuploidies of all autosomes and large CNVs of at least 7 Mb has a low “non-reportable”-rate (<0.2%) and allows the detection of additional conditions of clinical significance.


2022 ◽  
Vol 8 ◽  
Author(s):  
Bo Ma ◽  
Zaoqu Liu ◽  
Hui Xu ◽  
Long Liu ◽  
Tao Huang ◽  
...  

Background: Aldehyde dehydrogenase 2 (ALDH2) is well-known to be a key enzyme in alcohol metabolism. However, a comprehensive understanding of ALDH2 across human cancers is lacking.Methods: A systematic and comprehensive analysis of the molecular alterations and clinical relevance for ALDH2 in more than 10,000 samples from 33 cancer types was performed. qRT-PCR was performed on 60 cancer and 60 paired nontumor tissues.Results: It was observed that ALDH2 was generally downregulated in most cancers, which was mainly driven by DNA hypermethylation rather than mutations or copy number variations. Besides, ALDH2 was closely related to the inhibition and activation of tumor pathways and a variety of potential targeted agents had been discovered in our research. Last but not least, ALDH2 had the best prediction efficacy in assessing immunotherapeutic response compared with PD-L1, PD-1, CTLA4, CD8, and tumor mutation burden (TMB) in cutaneous melanoma. According to the analysis of large-scale public data and 60 pairs of clinical cancer samples, we found the downregulation of ALDH2 expression tends to suggest the malignant phenotypes and adverse prognosis, which might enhance the precise diagnosis and timely intervention of cancer patients.Conclusion: This study advanced the understanding of ALDH2 across cancers, and provided important insight into chemotherapy, immunotherapy and prognosis of patients with cancer.


2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Shin-ya Nishio ◽  
Shin-ichi Usami

AbstractThe STRC gene, located on chromosome 15q15.3, is one of the genetic causes of autosomal recessive mild-to-moderate sensorineural hearing loss. One of the unique characteristics of STRC-associated hearing loss is the high prevalence of long deletions or copy number variations observed on chromosome 15q15.3. Further, the deletion of chromosome 15q15.3 from STRC to CATSPER2 is also known to be a genetic cause of deafness infertility syndrome (DIS), which is associated with not only hearing loss but also male infertility, as CATSPER2 plays crucial roles in sperm motility. Thus, information regarding the deletion range for each patient is important to the provision of appropriate genetic counselling for hearing loss and male infertility. In the present study, we performed next-generation sequencing (NGS) analysis for 9956 Japanese hearing loss patients and analyzed copy number variations in the STRC gene based on NGS read depth data. In addition, we performed Multiplex Ligation-dependent Probe Amplification analysis to determine the deletion range including the PPIP5K1, CKMT1B, STRC and CATSPER2 genomic region to estimate the prevalence of the STRC-CATSPER deletion, which is causative for DIS among the STRC-associated hearing loss patients. As a result, we identified 276 cases with STRC-associated hearing loss. The prevalence of STRC-associated hearing loss in Japanese hearing loss patients was 2.77% (276/9956). In addition, 77.1% of cases with STRC homozygous deletions carried a two copy loss of the entire CKMT1B-STRC-CATSPER2 gene region. This information will be useful for the provision of more appropriate genetic counselling regarding hearing loss and male infertility for the patients with a STRC deletion.


2022 ◽  
Author(s):  
Brianna K Unda ◽  
Leon Chalil ◽  
Sehyoun Yoon ◽  
Savannah Kilpatrick ◽  
Sansi Xing ◽  
...  

Copy number variations (CNV) are associated with psychiatric and neurodevelopmental disorders (NDDs), and most, including the recurrent 15q13.3 microdeletion disorder, have unknown disease mechanisms. We used a heterozygous 15q13.3 microdeletion mouse model and patient iPSC-derived neurons to reveal developmental defects in neuronal maturation and network activity. To identify the underlying molecular dysfunction, we developed a neuron-specific proximity-labeling proteomics (BioID2) pipeline, combined with patient mutations, to target the 15q13.3 CNV genetic driver OTUD7A. OTUD7A is an emerging independent NDD risk gene with no known function in the brain, but has putative deubiquitinase (DUB) function. The OTUD7A protein-protein interaction (PPI) network revealed interactions with synaptic, axonal, and cytoskeletal proteins and was enriched for known ASD and epilepsy risk genes. The interactions between OTUD7A and the NDD risk genes Ankyrin-G (Ank3) and Ankyrin-B (Ank2) were disrupted by an epilepsy-associated OTUD7A L233F variant. Further investigation of Ankyrin-G in mouse and human 15q13.3 microdeletion and OTUD7AL233F/L233F models revealed protein instability, increased polyubiquitination, and decreased levels in the axon initial segment (AIS), while structured illumination microscopy identified reduced Ankyrin-G nanodomains in dendritic spines. Functional analysis of human 15q13.3 microdeletion and OTUD7AL233F/L233F models revealed shared and distinct impairments to axonal growth and intrinsic excitability. Importantly, restoring OTUD7A or Ankyrin-G expression in 15q13.3 microdeletion neurons led to a reversal of abnormalities. These data reveal a critical OTUD7A-Ankyrin pathway in neuronal development, which is impaired in the 15q13.3 microdeletion syndrome, leading to neuronal dysfunction. Further, our study highlights the utility of targeting CNV genes using cell-type specific proteomics to identify shared and unexplored disease mechanisms across NDDs.


2022 ◽  
Vol 12 (1) ◽  
Author(s):  
M. Gažiová ◽  
T. Sládeček ◽  
O. Pös ◽  
M. Števko ◽  
W. Krampl ◽  
...  

AbstractCopy number variants (CNVs) play an important role in many biological processes, including the development of genetic diseases, making them attractive targets for genetic analyses. The interpretation of the effect of these structural variants is a challenging problem due to highly variable numbers of gene, regulatory, or other genomic elements affected by the CNV. This led to the demand for the interpretation tools that would relieve researchers, laboratory diagnosticians, genetic counselors, and clinical geneticists from the laborious process of annotation and classification of CNVs. We designed and validated a prediction method (ISV; Interpretation of Structural Variants) that is based on boosted trees which takes into account annotations of CNVs from several publicly available databases. The presented approach achieved more than 98% prediction accuracy on both copy number loss and copy number gain variants while also allowing CNVs being assigned “uncertain” significance in predictions. We believe that ISV’s prediction capability and explainability have a great potential to guide users to more precise interpretations and classifications of CNVs.


Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 302
Author(s):  
Marcus Wölffer ◽  
Florian Battke ◽  
Martin Schulze ◽  
Magdalena Feldhahn ◽  
Lukas Flatz ◽  
...  

Immune checkpoint inhibitors (ICI) have revolutionized the therapeutic landscape of metastatic melanoma. However, ICI are often associated with immune-related adverse events (IRAE) such as colitis, hepatitis, pancreatitis, hypophysitis, pneumonitis, thyroiditis, exanthema, nephritis, myositis, encephalitis, or myocarditis. Biomarkers associated with the occurrence of IRAE would be desirable. In the literature, there is only little data available and furthermore mostly speculative, especially in view of genetic alterations. Our major aim was to check for possible associations between NGS-based genetic alterations and IRAE. We therefore analyzed 95 melanoma patients with ICI and evaluated their NGS results. We checked the data in view of potential associations between copy number variations (CNVs), small variations (VARs), human leucocyte antigen (HLA), sex, blood count parameters, pre-existing autoimmune diseases and the occurrence of IRAE. We conducted a literature research on genetic alterations hypothesized to be associated with the occurrence of IRAE. In total, we identified 39 genes that have been discussed as hypothetical biomarkers. We compared the list of these 39 genes with the tumor panel that our patients had received and focused our study on those 16 genes that were also included in the tumor panel used for NGS. Therefore, we focused our analyses on the following genes: AIRE, TERT, SH2B3, LRRK2, IKZF1, SMAD3, JAK2, PRDM1, CTLA4, TSHR, FAN1, SLCO1B1, PDCD1, IL1RN, CD274, UNG. We obtained relevant results: female sex was significantly associated with the development of hepatitis, combined immunotherapy with colitis, increased total and relative monocytes at therapy initiation were significantly associated with the development of pancreatitis, the same, pre-existing autoimmune diseases. Further significant associations were as follows: HLA homozygosity (hepatitis), and VARs on SMAD3 (pancreatitis). Regarding CNVs, significant markers included PRDM1 deletions and IL1RN (IRAE), CD274 duplications and SLCO1B1 (hepatitis), PRDM1 and CD274 (encephalitis), and PRDM1, CD274, TSHR, and FAN1 (myositis). Myositis and encephalitis, both, were associated with alterations of PRDM1 and CD274, which might explain their joined appearance in clinical practice. The association between HLA homozygosity and IRAE was clarified by finding HLA-A homozygosity as determining factor. We identified several genetic alterations hypothesized in the literature to be associated with the development of IRAE and found significant results concerning pre-existing autoimmune diseases and specific blood count parameters. Our findings can help to better understand the development of IRAE in melanoma patients. NGS might be a useful screening tool, however, our findings have yet to be confirmed in larger studies.


Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 269
Author(s):  
Mouna Tabebi ◽  
Małgorzata Łysiak ◽  
Ravi Kumar Dutta ◽  
Sandra Lomazzi ◽  
Maria V. Turkina ◽  
...  

Background: Somatic mutations, copy-number variations, and genome instability of mitochondrial DNA (mtDNA) have been reported in different types of cancers and are suggested to play important roles in cancer development and metastasis. However, there is scarce information about pheochromocytomas and paragangliomas (PCCs/PGLs) formation. Material: To determine the potential roles of mtDNA alterations in sporadic PCCs/PGLs, we analyzed a panel of 26 nuclear susceptibility genes and the entire mtDNA sequence of seventy-seven human tumors, using next-generation sequencing, and compared the results with normal adrenal medulla tissues. We also performed an analysis of copy-number alterations, large mtDNA deletion, and gene and protein expression. Results: Our results revealed that 53.2% of the tumors harbor a mutation in at least one of the targeted susceptibility genes, and 16.9% harbor complementary mitochondrial mutations. More than 50% of the mitochondrial mutations were novel and predicted pathogenic, affecting mitochondrial oxidative phosphorylation. Large deletions were found in 26% of tumors, and depletion of mtDNA occurred in more than 87% of PCCs/PGLs. The reduction of the mitochondrial number was accompanied by a reduced expression of the regulators that promote mitochondrial biogenesis (PCG1α, NRF1, and TFAM). Further, P62 and LC3a gene expression suggested increased mitophagy, which is linked to mitochondrial dysfunction. Conclusion: The pathogenic role of these finding remains to be shown, but we suggest a complementarity and a potential contributing role in PCCs/PGLs tumorigenesis.


2022 ◽  
Author(s):  
Etienne Sollier ◽  
Jack Kuipers ◽  
Niko Beerenwinkel ◽  
Koichi Takahashi ◽  
Katharina Jahn

Reconstructing the history of somatic DNA alterations that occurred in a tumour can help understand its evolution and predict its resistance to treatment. Single-cell DNA sequencing (scDNAseq) can be used to investigate clonal heterogeneity and to inform phylogeny reconstruction. However, existing phylogenetic methods for scDNAseq data are designed either for point mutations or for large copy number variations, but not for both types of events simultaneously. Here, we develop COMPASS, a computational method for inferring the joint phylogeny of mutations and copy number alterations from targeted scDNAseq data. We evaluate COMPASS on simulated data and show that it outperforms existing methods. We apply COMPASS to a large cohort of 123 patients with acute myeloid leukemia (AML) and detect copy number alterations, including subclonal ones, which are in agreement with current knowledge of AML development. We further used bulk SNP array data to orthogonally validate or findings.


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