scholarly journals Exome Sequencing of Glioblastoma-Derived Cancer Stem Cells Reveals Rare Clinically Relevant Frameshift Deletion in MLLT1 Gene

2021 ◽  
Author(s):  
Hany Marei ◽  
Asmaa Althani ◽  
Nahla Afifi ◽  
Anwarul Hasan ◽  
Thomas Caceci ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Allelic Frequency ◽  
Common Variants ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Frameshift Deletion ◽  
Prognostic Outcome ◽  
The Common ◽  
Recurrent Nature

Abstract Background: Glioblastoma multiforme (GBM) is a heterogeneous CNS neoplasm which causes significant morbidity and mortality. One reason for the poor prognostic outcome of GBM is attributed to the presence of cancer stem cells (CSC) which confer resistance against standard chemo- and radiotherapeutics modalities. Two types of GBM-associated CSC were isolated from the same patient: tumor core- (c-CSC) and peritumor tissue-derived cancer stem cells (p-CSC).Methods: In the present study, potential differences in genetic variants between c-CSC versus p-CSC derived from four GBM patients were investigated with the aims of 1) comparing the exome sequences between all the c-CSC or p-CSC to identify the common variants; 2) identifying the variants affecting the function of genes known to be involved in cancer origin and development.Results: By comparative analyses, we identified common gene single nucleotide variants (SNV) in all GBM c-CSC and p-CSC, a potentially deleterious variant was a frameshift deletion at Gln461fs in the MLLT1 gene, that was encountered only in p-CSC samples with different allelic frequency.Conclusions: Our study supports the hypothesis that the varied genetic composition of GBM-associated c-CSC and p-CSC may be involved in different therapeutic responses or the recurrent nature of GBM.

scholarly journals Exome sequencing of glioblastoma-derived cancer stem cells reveals rare clinically relevant frameshift deletion in MLLT1 gene

2022 ◽  
Vol 22 (1) ◽  
Author(s):  
Hany E. Marei ◽  
Asmaa Althani ◽  
Nahla Afifi ◽  
Anwarul Hasan ◽  
Thomas Caceci ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Allelic Frequency ◽  
Response To Therapy ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Tissue Samples ◽  
Frameshift Deletion ◽  
Prognostic Outcome ◽  
The Common

Abstract Background Glioblastoma multiforme (GBM) is a heterogeneous CNS neoplasm which causes significant morbidity and mortality. One reason for the poor prognostic outcome of GBM is attributed to the presence of cancer stem cells (CSC) which confer resistance against standard chemo- and radiotherapeutics modalities. Two types of GBM-associated CSC were isolated from the same patient: tumor core- (c-CSC) and peritumor tissue-derived cancer stem cells (p-CSC). Our experiments are focused on glioblastoma–IDH-wild type, and no disease-defining alterations were present in histone, BRAF or other genes. Methods In the present study, potential differences in genetic variants between c-CSC versus p-CSC derived from four GBM patients were investigated with the aims of (1) comparing the exome sequences between all the c-CSC or p-CSC to identify the common variants; (2) identifying the variants affecting the function of genes known to be involved in cancer origin and development. Results By comparative analyses, we identified common gene single nucleotide variants (SNV) in all GBM c-CSC and p-CSC, a potentially deleterious variant was a frameshift deletion at Gln461fs in the MLLT1 gene, that was encountered only in p-CSC samples with different allelic frequency. Conclusions We discovered a potentially harmful frameshift deletion at Gln461fs in the MLLT1 gene. Further investigation is required to confirm the presence of the identified mutations in patient tissue samples, as well as the significance of the frameshift mutation in the MLLT1 gene on GBM biology and response to therapy based on genomic functional experiments.

scholarly journals Low rate of somatic mutations in a long-lived oak tree

2017 ◽  
Author(s):  
Namrata Sarkar ◽  
Emanuel Schmid-Siegert ◽  
Christian Iseli ◽  
Sandra Calderon ◽  
Caroline Gouhier-Darimont ◽  
...  
Keyword(s):  
Stem Cells ◽  
Somatic Mutations ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Cell Divisions ◽  
Gamete Formation ◽  
Oak Tree ◽  
Sequential Appearance ◽  
Low Rate ◽  
Shoot Meristems

Because plants do not possess a proper germline, deleterious somatic mutations can be passed to gametes and a large number of cell divisions separating zygote from gamete formation in long-lived plants may lead to many mutations. We sequenced the genome of two terminal branches of a 234-year-old oak tree and found few fixed somatic single-nucleotide variants (SNVs), whose sequential appearance in the tree could be traced along nested sectors of younger branches. Our data suggest that stem cells of shoot meristems are robustly protected from accumulation of mutations in trees.

Genetics of Schizophrenia and Bipolar Disorder

2017 ◽  
Author(s):  
Alexander Charney ◽  
Pamela Sklar
Keyword(s):  
Bipolar Disorder ◽  
Copy Number ◽  
Psychotic Disorders ◽  
Copy Number Variants ◽  
Nucleotide Polymorphisms ◽  
Common Variants ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Number Variation

Schizophrenia and bipolar disorder are the classic psychotic disorders. Both diseases are strongly familial, but have proven recalcitrant to genetic methodologies for identifying the etiology until recently. There is now convincing genetic evidence that indicates a contribution of many DNA changes to the risk of becoming ill. For schizophrenia, there are large contributions of rare copy number variants and common single nucleotide variants, with an overall highly polygenic genetic architecture. For bipolar disorder, the role of copy number variation appears to be much less pronounced. Specific common single nucleotide polymorphisms are associated, and there is evidence for polygenicity. Several surprises have emerged from the genetic data that indicate there is significantly more molecular overlap in copy number variants between autism and schizophrenia, and in common variants between schizophrenia and bipolar disorder.

scholarly journals Liver cancer stem cells as a hierarchical society: yes or no?

2020 ◽  
Vol 52 (7) ◽  
pp. 723-735 ◽  
Author(s):  
Yuanzhuo Gu ◽  
Xin Zheng ◽  
Junfang Ji
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Recent Decade ◽  
Regulatory Pathways ◽  
Molecular Features ◽  
The Hierarchical Structure ◽  
Multiple Cell ◽  
The Common ◽  
Relationship Of ◽  
The Relationship

Abstract Cancer stem cells (CSCs) are cells possessing abilities of self-renewal, differentiation, and tumorigenicity in NOD/SCID mice. Based on this definition, multiple cell surface markers (such as CD24, CD133, CD90, and EpCAM) as well as chemical methods are discovered to enrich liver CSCs in the recent decade. Accumulated studies have revealed molecular signatures and signaling pathways involved in regulating different liver CSCs. Among liver CSCs positive for different markers, some molecular features and regulatory pathways are commonly shared, while some are only unique in certain CSC populations. These studies imply that liver CSCs exhibit diverse heterogeneity, while a functional relationship also exists. The aim of this review is to revisit the society of liver CSCs and summarize the common or unique molecular features of known liver CSCs. We hope to call for attention of researchers on the relationship of the liver CSC subgroups and to provide clues on the hierarchical structure of the liver CSC society.

scholarly journals Controlling homology-directed repair outcomes in human stem cells with dCas9

2021 ◽  
Author(s):  
William C Skarnes ◽  
Gang Ning ◽  
Sofia Giansiracusa ◽  
Alexander S Cruz ◽  
Cornelis Blauwendraat ◽  
...  
Keyword(s):  
Stem Cells ◽  
High Activity ◽  
Human Disease ◽  
Human Stem Cells ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Homology Directed Repair ◽  
Guide Rnas

Modeling human disease in human stem cells requires precise, scarless editing of single nucleotide variants (SNV) on one or both chromosomes. Here we describe improved conditions for Cas9 RNP editing of SNVs that yield high rates of biallelic homology-directed repair. To recover both heterozygous and homozygous SNV clones, catalytically inactive dCas9 was added to moderate high activity Cas9 RNPs. dCas9 can also block re-cutting and damage to SNV alleles engineered with non-overlapping guide RNAs.

scholarly journals Genetic variants in the SHISA6 gene are associated with delayed cognitive impairment in two family datasets

2021 ◽  
Author(s):  
Jairo Ramos ◽  
Laura J Caywood ◽  
Michael B. Prough ◽  
Jason E. Clouse ◽  
Sharlene D. Herington ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Statistical Significance ◽  
Age At Onset ◽  
Chromosome 17 ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Genome Wide ◽  
Cultural Isolation ◽  
A Genome ◽  
The Common

Background: Studies of cognitive impairment (CI) in Amish communities have identified sibships containing multiple CI and cognitively unimpaired (CU; unaffected after age 75) individuals. We hypothesize that these CU individuals may carry protective alleles delaying age at onset (AAO) of CI, preserving cognition in older age despite increased genetic risk. As well, the genetic and cultural isolation in the Amish since the early 1800s may have reduced the complexity of the genetic architecture of CI, increasing the power to detect protective alleles in this population. With this in mind we conducted a genome-wide study (GWAS) to identify loci associated with AAO of CI in a sample of Amish adults over age 75. Methods: 1,522 individuals aged 43-99 (mean age 73.1, 42% men) screened at least once for CI using the Modified Mini-Mental State exam (3MS) were genotyped using Illumina chipsets. Genotypes were imputed for 7,815,951 single nucleotide variants (SNV) with minor allele frequency (MAF) > 1%. The outcome studied was age, defined as 1) age at the first 3MS result indicating impairment (AAO; 3MS <87; 362 CI individuals) or 2) age at last normal exam (3MS >=87, 1,160 CU individuals). Cox mixed-effects models examined association between age and each SNV, adjusting for sex and familial relationships. To replicate genome-wide significant findings, SNVs in a 1 Megabase region centered on the peak SNV were examined for association with age using these same methods in the NIA-LOAD family study dataset (1,785 AD cases, 1,565 unaffected controls, mean age 73.5. Results: Three SNV were significantly associated (p<5 x 10-8) with AAO in the Amish, on chromosomes 6 (rs14538074; HR=3.35), 9 (rs534551495; HR=2.82), and 17 (rs146729640; Hazard Ratio (HR)=6.38). Each region found the common allele associated with later AAO. Replication analysis detected association at rs146729640, with nominal statistical significance (HR=1.49, p=0.02). Conclusions: The replicated genome-wide significant association with AAO on chromosome 17 suggest this may be novel locus associated with delayed onset of AD. The associated SNP is located in the SHISA6 gene, which is involved in post-synaptic transmission in the hippocampus and is a biologically plausible candidate gene for AD.

scholarly journals In-situ multiomics analysis reveals only minor genetic and epigenetic changes in human liver cancer stem cells

2021 ◽  
Author(s):  
Dan Liu ◽  
Hong Li ◽  
Hui Dong ◽  
Min-Cheng Qu ◽  
Liguang Yang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Liver Cancer ◽  
Human Cancer ◽  
Epigenetic Changes ◽  
Single Nucleotide Variants ◽  
Human Liver Cancer ◽  
Parenchymal Cells ◽  
Methylation Patterns

Abstract Cancer stem cells (CSCs) play pivotal roles in human cancer but their genetic and epigenetic changes are still largely unknown. Here we show that human CSCs are more similar to paratumor cells in liver cancer. Using single-cell-based in-situ multiomics analysis, we found that although liver CSCs (LCSCs) from patients had some potential key genetic and epigenetic changes in their genome, they had substantially fewer somatic single nucleotide variants (SNVs), copy number alterations (CNAs) and differentially methylated regions, and less change in the global levels of DNA cytosine modifications, than other tumor parenchymal cells. The cluster analysis of SNVs, CNAs and DNA methylation patterns and spatial transcriptomes all clearly showed that the LCSCs were clustered with the paratumor liver cells. Thus, only minor genetic and epigenetic changes occurred in human LCSCs. Targeting key changes in CSCs, not just changes in bulk tumor cells, should be more effective for human cancer therapy.

scholarly journals Integrative analysis of the common genetic characteristics in ovarian cancer stem cells sorted by multiple approaches

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Xiaoxiao Zhang ◽  
Yue Su ◽  
Xue Wu ◽  
Rourou Xiao ◽  
Yifan Wu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Ovarian Cancer Stem Cells ◽  
Genetic Characteristics ◽  
Protein Protein Interaction ◽  
The Common ◽  
Core Genes

Abstract Background Ovarian cancer is the second fatal malignancy of the female reproductive system. Based on the cancer stem cell (CSC) theory, its poor prognosis of ovarian cancer attributed to tumor recurrence caused by CSCs. A variety of cell surface-specific markers have been employed to identify ovarian cancer stem cells (OCSCs). In this study, we attempted to explore the common feature in ovarian cancer stem cells sorted by multiple approaches. Methods We collected the gene expression profiles of OCSCs were from 5 public cohorts and employed R software and Bioconductor packages to establish differently expressed genes (DEGs) between OCSCs and parental cells. We extracted the integrated DEGs by protein-protein interaction (PPI) network construction and explored potential treatment by the Cellminer database. Results We identified and integrated the DEGs of OCSCs sorted by multiple isolation approaches. Besides, we identified OCSCs share characteristics in the lipid metabolism and extracellular matrix changes. Moreover, we obtained 16 co-expressed core genes, such as FOXQ1, MMP7, AQP5, RBM47, ETV4, NPW, SUSD2, SFRP2, IDO1, ANPEP, CXCR4, SCNN1A, SPP1 and IFI27 (upregulated) and SERPINE1, DUSP1, CD40, and IL6 (downregulated). Through correlation analysis, we screened out ten potential drugs to target the core genes. Conclusion Based on the comprehensive analysis of the genomic datasets with different sorting methods of OCSCs, we figured out the common driving genes to regulating OCSC and obtained ten new potential therapies for eliminating ovarian cancer stem cells. Hence, the findings of our study might have potential clinical significance.

Cancer genes mutation profiling in calcifying epithelial odontogenic tumour

2017 ◽  
Vol 71 (3) ◽  
pp. 279-283 ◽  
Author(s):  
Sílvia Ferreira de Sousa ◽  
Marina Gonçalves Diniz ◽  
Josiane Alves França ◽  
Thaís dos Santos Fontes Pereira ◽  
Rennan Garcias Moreira ◽  
...  
Keyword(s):  
Tumour Suppressor ◽  
Driver Mutations ◽  
Tumour Suppressor Genes ◽  
Cancer Genes ◽  
Odontogenic Tumour ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Frameshift Deletion ◽  
Calcifying Epithelial Odontogenic Tumour ◽  
Generation Sequencing

AimsTo identify calcifying epithelial odontogenic tumour (CEOT) mutations in oncogenes and tumour suppressor genes.MethodsA panel of 50 genes commonly mutated in cancer was sequenced in CEOT by next-generation sequencing. Sanger sequencing was used to cover the region of the frameshift deletion identified in one sample.ResultsMissense single nucleotide variants (SNVs) with minor allele frequency (MAF) <1% were detected in PTEN, MET and JAK3. A frameshift deletion in CDKN2A occurred in association with a missense mutation in the same gene region, suggesting a second hit in the inactivation of this gene. APC, KDR, KIT, PIK3CA and TP53 missense SNVs were identified; however, these are common SNVs, showing MAF >1%.ConclusionCEOT harbours mutations in the tumour suppressor PTEN and CDKN2A and in the oncogenes JAK3 and MET. As these mutations occurred in only one case each, they are probably not driver mutations for these tumours.

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