Current Issue : October-December Volume : 2021 Issue Number : 4 Articles : 5 Articles
Background: DNA polymerase epsilon (POLE) is encoded by the POLE gene, and POLE-driven tumors are characterized by high mutational rates. POLE-driven tumors are relatively common in endometrial and colorectal cancer, and their presence is increasingly recognized in ovarian cancer (OC) of endometrioid type. POLE-driven cases possess an abundance of TCT > TAT and TCG > TTG somatic mutations characterized by mutational signature 10 from the Catalog of Somatic Mutations in Cancer (COSMIC). By quantifying the contribution of COSMIC mutational signature 10 in RNA sequencing (RNA-seq) we set out to identify POLE-driven tumors in a set of unselected Mayo Clinic OC. Methods: Mutational profiles were calculated using expressed single-nucleotide variants (eSNV) in the Mayo Clinic OC tumors (n = 195), The Cancer Genome Atlas (TCGA) OC tumors (n = 419), and the Genotype-Tissue Expression (GTEx) normal ovarian tissues (n = 84). Non-negative Matrix Factorization (NMF) of the mutational profiles inferred the contribution per sample of four distinct mutational signatures, one of which corresponds to COSMIC mutational signature 10. Results: In the Mayo Clinic OC cohort we identified six tumors with a predicted contribution from COSMIC mutational signature 10 of over five mutations per megabase. These six cases harbored known POLE hotspot mutations (P286R, S297F, V411L, and A456P) and were of endometrioid histotype (P = 5e−04). These six tumors had an early onset (average age of patients at onset, 48.33 years) when compared to non-POLE endometrioid OC cohort (average age at onset, 60.13 years; P = .008). Samples from TCGA and GTEx had a low COSMIC signature 10 contribution (median 0.16 mutations per megabase; maximum 1.78 mutations per megabase) and carried no POLE hotspot mutations. Conclusions: From the largest cohort of RNA-seq from endometrioid OC to date (n = 53), we identified six hypermutated samples likely driven by POLE (frequency, 11%). Our result suggests the clinical need to screen for POLE driver mutations in endometrioid OC, which can guide enrollment in immunotherapy clinical trials....
Background: Sepsis is a complicated disease with systemic inflammation or organ dysfunction, and it is the leading cause of acute lung injury (ALI). Long non-coding RNAs (lncRNAs) have played important roles in the pathogenesis of sepsis. This study was designed to explore the biological function and regulatory mechanism of cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1) in lipopolysaccharide (LPS)-induced lung injury. Methods: ALI model was established after human lung epithelial cell line BEAS-2B was exposed to LPS. CDKN2BAS1, microRNA-140-5p (miR-140-5p) and transforming Growth Factor Beta Receptor II (TGFBR2) levels were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell viability was measured using Cell Counting Kit-8 (CCK-8). Cell apoptosis was assessed by caspase3 activity and flow cytometry. Inflammatory cytokines were examined via enzyme-linked immunosorbent assay (ELISA). Protein analysis was performed through western blot. Dual-luciferase reporter, RNA immunoprecipitation (RIP) and pull-down assays were applied to validate the interaction between targets. Results: CDKN2B-AS1 and TGFBR2 were abnormally upregulated in sepsis patients. Functionally, CDKN2B-AS1 or TGFBR2 knockdown promoted cell growth but inhibited cell apoptosis and inflammatory response in LPS-treated BEAS-2B cells. Moreover, the regulation of CDKN2B-AS1 in LPS-induced cell injury was achieved by increasing the TGFBR2 expression. CDKN2B-AS1 was identified as a miR-140-5p sponge and TGFBR2 was a target of miR-140-5p. Furthermore, CDKN2B-AS1 could regulate the TGFBR2/Smad3 pathway by sponging miR-140-5p. Conclusions: These results suggested that CDKN2B-AS1 contributed to the LPS-mediated apoptosis and inflammation in BEAS-2B cells via the miR-140-5p/TGFBR2/Smad3 axis....
Background: Hereditary hemorrhagic telangiectasia (HHT) is a disease characterized by arteriovenous malformations in the skin and mucous membranes. We enrolled a large pedigree comprising 32 living members, and screened for mutations responsible for HHT. Methods: We performed whole-exome sequencing to identify novel mutations in the pedigree after excluding three previously reported HHT-related genes using Sanger sequencing. We then performed in silico functional analysis of candidate mutations that were obtained using a variant filtering strategy to identify mutations responsible for HHT. Results: After screening the HHT-related genes, activin A receptor-like type 1 (ACVRL1), endoglin (ENG), and SMAD family member 4 (SMAD4), we did not detect any co-segregated mutations in this pedigree. Whole-exome sequencing analysis of 7 members and Sanger sequencing analysis of 16 additional members identified a mutation (c.784A > G) in the NSF attachment protein gamma (NAPG) gene that co-segregated with the disease. Functional prediction showed that the mutation was deleterious and might change the conformational stability of the NAPG protein. Conclusions: NAPG c.784A > G may potentially lead to HHT. These results expand the current understanding of the genetic contributions to HHT pathogenesis....
In this clinical report, we describe a male infant and his mother, who had similar congenital heart defects. )ey were both diagnosed neonatally with total anomalous pulmonary venous connection (TAPVC) in combination with other heart defects. Neither of the two had any other organ malformations or dysmorphic facial features. SNP-array identified a central 22q11.2 microdeletion in the male infant and his mother as well as in the maternal grandmother and maternal aunt. )e mother and the maternal aunt additionally harbored a 15q11.2 BP1-BP2 microdeletion. )e maternal grandmother was unaffected by heart disease. However, heart computed tomography scan of the maternal aunt revealed a quadricuspid aortic valve. Additionally, the maternal grandmother and the maternal aunt both had significant learning disabilities. Rarely, TAPVC has been described in patients with the common 22q11.2 microdeletions. However, to the best of our knowledge, TAPVC has not previously been reported in patients with this small central 22q11.2 microdeletion. Haploinsufficiency of TBX1 was originally thought to be the main cause of the 22q11.2 microdeletion syndrome phenotype, but TBX1 is not included in the atypical central 22q11.2 microdeletion. Previous reports have suggested an association between TAPVC and the 15q11.2 BP1-BP2 microdeletion. Our report does not support this association as the maternal aunt, who harbors both microdeletions, is unaffected by TAPVC, and the male infant affected by TAPVC does not harbor the 15q11.2 BP1-BP2 microdeletion. Our findings support that genes located in the central 22q11.2 region are important for heart development and that haploinsufficiency of these genes plays a crucial role in the development of the rare heart defect TAPVC....
Background: tRNA-derived fragments have been reported to be key regulatory factors in human tumors. However, their roles in the progression of multiple myeloma remain unknown. Results: This study employed RNA-sequencing to explore the expression profiles of tRFs/tiRNAs in new diagnosed MM and relapsed/refractory MM samples. The expression of selected tRFs/tiRNAs were further validated in clinical specimens and myeloma cell lines by qPCR. Bioinformatic analysis was performed to predict their roles in multiple myeloma progression.We identified 10 upregulated tRFs/tiRNAs and 16 downregulated tRFs/tiRNAs. GO enrichment and KEGG pathway analysis were performed to analyse the functions of 1 significantly up-regulated and 1 significantly down-regulated tRNA-derived fragments. tRFs/tiRNAs may be involved in MM progression and drug-resistance. Conclusion: tRFs/tiRNAs were dysregulated and could be potential biomarkers for relapsed/refractory MM....
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