Abstract:The overwhelming amount of genetic alterations identified through cancer genome sequencing requires complementary approaches to interpret their significance and interactions. We developed a novel whole-body insertional mutagenesis screen in mice, designed for the discovery of Pten-cooperating tumor suppressors, in which mobilization of a single-copy inactivating Sleeping Beauty transposon is coupled to Pten disruption within the same genome. The analysis of 278 transposition-induced prostate, breast and skin t… Show more
“…Somatically acquired pathogenic variants in WAC are associated with a specific class of acute myeloid leukemia or lymphoma (Ding et al, ; Mitchell et al, ). Recent studies of mouse cancer cell lines have described that WAC is a novel PTEN ‐cooperating tumor suppressor gene, and the haploinsufficiency of WAC can contribute to tumorigenesis (de la Rosa et al, ). We screened the somatic pathogenic variant database COSMIC for WAC pathogenic variants that fulfill the following criteria: (a) a pathogenic variant that has been documented to be present in tumor tissue but absent in normal tissue; (b) a truncating variant including nonsense variants or frameshift variants; and (c) a pathogenic variant detected in hematologic malignancies (Ding et al, ; Garg et al, ; Kataoka et al, ; Metzeler et al, ; Morin et al, ; Rossi et al, ; Welch et al, ).…”
Somatic truncating variants of the WAC gene have been observed in patients with hematologic malignancies. Furthermore, de novo heterozygous constitutional pathogenic variants of WAC have recently been shown to cause a syndromic form of intellectual disability, DeSanto-Shinawi syndrome. It is unknown whether the constitutional pathogenic variants observed in the intellectual disability syndrome overlap with the somatic pathogenic variants observed in hematologic abnormalities. Herein, we report three patients with constitutional truncating variants of WAC in an attempt to address the above questions. All three of the patients had mild to moderate intellectual disability and dysmorphic features. We then reviewed the phenotypic features of 19 patients with DeSanto-Shinawi syndrome, including the three currently reported ones: eight and seven patients showed a bulbous nasal tip and short fingers, respectively. As for the pathogenetic mechanism, we demonstrated that the expression level of the mRNA derived from the wildtype allele was higher than that derived from the mutated allele, demonstrating nonsense-mediated mRNA decay. This observation makes a haploinsufficiency mechanism likely. Reviews of the constitutional and somatic pathogenic variants observed in patients with hematologic malignancies showed a significant overlap of the two. To date, no patients with DeSanto-Shinawi syndrome have been reported to have developed hematologic abnormalities, except for one of the three patients reported herein who developed leukopenia and thrombocytopenia at the age of 19 years. Larger data sets are required to determine hematologic prognosis of patients with constitutional WAC variants.
“…Somatically acquired pathogenic variants in WAC are associated with a specific class of acute myeloid leukemia or lymphoma (Ding et al, ; Mitchell et al, ). Recent studies of mouse cancer cell lines have described that WAC is a novel PTEN ‐cooperating tumor suppressor gene, and the haploinsufficiency of WAC can contribute to tumorigenesis (de la Rosa et al, ). We screened the somatic pathogenic variant database COSMIC for WAC pathogenic variants that fulfill the following criteria: (a) a pathogenic variant that has been documented to be present in tumor tissue but absent in normal tissue; (b) a truncating variant including nonsense variants or frameshift variants; and (c) a pathogenic variant detected in hematologic malignancies (Ding et al, ; Garg et al, ; Kataoka et al, ; Metzeler et al, ; Morin et al, ; Rossi et al, ; Welch et al, ).…”
Somatic truncating variants of the WAC gene have been observed in patients with hematologic malignancies. Furthermore, de novo heterozygous constitutional pathogenic variants of WAC have recently been shown to cause a syndromic form of intellectual disability, DeSanto-Shinawi syndrome. It is unknown whether the constitutional pathogenic variants observed in the intellectual disability syndrome overlap with the somatic pathogenic variants observed in hematologic abnormalities. Herein, we report three patients with constitutional truncating variants of WAC in an attempt to address the above questions. All three of the patients had mild to moderate intellectual disability and dysmorphic features. We then reviewed the phenotypic features of 19 patients with DeSanto-Shinawi syndrome, including the three currently reported ones: eight and seven patients showed a bulbous nasal tip and short fingers, respectively. As for the pathogenetic mechanism, we demonstrated that the expression level of the mRNA derived from the wildtype allele was higher than that derived from the mutated allele, demonstrating nonsense-mediated mRNA decay. This observation makes a haploinsufficiency mechanism likely. Reviews of the constitutional and somatic pathogenic variants observed in patients with hematologic malignancies showed a significant overlap of the two. To date, no patients with DeSanto-Shinawi syndrome have been reported to have developed hematologic abnormalities, except for one of the three patients reported herein who developed leukopenia and thrombocytopenia at the age of 19 years. Larger data sets are required to determine hematologic prognosis of patients with constitutional WAC variants.
“…Based on this innovation, we have identified sets of hundreds of known and novel cancer genes involved in prostate, breast, and skin cancer, all of them predicted to behave as TSGs. 6 We then focused on prostate cancer, for which PTEN relevance is well documented, and validated the implication of several of the genes identified for the progression of the disease in humans. 6 Figure 1.…”
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confidence: 98%
“… 6 We then focused on prostate cancer, for which PTEN relevance is well documented, and validated the implication of several of the genes identified for the progression of the disease in humans. 6 Figure 1. Transposon-based screen for identifying Pten -cooperating tumor suppressors in cancer.…”
mentioning
confidence: 98%
“… 4,5 By coupling Pten -disruption to mobilization of a Sleeping Beauty inactivating transposon within each cell, we have recently performed a novel genome-wide survey for Pten -cooperating TSGs in mice. 6 The transposon, targeted to the Pten locus, carries a critical exon of this gene when it is mobilized, leading to Pten inactivation and subsequent generation of an additional mutation when randomly reinserted into the genome ( Fig. 1 ).…”
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confidence: 99%
“…Cross-comparison with human cancer data sets supported the relevance of these genes for PTEN -cooperating human prostate tumor suppression as they are significantly enriched in (1) known and putative human cancer genes, (2) genes whose mRNA expression levels decline concomitantly with those of PTEN in human prostate cancer samples, and (3) genes frequently inactivated by homozygous deletion in human prostate cancer. 6 Among them, those encoding chromatin/histone modifiers and involved in RNA metabolic processes (RNA stability, splicing, and transcriptional regulation) are strongly overrepresented, followed by those implicated in ubiquitin-mediated proteolysis (mainly E3 ligases). Interestingly, some of these genes have been described previously to be altered in human prostate cancer through different mechanisms, including mutation ( ARID1A, KDM6A, MLL1, MLL5 , and MAGI3 ), copy-number variation ( ETV6 and FOXP1 ), gene fusion ( TBL1XR1, FUBP1 , and EPB41 ), transcriptional dysregulation ( MEIS1 and PBX1 ), or single nucleotide polymorphism ( RASA1 ).…”
We have recently performed a whole-body, genome-wide screen in mice using a single-copy inactivating transposon for the identification of Pten (phosphatase and tensin homolog)-cooperating tumor suppressor genes (TSGs). We identified known and putative TSGs in multiple cancer types and validated the functional and clinical relevance of several promising candidates for human prostate cancer.
To investigate the apoptosis and inflammatory response of microRNA‐27a‐5p (miR‐27a‐5p) in pancreatic acinar cells of acute pancreatitis (AP) and its related mechanisms. Rat pancreatic acinar cell line AR42J was treated with caerulein (10nmol/L) to construct an acute pancreatitis cell model. Quantitative real‐time polymerase chain reaction was performed to measure the expression of miR‐27a‐5p; The miR‐27a‐5p mimic was transfected into cell, and the apoptosis rate of the cells was detected by flow cytometry; The levels of TNF‐α, IL‐1, and IL‐6 in the culture supernatant were determined by enzyme‐linked immunosorbent assay; TargetScans database predicted and dual luciferase reporter gene assay verified the relationship between miR‐27a‐5p and the phosphatase and tensin homolog deleted on chromosome 10 (PTEN); The recovery experiment explored the apoptosis and the effects of inflammatory responses. The expression of miR‐27a‐5p decreased gradually (P < 0.05) and the expression of PTEN increased gradually (P < 0.05) with the prolongation of acting time. Upregulation of miR‐27a‐5p significantly promoted cell apoptosis (P < 0.05) and inhibited inflammatory response (P < 0.05); The TargetScans database predicted that the 3'UTR of PTEN contains a base complementary to the miR‐27a‐5p seed region. Cotransfection of wild‐type vector (PTEN‐WT) with miR‐27a‐5p mimic or miR‐27a‐5p inhibitor significantly affected the relative activity of luciferase (P < 0.05), and no significant impact was observed in mutant PTEN‐MUT. Compared with miR‐27a‐5p + pcDNA group, transfection of miR‐27a‐5p mimic and pcDNA‐PTEN significantly increased the expression of PTEN (P < 0.05), decreased the apoptotic rate (P < 0.05), and increased the inflammatory response (P < 0.05). miR‐27a‐5p induced apoptosis and inhibited the inflammatory response of pancreatic acinar cells in AP by targeting PTEN.
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