Cancer Genetics最新文献

Background

Objective

Methods

Results

Conclusions

Introduction

Materials and Methods

Results

Conclusion

Objective

Methods

Results

Conclusion

The translocation between chromosomes 1 and 19 t(1;19) produces the TCF3::PBX1 fusion protein, which leads to childhood pre-B-cell acute lymphoblastic leukemia (ALL). The molecular mechanism of oncogenesis, however, remains obscure. This study aims to identify the genes specifically dysregulated in TCF3::PBX1 translocation. The publicly available expression microarray datasets on ALL were used for weighted gene co-expression network analysis (WGCNA) to identify modules associated with TCF3::PBX1. The available knockdown and ChIP-Seq datasets were used to assess the direct targets of TCF3::PBX1. The WGCNA revealed a module enriched in genes involved in the metal ion stress to be positively correlated with TCF3::PBX1, with metallothionein isoform MT1 subtypes MT1E, MT1F, MT1G, MT1H, and MT1X as the hub genes. Of the 145 positively correlated genes, 19 were downregulated upon TCF3::PBX1 knockdown. Eleven of these 19 genes including MT1G, showed TCF3::PBX1 occupancy at the promoter. The Metallothionein 1 family has been implicated in various cancers; however, their role in t(1;19) pre-B-cell ALL has not been previously demonstrated. Our analysis effectively accounts for the cellular and population-level heterogeneity and identifies a novel mechanism for the TCF3::PBX1 action.

Background

Gene therapy in bladder cancer (BLCA) remains an area ripe for exploration. Recent studies have highlighted the crucial role of SHTN1 in the initiation and progression of various cancers and SHTN1 may have interacted with the FGFR gene. However, its specific function in BLCA remains unclear.

Materials and methods

We investigated the association between SHTN1 expression and prognosis, immune infiltration, and the tumor microenvironment (TME) across multiple malignancies using 433 BLCA samples from The Cancer Genome Atlas (TCGA). Differential gene expression analysis, functional annotation via Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) were performed for SHTN1-related genes by using R packages. Immune response and TME scores, along with drug sensitivity profiles of SHTN1, were analyzed using R packages. Immunohistochemistry (IHC) and western blotting were conducted to assess SHTN1 expression in surgical specimens from BLCA patients.CCK8 assay and cells wound healing assay were performed.The bioinformatics was analyzed by R software. Significant differences were evaluated using unpaired t test.

Results

SHTN1 expression levels were significantly elevated in BLCA associated with poor prognosis (p < 0.01). Receiver operating characteristic (ROC) curves and nomograms demonstrated the diagnostic and prognostic efficacy of SHTN1 in BLCA. Notably, SHTN1 expression was higher in high-grade BLCA compared to lower-grade (p = 5.6e-10), a finding corroborated by IHC and western blotting. Pathway enrichment analysis revealed significant involvement of the Neuroactive ligand-receptor interaction and Chemical carcinogenesis - DNA adducts signaling pathways among SHTN1 differentially expressed genes. In terms of immune infiltration, T cells CD8, T cells follicular helper, and dendritic cells were predominant in the SHTN1 low-expression group, whereas macrophages M0 and M2, and mast cells were predominant in the high-expression group. Multivariate Cox regression analysis identified SHTN1 as an independent prognostic factor for overall survival (HR = 2.93; 95 % CI = 1.40–6.13; p = 0.004).CCK8 and wound healing experiments showed that SHTN1 knockdown reduced the cell proliferation and migration. Western blot showed that the EMT pathway was clearly associated with SHTN1.

Conclusions

Our findings suggest that SHTN1 holds promise as a prognostic and diagnostic biomarker for BLCA. Moreover, it is closely associated with elevated immune infiltration and distinct characteristics of the tumor microenvironment in BLCA.

Tyrosine Kinase Inhibitors (TKI), such as Imatinib, are known for their effectiveness in achieving complete remission from Chronic Myeloid Leukemia (CML), a malignancy caused by a reciprocal translocation between the terminal fragments of the long arms of chromosomes 9 and 22 that leads to the famous chimeric BCR::ABL1 gene. Mutations in this fusion gene may induce resistance to TKI treatment, which requires prescribing a second-, or third-generation TKI medication. We report here a case of a Moroccan CML patient with secondary resistance to the frontline TKI treatment (Imatinib), in which, BCR::ABL1 cDNA sequencing reveals the novel mutation p.K375M at the ABL1 Kinase Domain. In-silico prediction tools confirm the pathogenicity of the p.K375M substitution. Homology analysis indicated that the residue is highly conserved and located in a stable region. This potentially pathogenic mutation is likely to disrupt the BCR::ABL1-Imatinib binding, leading to the observed resistance. To overcome the treatment resistance, Imatinib should be substituted with a second-generation TKI medication, such as Dasatinib, Bosutinib, or Nilotinib. The present study further widens the spectrum of TKI resistance mutations and emphasizes particularly the crucial role of molecular investigation in personalizing treatment for CML patients, ensuring efficient follow-up and appropriate healthcare.