Cancer Genomics & Proteomics最新文献

Background/aim: Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy due to limited therapeutic options. Identifying novel genes that influence its progression is critical. This study aimed to investigate the role of CTDNEP1, a phosphatase-encoding gene, in PDAC using multi-omics data from The Cancer Genome Atlas (TCGA).

Materials and methods: We analyzed CTDNEP1 expression in PDAC using the TCGA and Pan-Cancer Atlas datasets. Kaplan-Meier survival analysis was performed to assess the association between CTDNEP1 expression and patient prognosis. Gene Ontology (GO) and KEGG pathway enrichment analyses were conducted to explore the biological processes linked to CTDNEP1 expression. Finally, we examined the relationship between CTDNEP1 expression and the tumor immune microenvironment using immune infiltration analysis.

Results: CTDNEP1 expression was found to be significantly lower in PDAC tissues compared to normal tissues, especially in early-stage tumors. This downregulation was associated with mutations in key driver genes, including KRAS, CDKN2A, TP53, and SMAD4. Importantly, low CTDNEP1 expression correlated with significantly poorer patient prognosis, particularly in stage II PDAC. Functional enrichment analysis revealed that low CTDNEP1 expression is associated with macroautophagy, protein degradation, and immune/inflammatory pathways, while high expression is linked to mitochondrial function and metabolic activity. Furthermore, CTDNEP1 expression showed a positive correlation with immune cell infiltration.

Conclusion: CTDNEP1 functions as a tumor suppressor in PDAC, influencing tumor progression, immune response, and patient survival. Future studies should investigate the detailed regulatory mechanisms of CTDNEP1 and explore its potential as a therapeutic target or biomarker for PDAC.

Background/aim: SIRT4 is a mitochondrial regulator of metabolism and stress responses, yet the mechanisms underlying its induction upon DNA damage remains unclear. This study aimed to define the mechanism of SIRT4 regulation and the role of the miR-15/16 family in this process.

Materials and methods: SIRT4 expression was examined after DNA-damaging treatments in MEFs and HeLa cells. Reporter assays, mRNA decay analysis, and mutagenesis of the SIRT4 3'UTR were performed to identify regulatory mechanisms. Gain- and loss-of-function studies assessed the involvement of the miR-15/16 family. Cell viability was evaluated.

Results: SIRT4 was strongly induced by DNA damage and required for cell survival under genotoxic stress. This induction occurred through mRNA stabilization with the 3'UTR of SIRT4 serving as the determinant of stability. The miR-15/16 family targeted a conserved site within the SIRT4 3'UTR to destabilize its mRNA. Overexpression of miR-15/16 reduced SIRT4 expression and sensitized cells to chemotherapy.

Conclusion: The miR-15/16-SIRT4 axis represents a novel mechanism of post-transcriptional regulation in the DNA damage response and may serve as a therapeutic target to improve the efficacy of chemotherapy.

Myxoid pleomorphic liposarcoma (MPLPS) is an exceedingly rare and recently recognized adipocytic neoplasm that primarily occurs in children and young adults and shows a strong predilection for the mediastinum. Clinically, MPLPS demonstrates aggressive behavior and exhibits a high propensity for systemic spread and a worse overall survival. Some cases have been associated with Li-Fraumeni syndrome. Histologically, MPLPS is composed of a variable mixture of myxoid and pleomorphic liposarcoma-like components. Immunohistochemically, the tumor cells show diffuse expression of CD34 and p16 and loss of nuclear RB expression. MPLPS lacks DNA damage inducible transcript 3 (DDIT3) rearrangements and MDM2 proto-oncogene (MDM2) amplifications but shows tumor protein p53 (TP53) mutations and RB transcriptional co-repressor 1 (RB1) deletions. Moreover, recent studies have demonstrated that the most consistent molecular feature of MPLPS is genome-wide loss of heterozygosity. Surgical excision with negative margins is the mainstay of treatment for localized MPLPS. The treatment of advanced/metastatic MPLPS still poses a huge therapeutic challenge. This review provides information about the clinicoradiological features, pathogenesis, histopathology, and management currently available for MPLPS. In addition, we discuss the differential diagnosis of this novel entity.

Background/aim: Locally advanced Rectal cancer (RC) is treated with neoadjuvant chemoradiation, but treatment resistance is common. We have previously shown that ST6GAL1 causes RC chemoradiation resistance. Exosomes are small particles that can transfer proteins between cells. We hypothesized that exosomes transfer ST6GAL1 between RC cells, spreading treatment resistance.

Materials and methods: We characterized exosomes isolated from multiple ST6GAL1-expressing colorectal cancer (CRC) cell lines. Treatment response was assessed in ST6GAL1-knockdown (KD) cells treated with these exosomes. Single cell RNA sequencing (scRNA-seq) and flow cytometry for surface sialylation were performed on CRC organoids to compare presence of ST6GAL1 RNA and protein activity.

Results: Exosomes from multiple CRC cell lines contained ST6GAL1 protein and ST6GAL1 KD cells treated with these exosomes demonstrated transfer of ST6GAL1 with increase in protein in treated cells, but not mRNA, and the protein localized to the Golgi complex. In addition, treated cells demonstrated increased resistance to chemoradiation-induced apoptosis (p=0.02, n=4) and increased colony formation after treatment (p=0.01, n=4). Single cell sequencing revealed that only 16 percent of cells have ST6GAL1 mRNA but 86 percent have evidence of ST6GAL1 protein activity.

Conclusion: These findings demonstrate that ST6GAL1-containing rectal cancer exosomes transfer ST6GAL1 between cells causing treatment resistance.

Background/aim: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype lacking targeted therapies, characterized by high heterogeneity and poor prognosis. Dysregulated cell cycle progression and aberrant Wnt/β-catenin signaling are critical drivers of TNBC proliferation. This study aimed to advance understanding of TTK driven oncogenesis and assess its promise as a prognostic biomarker and therapeutic target in TNBC.

Materials and methods: We analyzed bulk and single-cell RNA sequencing datasets to assess TTK expression and clinical relevance in breast cancer. TNBC cell lines and normal breast epithelial cells were used for in vitro functional assays, including cell proliferation, colony formation, migration, and cell cycle analysis following TTK knockdown with siRNA. Immunofluorescence and Western blotting evaluated TTK expression and β-catenin pathway activity. Functional enrichment, protein-protein interaction, and pseudotime trajectory analyses elucidated TTK's mechanistic roles.

Results: TTK was overexpressed in breast tumors versus normal tissues, with elevated levels correlating with worse overall and relapse-free survival. TTK knockdown impaired TNBC cell proliferation, colony formation, and migration, and induced G₁ arrest. Single-cell analyses demonstrated TTK enrichment in cancer cells, peaking during S and G₂/M phases. Pseudotime trajectory revealed dynamic TTK upregulation during G₁-S-G₂/M transition. Mechanistically, TTK maintained β-catenin signaling and downstream Cyclin D1 expression, facilitating G₁/S entry and supporting mitotic checkpoint fidelity. Pathway enrichment analyses further confirmed TTK's centrality in cell cycle regulation and proliferative programs.

Conclusion: TTK drives TNBC progression by orchestrating G₁/S and G₂/M transitions and sustaining β-catenin-Cyclin D1 signaling. Its restricted expression in normal tissues, combined with oncogenic effects, positions TTK as a promising prognostic biomarker and therapeutic target. Pharmacological inhibition of TTK, potentially combined with β-catenin pathway inhibitors, may offer an effective strategy for TNBC treatment.

Background/aim: Pathologic complete response (pCR) to neoadjuvant chemotherapy (NACT) is a strong prognostic indicator in triple-negative breast cancer (TNBC). However, reliable predictive biomarkers for pCR remain limited. This study aimed to identify gene expression signatures associated with pCR in TNBC to facilitate more precise treatment stratification.

Materials and methods: Tumor samples from 16 TNBC patients treated with NAC at the Kaohsiung Medical University Hospital (KMUH) were analyzed, including 5 pCR and 11 non-pCR cases. RNA sequencing (RNA-seq) was performed, and differentially expressed genes (DEGs) were identified using DESeq2 (|log₂FC| ≥2, adjusted p<0.05). Gene expression profiles were compared with a validation cohort of 27 NAC-responsive TNBC cases from The Cancer Genome Atlas (TCGA). Overlapping DEGs were identified using Venn diagram analysis, and drug-gene interaction databases were queried to explore therapeutic relevance.

Results: In the KMUH cohort, 175 DEGs were identified, including 146 up-regulated and 29 down-regulated genes in non-pCR tumors. Fifteen DEGs demonstrated consistent differential expression patterns between KMUH and TCGA datasets, showing enrichment in pCR samples. These genes may serve as predictive biomarkers for NAC response. Notably, several of these genes are potentially druggable, suggesting opportunities for targeted therapy in chemoresistant TNBC.

Conclusion: We identified and validated a 15 gene signature associated with pCR in TNBC across independent cohorts. These findings offer a promising basis for improving patient stratification, guiding treatment decisions, and developing targeted therapies for NAC-resistant TNBC.

Background/aim: T-cell large granular lymphocyte leukemia (T-LGLL) is a rare, indolent lymphoproliferative disorder of cytotoxic T cells in the peripheral blood, bone marrow, and spleen. This analysis was conducted to characterize genomic alterations and highlight potential therapeutic targets, with the goal of refining the molecular landscape of T-LGLL by emphasizing population-specific biomarkers.

Materials and methods: This study utilized the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database to identify common gene mutations. Using the AACR GENIE database, a retrospective analysis of T-cell large granular lymphocyte leukemia (T-LGLL) samples was performed. The data was evaluated by extracting patient demographics and excluding synonymous mutations from consideration. Statistical significance was assessed using chi-squared tests and computational analyses in RStudio (R Foundation for Statistical Computing, Boston, MA, USA). Somatic mutations and chromosomal copy number variations were evaluated, with statistical significance defined as p=0.001.

Results: Frequently observed somatic mutations included STAT3 (41.7%), STAT2 (20.9%), KMT2D (11.3%), SETD1B (8.7%), TP53 (7.0%), TNFAIP3 (6.1%), DNMT3A (5.2%), FAS (4.3%), SMARCA4 (3.5%), EPHB1 (2.6%), KSR2 (2.6%), ALOX12B (2.6%), EGFR (2.6%), DDX3X (7.0%), and IKZF3 (1.7%). When stratified by demographic variables, males and White patients demonstrated a higher frequency of mutations.

Conclusion: This study provides a comprehensive genomic profile of T-LGLL, identifying recurrent somatic mutations and commonly affected pathways. Notably, frequent alterations were observed in the FAS-FASL signaling pathway, underscoring its potential as a target for therapeutic development.

Background/aim: Circulating tumor DNA (ctDNA) testing has emerged as a minimally invasive tool for precision oncology, enabling dynamic monitoring of tumor burden and treatment response. However, commercial ctDNA NGS assays often omit clinically important oncogenes, limiting accurate assessment of copy-number variation (CNV). Amplifications of MYC and MYCN are key drivers of tumor progression and therapeutic resistance, and their detection is required under the Korean National Health Insurance coverage criteria. We evaluated whether a custom spike-in panel added to the Avenio ctDNA Expanded Kit improves CNV detection for MYC and MYCN to meet these clinical and regulatory requirements.

Materials and methods: Spike-in targets were designed with KAPA Target Enrichment Custom Designs and integrated into the Avenio panel. Reference materials (Horizon Structural Multiplex cfDNA Standard, 5% (MYCN ≈9.5 copies); Seraseq ctDNA Complete, 1% (MYC≈3.07 copies)) were measured in triplicate; Seraseq was additionally diluted 1:2 and 1:10. Eight cancer-free plasma samples established the baseline. Libraries were sequenced on a NextSeq 550Dx (high-output). CNV analysis used CNVkit v0.9.9 with custom parameters (reference spread threshold increased 1.0→1.5; GC upper limit relaxed 0.7→0.8, lower limit retained at 0.3). Log2 fold-change versus healthy controls assessed CNV signals.

Results: Mean exon coverage was 698.5 for MYCN (range=325.4-1081.2) and 740.3 for MYC (range=438.8-1221.7). In the Horizon material, all MYCN exons showed ≥3.6-fold change (mean 4.2; inferred CNV ≈8.2), concordant with expected amplification. Seraseq showed a mean MYC fold change of 1.46 (inferred CNV ≈2.94); diluted samples yielded CNV estimates of 2.79 (1:2) and 2.67 (1:10), indicating limited sensitivity below ~3 copies. One MYC exon reproducibly underperformed despite adequate coverage.

Conclusion: Incorporation of a spike-in panel into the Avenio ctDNA assay enabled reliable detection of high-level MYC/MYCN amplifications and fulfilled practical requirements for local reimbursement. The estimated CNV limit of detection in this setting is ≈3 copies. Further replicate testing and validation with clinical specimens are warranted to refine sensitivity and interlaboratory robustness.

Background/aim: Oral squamous cell carcinoma (OSCC) prognosis is often poor due to metastasis driven by the epithelial-mesenchymal transition (EMT), creating a need for biomarkers that reflect this process. Exosomal microRNAs (miRNAs) secreted by cancer cells regulate EMT, but their complex, network-level interactions are poorly understood. This study aimed to identify a prognostic gene signature by analyzing the exosomal miRNA network from a TGFβ1-induced EMT cell model and validating its clinical relevance in a patient cohort.

Materials and methods: A TGFβ1-induced EMT model was established in OSCC cells and the exosomal miRNAs from their conditioned media was profiled using microarrays. A 43-gene signature was developed based on the collective targets of the EMT-regulated miRNA network. The prognostic significance of this signature was then validated in The Cancer Genome Atlas (TCGA) OSCC patient cohort (n=315) using hierarchical clustering and Kaplan-Meier survival analysis.

Results: The analysis identified an Exo-miR EMT signature comprising miRNAs that collectively regulate EMT-associated gene networks. Using this signature, hierarchical clustering successfully stratified patients into two distinct subgroups with different prognoses. Kaplan-Meier analysis revealed that the high-risk group had a significantly poorer overall survival than the low-risk group (p=0.02). Multivariate analysis confirmed that the Exo-miR EMT signature was an independent prognostic factor for OSCC.

Conclusion: EMT-related gene networks regulated by exosomal miRNAs carry clinically meaningful information about tumor aggressiveness in OSCC. The derived Exo-miR EMT signature offers biologically grounded risk stratification that complements conventional clinicopathological factors and supports further development of exosome-based liquid biopsies for prognostic assessment in OSCC.