Genetics Research

Systematically Prognostic Analyses of Gastric Cancer Patients with Ovarian Metastasis

Ovarian metastasis of gastric cancer indicates that the disease has reached the late stage and the opportunity for radical surgery is restricted. However, the clinical characteristics and prognosis of patients with gastric cancer ovarian metastasis (GCOM) remain to be illustrated. Here, we retrieved the information of 780 GCOM cases from the Surveillance, Epidemiology, and End Results (SEERs) database and analyzed their clinicopathological characteristics as well as their survival. According to our data, most GCOM patients showed poor pathological differentiation, advanced T and N stages. The prognostic factors include patients’ age, tumor size, surgical resection, and chemotherapy treatment. Of note, the marriage status was also identified as an independent prognostic factor. Besides the identification of prognostic factors, we established nomograms to help predict the overall survival and cancer-specific survival of GCOM, respectively.

BRCA1 Exon 11 Mutations in Breast Cancer: A Study From Pakistan

Breast cancer ranks among the top causes of cancer‐related deaths in women around the globe, with genetic mutations in the BRCA1 gene being a frequent cause of breast or ovarian cancer. This study investigates hotspot mutations in exon 11 of the BRCA1 gene among Pakistani women diagnosed with breast cancer. Thirty clinically diagnosed breast cancer patients, all women, were enrolled in the current study, and high‐quality DNA was extracted from peripheral blood samples. Two of the twenty‐five successfully sequenced samples had a homozygous missense variant (c.2312T > C: p.Leu771Ser) detected by Sanger sequencing after PCR amplification. Upon investigation in the ClinVar database, the identified variant showed conflicting interpretations of pathogenicity. Demographic data highlighted an early disease onset, showing that 56% of patients were under 50 years of age. The need for genetic screening was further supported by the fact that 24% of the patients had a positive family history of cancer. Our study emphasizes the necessity of screening BRCA1 gene mutations to better understand the pathogenic potential of the identified variants in the Pakistani population.

ASPM, CDC20, DLGAP5, BUB1B, CDCA8, and NCAPG May Serve as Diagnostic and Prognostic Biomarkers in Endometrial Carcinoma

Uterine Corpus Endometrial Carcinoma (UCEC), the most common gynecologic malignancy in developed countries, remains to be a major public health problem. Further studies are surely needed to elucidate the tumorigenesis of UCEC. Herein, intersecting 203 differentially expressed genes (DEGs) were identified with the GSE17025, GSE63678, and The Cancer Genome Atlas-UCEC datasets. The Gene Ontology/Kyoto Encyclopedia of Genes and Genomes functional enrichment analysis and protein-protein interaction (PPI) network were performed on those 203 DEGs. Intriguingly, 6 of the top 10 nodes in the PPI network were related to unfavorable prognosis, that is, ASPM, CDC20, DLGAP5, BUB1B, CDCA8, and NCAPG. The mRNA and protein expression levels of the 6 hub genes were elevated in UCEC tissues compared to normal tissues. Higher expression of the 6 hub genes was associated with poor prognostic clinicopathological characteristics. The receiver operating characteristic curve suggested the significant diagnostic ability of the 6 hub genes for UCEC. Then, underlying pathogeneses of UCEC including promoter methylation level, TP53 mutation status, genomic genetic variation, and immune cells infiltration were analyzed. The mRNA expression level of the 6 hub genes was also higher in cervical squamous cell carcinoma and endocervical adenocarcinoma, uterine carcinosarcoma, and ovarian serous cystadenocarcinoma tissues than in corresponding normal tissues. In conclusion, ASPM, CDC20, DLGAP5, BUB1B, CDCA8, and NCAPG may be considered diagnostic and prognostic biomarkers in UCEC.

TPX2 Serves as a Cancer Susceptibility Gene and Is Closely Associated with the Poor Prognosis of Endometrial Cancer

Background. Endometrial cancer (EC) is a common tumor of the genital tract that affects the female reproductive system but with only limited treatment options. We aimed to discover new prognostic biomarkers for EC. Methods. We used mRNA-seq data to detect differentially expressed genes (DEGs) between EC and control tissues. Detailed clinicopathological information was collected, and changes in the mRNA and protein levels of hub DEGs were analyzed in EC. Copy number variation (CNV) was also evaluated for its association with the pathogenesis of EC. Gene set enrichment analysis (GSEA) was conducted to enrich significant pathways driven by the hub genes. Cox regression analysis was used to select variables to create a nomogram. The nomogram was calibrated by applying the concordance index (C-index), and net benefits of the nomogram at different threshold probabilities were quantified using decision curve analysis (DCA). Results. Differential expression analysis identified 24 DEGs as potential risk factors for EC. Survival analysis revealed that TPX2 expression was related to worsening overall survival in patients with advanced EC. A high CNV was associated with the overexpression of TPX2; this suggested that modifications in the cell-cycle pathway might be crucial in the advancement of EC. Moreover, an individualized nomogram was developed for TPX2 incorporating clinical factors; this was also evaluated for its ability to predict EC. Calibration and DCA analyses confirmed the robustness and clinical usefulness of the nomogram. Conclusion. We offer novel insights into the pathogenesis and molecular mechanisms of EC. The overexpression of TPX2 was related to a poorer prognosis and could serve as a biomarker for predicting prognostic outcomes in EC patients.

Association Between rs920778 Polymorphisms and Cancer Risk: An Updated Meta‐Analysis

Background: A growing number of studies are exploring the association between HOTAIR rs920778 polymorphisms and cancer risk, but to date, there has been controversy and uncertainty. Preliminary evidence suggests that this polymorphism may influence cancer susceptibility, particularly in Asian populations and specific cancer types such as cervical cancer (CC) and breast cancer (BC). We therefore conducted an updated meta‐analysis to accurately assess the association of the HOTAIR rs920778 polymorphism with cancer risk. Method: Comprehensive literature searches were performed in PubMed, Embase, and Web of Science up to September 8, 2023. Inclusion criteria included case‐control studies with allele frequency data for both cases and controls. A total of 29 case‐control studies were selected for quantitative analysis. Crude odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using Stata software (Version 11) to evaluate the association between the rs920778 polymorphism and cancer risk. Heterogeneity and publication bias were assessed using chi‐square tests, I 2 statistics, and funnel plots with Egger’s test. Results: Our analysis of the results found a significant association between the rs920778 polymorphism and cancer susceptibility. In Asian populations, all five genetic models of the rs920778 polymorphism have been shown to increase overall cancer susceptibility. At the same time, we performed stratified analyses based on cancer type and found that all genetic models revealed significantly increased susceptibility to CC in Asian populations. Conversely, the heterozygote model of rs920778 demonstrated significantly reduced susceptibility to BC, with consistent effects across racial groups. Conclusions: Our meta‐analysis demonstrated that the HOTAIR rs920778 polymorphism may be a risk factor for cancer but may serve as a protective factor for BC. Future studies require larger sample sizes and gene function analysis, suggesting that the rs920778 polymorphism could serve as a genetic biomarker to guide targeted therapies or cancer screening.

Ultrasound-Targeted Microbubble Destruction-Mediated Inhibition of Livin Expression Accelerates Ovarian Cancer Cell Apoptosis

Objective. Ultrasound-targeted microbubble destruction (UTMD) technique has recently been developed as a nonviral delivery of gene therapy. This study aimed at investigating the survival and apoptosis of ovarian cancer cell line OVCA-433 by inhibiting Livin expression through ultrasound-targeted microbubble destruction. Methods. We synthesized a targeted microbubble agent for UTMD-mediated shRNA against Livin gene in human ovarian cancer OVCA-433 cells. Lipid microbubbles were conjugated with a luteinizing hormone-releasing hormone analog (LHRHa) by an avidin-biotin linkage to target the ovarian cancer OVCA-433 cells expressing LHRH receptors. The microbubbles were mixed with the recombinant plasmid harboring shRNA-Livin. shRNA-Livin was transfected into OVCA-433 cells upon exposure to 1 MHz pulsed ultrasound beam (0.5 W/cm2) for 8 s. Cell survival was measured by the MTT assay, cell apoptosis by flow cytometry using annexin V/PI double staining, and cell ultrastructure by using the transmission electron microscope. The mRNA and protein expression levels of caspase-3 and caspase-8 were detected by RT-qPCR and western blotting. Results. UTMD-mediated delivery of shRNA-Livin remarkably reduced the survival of OVCA-433 cells but promoted the apoptosis compared with shRNA-Livin alone, shRNA-Livin plus nontargeted microbubbles, and shRNA-Livin plus LHRHa-conjugated microbubbles containing shRNA-Livin with or without exposure to ultrasound pulses. It was also found that UTMD-mediated delivery of shRNA-Livin notably declined the mRNA and protein expression levels of caspase-3 and caspase-8 in OVCA-433 cells compared with shRNA-Livin alone, shRNA-Livin plus nontargeted microbubbles, and shRNA-Livin plus LHRHa-conjugated microbubbles containing shRNA-Livin with or without exposure to ultrasound pulses. Conclusion. Our experiment verifies the hypothesis that ultrasound mediation of targeted microbubbles can enhance the transfection efficiency of shRNA-Livin in ovarian cancer cells.

Molecular Subtype Classification and Mechanistic Investigation Based on Ferroptosis‐Related lncRNAs in Ovarian Cancer

Ovarian cancer (OC) ranks among the most prevalent malignant tumors in women, contributing significantly to mortality rates. This disease exhibits considerable heterogeneity, characterized by intricate molecular and genetic alterations. Ferroptosis, a distinct form of cell death, has emerged as a critical factor in various cancers, including OC. However, the regulatory mechanisms underlying ferroptosis in OC patients remain unclear and require further investigation. This study aimed to identify lncRNA associated with OC and elucidate the underlying mechanisms through bioinformatics methods and experimental validation. Ferroptosis‐related lncRNAs (FRLs) was identified in OC, and its prognostic value was assessed using univariate Cox analysis. Additionally, the molecular subtypes of FRLs were evaluated through the ConsensusClusterPlus software package. Notably, Cluster 2 exhibited a low TME score, which was linked to a poorer prognosis. The GSEA suggested that Cluster 2 shared similarities with other clusters associated with worse survival outcomes, likely due to the activation of tumor‐associated pathways. In vitro experiments further confirmed that certain lncRNAs could be upregulated under ferroptotic conditions. We focused on two lncRNAs, AC027348.1 and TRAM2‐AS1, which were not noticed before and were significantly upregulated, to explore their regulatory effects on ferroptosis. The underlying mechanisms were preliminarily investigated through transcriptome sequencing. In summary, our findings offer new insights into the pathogenesis of OC, particularly regarding the role of lncRNAs related to ferroptosis.