Concurrent OPA1 mutation and chromosome 3q deletion leading to Behr syndrome: a case report.

BACKGROUND: Optic atrophy 1 (OPA1) gene mutations are associated with dominantly inherited optic neuropathy resulting in a progressive loss of visual acuity. Compound heterozygous or homozygous variants that lead to severe phenotypes, including Behr syndrome, have been reported rarely. CASE PRESENTATION: Here, we present a 14-month-old boy with early onset optic atrophy, congenital cataracts, neuromuscular disorders, mental retardation, and developmental delay. Combined genetic testing, including whole exome sequencing (WES) and chromosomal microarray analysis, revealed a concurrent OPA1 variant (c.2189 T > C p.Leu730Ser) and de novo chromosome 3q deletion as pathogenic variants leading to the severe phenotype. CONCLUSIONS: Our case is the first reporting a novel missense OPA1 variant co-occurring with a chromosomal microdeletion leading to a severe phenotype reminiscent of Behr syndrome. This expands the mutation spectrum of OPA1 and inheritance patterns of this disease.

Use of magnetic resonance imaging combined with gene analysis for the diagnosis of fetal congenital heart disease.

BACKGROUND: Fetal deformity is a disease caused by abnormal chromosome structure, which may be influenced by genetic factors as well as the maternal and external environment. Magnetic resonance imaging (MRI) may be used to effectively diagnose fetus deformities. However it has been reported that gene analysis is a more accurate diagnostic method. The aim of the present study was to investigate the effectiveness of MRI in combination with gene analysis for the diagnosis of fetal congenital heart disease, a form of fetus deformity. METHODS: MRI, array comparative genome hybridization analysis and fluorescence in situ hybridization were used to analyze the effectiveness of the two methods in a total of 78 pregnant women with suspected fetal congenital heart disease. RESULTS: Our findings demonstrated that the combination of MRI and gene analysis resulted in significantly improved diagnostic accuracy, sensitivity and specificity for fetal congenital heart disease compared with either method alone. MRI combined with gene analysis confirmed 42 fetuses with pulmonary stenosis, 24 with aortic stenosis and 12 healthy fetuses, which was significantly improved compared with MRI or gene analysis alone. It was also observed that gene analysis was a more efficient method of diagnosis compared with MRI; however, the combination of the two methods was the most effective. CONCLUSION: In conclusion, the results of the present study suggest that MRI combined with gene analysis may be a more effective diagnostic method for fetal congenital heart disease compared with the current protocol.

OSM May Serve as a Biomarker of Poor Prognosis in Clear Cell Renal Cell Carcinoma and Promote Tumor Cell Invasion and Migration.

Background: Currently, the role of oncostatin M (OSM) in clear cell renal cell carcinoma (ccRCC) has not been investigated. This study will explore the impact of OSM on ccRCC expression, prognosis, and cell function. Materials and Methods: In this study, we used The Cancer Genome Atlas (TCGA) database to evaluate OSM expression characteristics, pathogenic factor distribution, and prognostic aspects in ccRCC. We also combined this analysis with qRT-PCR to verify OSM mRNA expression levels at the tissue level. Then, the effects of OSM on the proliferation, invasion, and migration abilities of ccRCC cells were explored through CCK8, Transwell, Western blotting, and immunofluorescence experiments. Finally, the oncogenic mechanisms associated with OSM in ccRCC were explored through signaling pathway enrichment and single-cell analysis. Results: The results demonstrated that OSM was significantly more expressed in ccRCC than in normal tissues. According to the survival analysis, OSM in ccRCC was considerably worse in the group with high expression than in the group with low expression. Also, the univariate and multivariate Cox analyses of clinical characteristics show that OSM in ccRCC may be able to predict a poor prognosis on its own as a biomarker. In vitro cellular experiments demonstrated that high OSM expression had no discernible impact on ccRCC cell proliferation compared to the control group, but it did promote tumor cell invasion and migration. Signaling pathways and single-cell analysis revealed that OSM might promote ccRCC invasion and migration through M2 macrophages. Conclusion: In conclusion, OSM may serve as an independent poor prognostic biomarker in ccRCC and promote tumor cell invasion and migration. This discovery is expected to provide a new therapeutic target for patients with recurrent and metastatic ccRCC.

NUPR1 imparts oncogenic potential in bladder cancer.

BACKGROUND: NUPR1, or p8, is a small chromatin protein that plays a central role in the resistance to treatment and progression of cancer. Nevertheless, the molecular mechanism of NUPR1 in bladder cancer (BLCA) remains unclear. METHODS: We used online databases and immunohistochemistry (IHC) to explore the expression of NUPR1 in BLCA tissues and controls. Lentivirus-mediated small interfering ribonucleic acid (siRNA) was used to knockdown the expression of NUPR1 in two human BLCA cell lines. We used an in vivo experiment to investigate the effect of NUPR1 knockdown on the growth of BLCA. Moreover, an in silico analysis was conducted to assess the differential expression profile after NUPR1 interference. The CIBERSORT algorithm was utilized to evaluate the effects of tumor-infiltrating immune cells among BLCA patients. RESULTS: The expression of NUPR1 in BLCA tissues was significantly higher than in the control. NUPR1 expression was also positively correlated with the stage of BLCA. After lentivirus-mediated interference, the expression of NUPR1 was significantly down-regulated in BLCA cell lines. The cell cycle was blocked in G1 phase and the cell proportion of S phase was decreased in both two cell lines. Moreover, in vivo experiment revealed that the tumor growth of BLCA can be delayed by inhibiting the expression of NUPR1. Both in silico analysis and functional experiments revealed that NUPR1 was correlated with epithelial-mesenchymal transition (EMT). We also revealed that macrophages were the most related immune cells associated with the expression of NUPR1 in BLCA. CONCLUSIONS: This study suggests that NUPR1 plays a carcinogenic role in BLCA. NUPR1 lentivirus-mediated interference could interfere with cycle progression of the BLCA cell, resulting in cell cycle arrest in the G1-phase. The carcinogenic effect of NUPR1 in BLCA is likely achieved through EMT. NUPR1 is correlated with the M0-type macrophage markers CD68 and CD11b-integrin.

Nuclear Protein 1 Expression Is Associated with PPARG in Bladder Transitional Cell Carcinoma.

Background: The Nuclear protein 1 gene was first discovered in acute pancreatitis and functions as an oncogene in cancer progression and drug resistance. However, the role of Nuclear protein 1 in bladder transitional cell carcinoma (BTCC) is still unclear. Methods: The Cancer Genome Atlas database and immunohistochemical analysis were adopted to evaluate Nuclear protein 1 expression in BTCC. We applied lentivirus-mediated small-interfering RNA to down-regulate the expression of Nuclear protein 1 in BTCC cell lines. We further performed an Affymetrix microarray and Gene Set Enrichment Analysis (GSEA) to assess the genes and signaling pathways related to Nuclear protein 1. Results: We found that Nuclear protein 1 expression was up-regulated in BTCC and positively related to the degree of BTCC malignancy. Compared with Caucasian patients with BTCC, Nuclear protein 1 expression was attenuated in Asian patients. The Affymetrix microarray showed that lipopolysaccharide was the upstream regulatory factor of Nuclear protein 1 in BTCC. The GSEA indicated that Nuclear protein 1 expression was associated with signaling pathways in cancer, peroxisome proliferator-activated receptor (PPAR) pathways, and RNA degradation. The expression of Nuclear protein 1 was negatively correlated with PPARG (R = -0.290, P < 0.001), but not with PPARA (R = 0.047, P = 0.344) and PPARD (R = -0.055, P = 0.260). Conclusions: The study findings indicate that Nuclear protein 1 is positively associated with the malignancy degree of BTCC and that Nuclear protein 1 expression is negatively correlated with PPARG.

Impact of the cytotoxic T-lymphocyte associated antigen-4 rs231775 A/G polymorphism on cancer risk.

Background: Cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) is an immunosuppressive checkpoint that is involved in the development and metastasis of cancers. Several studies revealed that CTLA-4 rs231775A/G polymorphism may be associated with the risk of cancer in some populations, but the conclusions of these studies are not consistent. Methods: We conducted a pooled analysis with eligible studies to explore the association between the CTLA-4 rs231775 variant and cancer risk. Additionally, we used in silico tools to evaluated the expression of CTLA-4 on urinary system cancer. Moreover, we adopted the enzyme-linked immunosorbent assay (ELISA), and Gene Set Enrichment Analysis (GSEA) to investigate the effects of CTLA-4 on bladder cancer (BLCA). Results: In total, 92 case-control studies involving 29,987 patients with cancer and 36,484 healthy individuals (controls) were included in the pooled analysis. In the stratified analysis based on cancer type, the rs231775 A/G polymorphism was associated with increased bladder cancer risk in the heterozygote contrast model (OR = 1.23, 95% CI = 1.01-1.51, P = 0.040). The race-stratified analysis revealed that East Asians with the GG genotype had a 12% lower risk of developing cancer than those with the GA + AA genotype (95% CI = 0.81-0.95, P = 0.001). The in silico analysis showed that CTLA-4 expression was augmented in patients with BLCA. The ELISA results revealed that CTLA-4 expression was reduced in patients with BLCA carrying the AA genotype. Several signaling pathways, including cytokine-cytokine receptor interactions and T-cell receptor signaling, were associated with CTLA-4 expression. Conclusion: The CTLA-4 rs231775 A/G polymorphism is associated with cancer risk in East Asian population. This polymorphism is especially associated with BLCA.

Gene expression and prognosis of x-ray repair cross-complementing family members in non-small cell lung cancer.

The X-ray repair cross-complementing gene (XRCC) family participates in DNA damage repair and its dysregulation is associated with the development and progression of a variety of cancers. However, XRCCs have not been systematically studied in non-small cell lung cancer (NSCLC). Using The Cancer Genome Atlas (TCGA) and Oncomine databases, we compared the expression levels of XRCCs between NSCLC and normal tissues and performed survival analysis using the data from TCGA. The correlations of XRCCs with the clinical parameters were then analyzed using UCSC Xena. Genetic alterations in XRCCs in NSCLC and their effects on the prognosis of patients were presented using cBioPortal. SurvivalMeth was used to explore the differentially methylated sites associated with NSCLC and their effect on prognosis. Next, the immunological correlations of XRCCs expression level were analyzed using TIMER 2.0. Finally, GeneMANIA was used to visualize and analyze the functionally relevant genes, while Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used for functional and pathway enrichment analyses of prognostic genes. Our results revealed that XRCCs were overexpressed in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Univariate and multivariate Cox analyses showed that XRCC4/5/6 were independent risk factors for LUAD. Additionally, genetic alterations, methylation, and immune cell infiltration demonstrated an association between XRCC4/5/6 and poor prognosis in LUAD. Finally, the KEGG-enriched and non-homologous end-joining (NHEJ) pathways were shown to be associated with XRCC4/5/6. In conclusion, our study demonstrated that XRCC4/5/6 could be used as diagnostic and prognostic biomarkers for LUAD.

Effect of interleukin-8 receptor B (IL8RB) rs1126579 C>T variation on the risk to cancer.

Chemokines are a type of cytokine that participate in the migration of macrophages and monocytes to inflammatory cells. In particular, CXC chemokines are involved in the development of many cancers. Evidence for the association between interleukin-8 receptor B (IL8RB) rs1126579 C > T variation and cancer risk remains contradictory. Here, we utilized a comprehensive analysis containing odds ratios (ORs), regression, and in silico tools to evaluate the effect of IL8RB polymorphism on cancer risk. We further employed Gene set enrichment analysis combined with ELISA to evaluate the IL8RB expression in patients with prostate cancer (PRAD). A total of 5,187 cancer cases and 6,691 controls were included in the present analysis. Individuals with the TT genotype were associated with an increased risk of cancer compared to those with the TC+CC genotype. In a subgroup analysis by type of cancer, individuals with the TT genotype had a 39% increased risk of urinary cancer compared to those with the CC genotype. A subgroup analysis by ethnicity showed that Asians carrying the TC genotype had a 26% lower risk of cancer than those carrying the CC genotype. We found that the expression of IL8RB was down-regulated in PRAD. Compared to that in PRAD subjects carrying the CC genotype, the expression of IL8RB was decreased in patients with the TT+TC genotype. In conclusion, the IL8RB rs1126579 C > T variation may be associated with cancer risk, especially in Asian populations and patients with PRAD.

ATF3 Suppresses Growth and Metastasis of Clear Cell Renal Cell Carcinoma by Deactivating EGFR/AKT/GSK3ß/ß-Catenin Signaling Pathway.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is one of the most common malignant cancers in East Asia, with high incidence and mortality. Accumulating evidence has shown that ATF3 is associated with tumor progression. METHODS: Using qPCR, the expression of ATF3 was detected in 93 patients with ccRCC, including 24 paired normal and tumor tissues, which were used to further compare ATF3 expression through western blotting and immunohistochemistry. Lentivirus was used for the overexpression or knockdown of ATF3, and the consequent alteration in function was analyzed through CCK8 assay, colony formation assay, wound healing assay, invasion assay, and flow cytometry. The potential mechanism affected by ATF3 was analyzed through gene set enrichment analysis (GSEA) and verified using western blotting, invasion assay, or immunofluorescence staining. Furthermore, a xenograft mouse model was used to assess the function of ATF3 in vivo. RESULTS: ATF3 expression was significantly decreased in ccRCC compared to that in adjacent normal tissues. Through gain- and loss-of-function experiments performed in an in vitro assay, we found that ATF3 could regulate ccRCC cell proliferation, cycle progression, migration, and invasion. In the in vivo study, the xenograft mouse model revealed that ATF3 overexpression can inhibit the growth of ccRCC. Moreover, the mechanism analysis showed that suppression of ATF3 could lead to an increase the expression of ß-catenin and promote ß-catenin transfer to the nucleus, and might be affected by EGFR/AKT/GSK3ß signaling. CONCLUSION: ATF3 could be utilized as an independent protective factor to inhibit the progression of ccRCC. Potential treatment strategies for ccRCC include targeting the ATF3/EGFR/AKT/GSK3ß/ß-catenin signaling pathway.