Wnt/β-catenin and NOTCH signaling contribute to the pathogenesis and growth of (PanNENs). The wnt and Notch signaling pathways form an integrated signaling device termed "wntch" and regulate stochastic cell fate decisions, suggesting the essentiality of Wnt/Notch interactions in disease progression. However, the function of Wnt/Notch interactions in PanNENs is unclear. We analyzed RNA sequencing (RNA-seq) data to identify differentially expressed lncRNAs, mRNAs and pathways according to enriched Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with PanNENs. RNA-seq analysis revealed that the levels of the lncRNA XLOC_221242 and the mRNA encoding Delta/Notch-like epidermal growth factor (EGF)-related receptor (DNER) were significantly increased in tumor tissues compared with normal tissues (n = 3). Protein-protein interaction (PPI) prediction combined with transcriptional profiling data analysis revealed that DNER expression levels were positively correlated with those of DNA-binding factor (RBPJ), S phase kinase-associated protein 1 (Skp1), CTNNB1 and Cadherin-2 (CDH2), which promote PanNEN tumorigenesis and progression. These results were consistent with those of immunohistochemical analysis of DNER, RBPJ, SKP1, CTNNB1, and CDH2 expression (n = 15). These findings provide compelling clinical and molecular evidence supporting the conclusion that DNER and the related RBPJ, SKP1, CTNNB1, and CDH2 signaling contribute to PanNEN tumorigenesis and progression by activating wnt/Notch interactions.

In recent years, more and more studies have shown that miRNAs can affect a variety of biological processes. It is important for disease prevention, treatment, diagnosis, and prognosis to study the relationships between human diseases and miRNAs. However, traditional experimental methods are time-consuming and labour-intensive. Hence, in this paper, a novel neighborhood-based computational model called NBMDA is proposed for predicting potential miRNA-disease associations. Due to the fact that known miRNA-disease associations are very rare and many diseases (or miRNAs) are associated with only one or a few miRNAs (or diseases), in NBMDA, the K-nearest neighbor (KNN) method is utilized as a recommendation algorithm based on known miRNA-disease associations, miRNA functional similarity, disease semantic similarity, and Gaussian interaction profile kernel similarity for miRNAs and diseases to improve its prediction accuracy. And simulation results demonstrate that NBMDA can effectively infer miRNA-disease associations with higher accuracy compared with previous state-of-the-art methods. Moreover, independent case studies of esophageal neoplasms, breast neoplasms and colon neoplasms are further implemented, and as a result, there are 47, 48, and 48 out of the top 50 predicted miRNAs having been successfully confirmed by the previously published literatures, which also indicates that NBMDA can be utilized as a powerful tool to study the relationships between miRNAs and diseases.

Pleomorphic xanthoastrocytoma is rare, accounting for <1 % of all central nervous system (CNS) neoplasms. Angiomatous pleomorphic xanthoastrocytoma is an extremely rare variant of pleomorphic xanthoastrocytoma, with only six cases reported thus far.

Solitary fibrous tumors are rare neoplasms of mesenchymal origin. They are often of low malignant potential and rarely metastasize. They frequently arise from the pleura and can occur at any soft tissue site in the body. However, these tumors rarely develop in the mesentery, peritoneal cavity or peritoneum.

Gastric cancer (GC) is a common tumour that affects humans worldwide, is highly malignant and has a poor prognosis. Small extracellular vesicles (sEVs), especially exosomes, are nanoscale vesicles released by various cells that deliver bioactive molecules to recipient cells, affecting their biological characteristics, changing the tumour microenvironment and producing long-distance effects. In recent years, many studies have clarified the mechanisms by which sEVs function with regard to the initiation, progression, angiogenesis, metastasis and chemoresistance of GC. These molecules can function as mediators of cell-cell communication in the tumour microenvironment and might affect the efficacy of immunotherapy. Due to their unique physiochemical characteristics, sEVs show potential as effective antitumour vaccines as well as drug carriers. In this review, we summarize the roles of sEVs in GC and highlight the clinical application prospects in the future.

Avian leukosis virus (ALV) is an oncogenic virus causing a variety of neoplasms in chickens. The group of avian leukosis virus in chickens contains six closely related subgroups, A to E and J. The prevalence of ALVs in hosts may have imposed strong selective pressure toward resistance to ALVs infection. The tvb gene encodes Tvb receptor and determines susceptibility or resistance to the subgroups B, D, and E ALV. In this study, we characterized a novel resistant allele of the tvb receptor gene, tvbr3, which carries a single-nucleotide substitution (c.298C>T) that constitutes a premature termination codon within the fourth exon and leads to the production of a truncated TvbR3 receptor protein. As a result, we observed decreased susceptibility to infection by ALV-B, ALV-D and ALV-E both in vitro and in vivo, and decreased the binding affinity of the TvbR3 receptor for the subgroups B, D, and E ALV envelope glycoproteins. Additionally, we found that the tvbr3 allele was prevalent in Chinese broiler lines. This study demonstrated that premature termination codon in the tvb receptor gene can confer genetic resistance to subgroups B, D, and E ALV in the host, and indicates that tvbr3 could potentially serve as a resistant target against ALV-B, ALV-D and ALV-E infection.

The aim of the present study was to investigate the expression of B7-H1 and B7-H4 in ovarian neoplasm tissues and to examine their clinical relevance. A total of 112 ovarian biopsies were collected from patients with epithelial ovarian cancer (EOC) and 10 were taken from ovarian benign neoplasms. The samples were processed in paraffin tissue chips, and subjected to immunohistochemical staining and analysis. Associations of B7-H1 and B7-H4 expression with patients' clinical parameters, such as histological typing, cell grading, International Federation of Gynecology and Obstetrics staging, tumor size, and metastatic status, were examined by statistical analysis. Survival curves were constructed using the Kaplan-Meier method and the log-rank test. Independent prognostic factors were evaluated using the Cox regression model. The results showed an extremely low or negative expression of B7-H1 and B7-H4 in the 10 benign ovarian neoplasm tissues (control): By contrast, a positive expression of B7-H1 and B7-H4 was observed in 55.4% (62/112) and 37.5% (42/112) of the EOC tissues, respectively. The differences between the two groups were significant. In addition, the co-expression of B7-H1 and B7-H4 was found in 31.3% (35/112) of the EOC cases. Furthermore, the progression-free survival and overall survival were significantly lower in EOC patients with a high expression of B7-H1 and B7-H4 (χ2=45.60 and 37.99, respectively). These results demonstrated that the expression of B7-H1 and B7-H4 in EOC tissues was significantly associated with poor prognosis and high relapse rate of EOC. The findings suggest that B7-H1 and B7-H4 is a negative prognostic marker for EOC and a potential immunotherapeutic target for patients with EOC.

Background: The ubiquitin-conjugating enzyme E2 T (UBE2T) has been shown to contribute to several types of cancer. However, no publication has reported its implication in esophageal squamous cell cancer (ESCC). Methods: We explored several public databases, including The Cancer Genome Atlas (TCGA), Oncomine, and gene expression Omnibus (GEO). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and gene set enrichment analysis (GSEA) were adopted to explore involved signaling pathways. We used R software to develop prognostic gene signatures with the LASSO and stepwise Cox regression analysis, separately. Immunohistochemistry staining was performed to detect UBE2T in 90 ESCC patients, followed by survival analysis. We also used an R package pRRophetic to evaluate chemotherapy sensitivity for the TCGA-ESCC cohort. Results: We found significantly increased UBE2T transcript levels and DNA copy numbers in ESCC tissues. UBE2T was associated with the p53 signaling pathway, cell cycle, Fanconi anemia pathway, and DNA replication, as indicated by Go, KEGG pathway enrichment analysis. These pathways were also upregulated in ESCC. The prognostic signatures with UBE2T-associated genes could stratify ESCC patients into low- and high-risk groups with significantly different overall survival in the TCGA-ESCC cohort. We also validated the association of UBE2T with unfavorable survival in 90 ESCC patients recruited for this study. Moreover, we found that the low-risk group was significantly more sensitive to chemotherapy than the high-risk group. Conclusions: UBE2T is involved in the development of ESCC, and gene signatures derived from UBE2T-associated genes are predictive of prognosis in ESCC.

Immune checkpoint inhibitor (ICI) therapy has achieved remarkable clinical benefit in melanoma and non-small cell lung cancer (NSCLC). Tumor mutational signatures are the fingerprints of endogenous and exogenous factors that have acted throughout tumorigenesis and heterogeneity; however, their association with immune response in ICI-treated samples remains unclear. Here, we leveraged whole-exome sequencing (WES)-based mutational profiles combined with clinicopathologic characteristics from melanoma and NSCLC datasets to examine whether tumor genomic features contribute to clinical benefit of ICI treatment. Mutational data acquired from targeted next-generation sequencing (NGS) assays (MSK-IMPACT panels) were also employed for further corroboration. A mutational signature (known as age-related clock-like processing) characterized by enrichment of C>T mutations at NpCpG trinucleotides were identified to be associated with a worse prognosis and lower tumor mutation load (TML) in both WES and targeted NGS immunotherapy cohorts. We also analyzed gene transcriptomic profiles and identified immune regulation-related gene pathways that were significantly altered in samples with different clock-like signature grouping. Leucocyte subset analysis further revealed that clock-like signature was associated with the reduction of cytotoxic cell infiltration and elevation of regulatory T cells. Overall, our work re-annotated that the age-related clock-like signature was associated with worse prognosis and lower immune activity, offering opportunities to stratify patients into optimal immunotherapy plans based on genomic subtyping.

MicroRNA (miRNA) played an important role in the progression of liver cancer and its diagnostic and prognostic values have been frequently studied. However, different microarray techniques and small sample size led to inconsistent findings in previous studies. We performed a comprehensive meta-analysis of a total of 357 tumor and 283 noncancerous samples from 12 published miRNA expression studies using robust rank aggregation method. As a result, we identified a statistically significant meta-signature of five upregulated (miR-221, miR-222, miR-93, miR-21 and miR-224) and four downregulated (miR-130a, miR-195, miR-199a and miR-375) miRNAs. We then conducted miRNA target prediction and pathway enrichment analysis to find what biological process these miRNAs might affect. We found that most of the pathways were frequently associated with cell signaling and cancer pathogenesis. Thus these miRNAs may involve in the onset and progression of liver cancer and serve as potential diagnostic and therapeutic targets of this malignancy.

Renal angiomyolipoma is a kidney tumor in the perivascular epithelioid (PEComa) family that is common in patients with Tuberous Sclerosis Complex (TSC) and Lymphangioleiomyomatosis (LAM) but occurs rarely sporadically. Though histologically benign, renal angiomyolipoma can cause life-threatening hemorrhage and kidney failure. Both angiomyolipoma and LAM have mutations in TSC2 or TSC1. However, the frequency and contribution of other somatic events in tumor development is unknown. We performed whole exome sequencing in 32 resected tumor samples (n = 30 angiomyolipoma, n = 2 LAM) from 15 subjects, including three with TSC. Two germline and 22 somatic inactivating mutations in TSC2 were identified, and one germline TSC1 mutation. Twenty of 32 (62%) samples showed copy neutral LOH (CN-LOH) in TSC2 or TSC1 with at least 8 different LOH regions, and 30 of 32 (94%) had biallelic loss of either TSC2 or TSC1. Whole exome sequencing identified a median of 4 somatic non-synonymous coding region mutations (other than in TSC2/TSC1), a mutation rate lower than nearly all other cancer types. Three genes with mutations were known cancer associated genes (BAP1, ARHGAP35 and SPEN), but they were mutated in a single sample each, and were missense variants with uncertain functional effects. Analysis of sixteen angiomyolipomas from a TSC subject showed both second hit point mutations and CN-LOH in TSC2, many of which were distinct, indicating that they were of independent clonal origin. However, three tumors had two shared mutations in addition to private somatic mutations, suggesting a branching evolutionary pattern of tumor development following initiating loss of TSC2. Our results indicate that TSC2 and less commonly TSC1 alterations are the primary essential driver event in angiomyolipoma/LAM, whereas other somatic mutations are rare and likely do not contribute to tumor development.

An important challenge in cancer biology is to computationally screen mutations in cancer cells, separating those that might drive cancer initiation and progression, from the much larger number of bystanders. Since mutations are large in number and diverse in type, the frequency of any particular mutation pattern across a set of samples is low. This makes statistical distinctions and reproducibility across different populations difficult to establish.

Colorectal cancer is a heterogeneous group of malignancies with complex molecular subtypes. While colon cancer has been widely investigated, studies on rectal cancer are very limited. Here, we performed multi-region whole-exome sequencing and single-cell whole-genome sequencing to examine the genomic intratumor heterogeneity (ITH) of rectal tumors.

Esophageal squamous dysplasia is believed to be the precursor lesion of esophageal squamous cell carcinoma (ESCC); however, the genetic evolution from dysplasia to ESCC remains poorly understood. Here, we applied multi-region whole-exome sequencing to samples from two cohorts, 45 ESCC patients with matched dysplasia and carcinoma samples, and 13 tumor-free patients with only dysplasia samples. Our analysis reveals that dysplasia is heavily mutated and harbors most of the driver events reported in ESCC. Moreover, dysplasia is polyclonal, and remarkable heterogeneity is often observed between tumors and their neighboring dysplasia samples. Notably, copy number alterations are prevalent in dysplasia and persist during the ESCC progression, which is distinct from the development of esophageal adenocarcinoma. The sharp contrast in the prevalence of the 'two-hit' event on TP53 between the two cohorts suggests that the complete inactivation of TP53 is essential in promoting the development of ESCC.The pathogenesis of oesophageal squamous cell carcinoma is a multi-step process but the genetic determinants behind this progression are unknown. Here the authors use multi-region exome sequencing to comprehensively investigate the genetic evolution of precursor dysplastic lesions and untransformed oesophagus.

A number of studies have demonstrated the crucial functions of GINS2 within the GINS complex in various types of cancer. However, the molecular mechanisms and prognostic value of GINS2 in breast cancer remain unknown. The present study used; BC-GenExMiner, COSMIC, UCSC Xena, The Human Protein Atlas, GEPIA, cBioPortal, GeneMANIA, TIMER and Oncomine, in order to investigate gene expression, co-expression, clinical parameters and mutations in GINS2 in patients with breast cancer. Furthermore, the present study assessed the prognostic value of GINS2 in patients with breast cancer via the Kaplan-Meier plotter database. The results of the present study demonstrated that the mRNA levels of GINS2 were significantly higher in breast cancer tissue compared with normal tissue. In addition, high mRNA expression levels of GINS2 were associated with high Scarff-Bloom-Richardson status grades, a basal-like status and age (≤51 years); however, it was not associated with lymph node metastasis. The survival analysis revealed that increased GINS2 mRNA levels were associated with a worse prognosis for relapse-free survival in all patients with breast cancer, particularly in those with estrogen receptor-positive and progesterone receptor-positive subtypes. In addition, a positive association between the GINS2, CENPM and MCM4 genes was confirmed. The results of the present study suggest that GINS2 could be used as a potential prognostic biomarker for breast cancer. Nevertheless, further studies are necessary to confirm the effects of GINS2 on the pathogenesis and development of patients with breast cancer.

Recent studies have highlighted the biological significance of RNA N6-methyladenosine (m6A) modification in tumorigenicity and progression. However, it remains unclear whether m6A modifications also have potential roles in immune regulation and tumor microenvironment (TME) formation. Methods: In this study, we curated 23 m6A regulators and performed consensus molecular subtyping with NMF algorithm to determine m6A modification patterns and the m6A-related gene signature in colon cancer (CC). The ssGSEA and CIBERSORT algorithms were employed to quantify the relative infiltration levels of various immune cell subsets. An PCA algorithm based m6Sig scoring scheme was used to evaluate the m6A modification patterns of individual tumors with an immune response. Results: Three distinct m6A modification patterns were identified among 1307 CC samples, which were also associated with different clinical outcomes and biological pathways. The TME characterization revealed that the identified m6A patterns were highly consistent with three known immune profiles: immune-inflamed, immune-excluded, and immune-desert, respectively. Based on the m6Sig score, which was extracted from the m6A-related signature genes, CC patients can be divided into high and low score subgroups. Patients with lower m6Sig score was characterized by prolonged survival time and enhanced immune infiltration. Further analysis indicated that lower m6Sig score also correlated with greater tumor mutation loads, PD-L1 expression, and higher mutation rates in SMGs (e.g., PIK3CA and SMAD4). In addition, patients with lower m6Sig scores showed a better immune responses and durable clinical benefits in three independent immunotherapy cohorts. Conclusions: This study highlights that m6A modification is significantly associated with TME diversity and complexity. Quantitatively evaluating the m6A modification patterns of individual tumors will strengthen our understanding of TME characteristics and promote more effective immunotherapy strategies.

There is an urgent need for biomarkers of radiation response in organ-sparing therapies. Bladder preservation with trimodality therapy (TMT), consisting of transurethral tumor resection followed by chemoradiation, is an alternative to radical cystectomy for muscle-invasive bladder cancer (MIBC), but molecular determinants of response are poorly understood.

Microphthalmia transcription factor (MiT) family translocation renal cell carcinoma (tRCC) is a rare type of kidney cancer, which is not well characterized. Here we show the comprehensive proteogenomic analysis of tRCC tumors and normal adjacent tissues to elucidate the molecular landscape of this disease. Our study reveals that defective DNA repair plays an important role in tRCC carcinogenesis and progression. Metabolic processes are markedly dysregulated at both the mRNA and protein levels. Proteomic and phosphoproteome data identify mTOR signaling pathway as a potential therapeutic target. Moreover, molecular subtyping and immune infiltration analysis characterize the inter-tumoral heterogeneity of tRCC. Multi-omic integration reveals the dysregulation of cellular processes affected by genomic alterations, including oxidative phosphorylation, autophagy, transcription factor activity, and proteasome function. This study represents a comprehensive proteogenomic analysis of tRCC, providing valuable insights into its biological mechanisms, disease diagnosis, and prognostication.

The subtypes of duodenal cancer (DC) are complicated and the carcinogenesis process is not well characterized. We present comprehensive characterization of 438 samples from 156 DC patients, covering 2 major and 5 rare subtypes. Proteogenomics reveals LYN amplification at the chromosome 8q gain functioned in the transmit from intraepithelial neoplasia phase to infiltration tumor phase via MAPK signaling, and illustrates the DST mutation improves mTOR signaling in the duodenal adenocarcinoma stage. Proteome-based analysis elucidates stage-specific molecular characterizations and carcinogenesis tracks, and defines the cancer-driving waves of the adenocarcinoma and Brunner's gland subtypes. The drug-targetable alanyl-tRNA synthetase (AARS1) in the high tumor mutation burden/immune infiltration is significantly enhanced in DC progression, and catalyzes the lysine-alanylation of poly-ADP-ribose polymerases (PARP1), which decreases the apoptosis of cancer cells, eventually promoting cell proliferation and tumorigenesis. We assess the proteogenomic landscape of early DC, and provide insights into the molecular features corresponding therapeutic targets.

Primary gastrointestinal diffuse large B-cell lymphoma (GI-DLBCL) is the most common gastrointestinal lymphoma, but its genetic features are poorly understood. We performed whole-exome sequencing of 25 primary tumor samples from patients with GI-DLBCL and 23 matched normal tissue samples. Oncogenic mutations were screened, and the correlations between genetic mutations and clinicopathological characteristics were analyzed. Twenty-five patients with GI-DLBCL were enrolled in the genetic mutation analysis with a median of 184 (range 79-382) protein-altering variants per patient. We identified recurrent oncogenic mutations in GI-DLBCL, including those in TP53, MUC16, B2M, CCND3, HIST1H1C, NEB, and ID3. Compared with nodal DLBCL, GI-DLBCL exhibited an increased mutation frequency of TP53 and reduced mutation frequencies of PIM1, CREBBP, BCL2, KMT2D, and EZH2. Moreover, GI-DLBCL exhibited fewer MYD88 and CD79B mutations than DLBCL in the testis and central nervous system. GI-DLBCLs with HLA-B, MEF2A, RHOA, and NAV3 mutations exhibited a tendency toward a high proliferation index. MUC16 and ETV6 mutations often occurred in tumors with early clinical staging. Our data provide a comprehensive understanding of the landscape of mutations in a small subset of GI-DLBCLs. The genetic mutation profiles of GI-DLBCL differ from those of nodal DLBCL and DLBCL in immune-privileged sites. The different mutated genes are related to the NF-κB and JAK-STAT pathways, and the different pathogenetic mechanisms leading to the development of DLBCL may be influenced by the tissue microenvironment. Differences in genetic alterations might influence the clinicopathological characteristics of GI-DLBCL.