The cancer susceptibility candidate 9 (CASC9) gene has been reported to exert an oncogenic effect in several types of cancer. However, its role in lung squamous cell carcinoma (LUSC) is unknown. Therefore, the present study examined the expression of CASC9 in LUSC and non‑cancer tissues by reverse transcription‑quantitative polymerase chain reaction assays and by data mining of high‑throughput public databases, including The Cancer Genome Atlas, the Gene Expression Omnibus, ArrayExpress and the Cancer Cell Line Encyclopedia. In vitro experiments were conducted to investigate the effects of CASC9 on the viability and the proliferation of LUSC cells. Furthermore, consulting the alteration status of CASC9 in LUSC from cBioPortal, functional enrichment analysis of co‑expressed genes, prediction of potential transcription factors, and inspection of adjacent protein‑coding genes were conducted to explore the potential molecular mechanism of CASC9 in LUSC. The results revealed that CASC9 was overexpressed in LUSC tissue, and significantly associated with the malignant progression of LUSC. In vitro experiments demonstrated that CASC9 knockdown by RNA interference attenuated the viability and proliferation of LUSC cells. Multiple copies of CASC9 gene were detected in 4 of 179 available sequenced LUSC cases. A functional enrichment analysis of 200 co‑expressed genes indicated that these genes were significantly associated with terms, including 'cell‑cell junction organization', 'desmosome organization', 'epidermis development', 'Hippo signaling pathway', 'pathogenic Escherichia coli infection' and 'PID HIF1 TF pathway'. Three genes, Fos‑related antigen 2 (FOSL2), SWI/SNF complex subunit SMARCC2, and transcription factor COE1 (EBF1), were predicted by lncRNAMap to be associated with CASC9. Among these, the expression of FOSL2 and EBF1 was positively and negatively correlated with the expression of CASC9, respectively. Two adjacent protein‑coding genes, cysteine‑rich secretory protein LCCL domain‑containing 1 and hepatocyte nuclear factor 4‑γ, were also positively correlated with CASC9 expression. In conclusion, the present data suggest that CASC9 serves as an oncogene in LUSC and may be a promising target for alternative therapeutic options for patients with this condition.

BACKGROUND: Clinical assays for the assessment of the human epidermal growth factor receptor-2 (HER2) status in breast cancer include immunohistochemistry (IHC) and in situ hybridization (ISH), both of which have limitations. Recent studies have suggested that a more quantitative approach to the measurement of HER2 protein expression may improve specificity in selecting patients for HER-2 targeted therapy. In the current study, we have used HER2 expression in breast cancer cell lines and clinical samples as a model to explore the potential utility of a novel immunodetection technique, using streptavidin coated Phosphor Integrated Dot fluorescent nanoparticles (PID), which can be quantitatively measured using computer analysis.
METHODS: The expression of HER2 protein in cell lines was evaluated with antibody-binding capacity using fluorescence-activated cell sorting (FACS) for comparison with PID measurements to test for correlations with existing quantitative protein analysis methodologies. Various other analytic validation tests were also performed, including accuracy, precision, sensitivity, robustness and reproducibility. A methods comparison study investigated correlations between PID versus IHC and ISH in clinical samples. Lastly, we measured HER2 protein expression using PID in the pretreatment biopsies from 34 HER2-positive carcinomas that had undergone neoadjuvant trastuzumab-based chemotherapy.
RESULTS: In the analytic validation, PID HER2 measurements showed a strong linear correlation with FACS analysis in breast cell lines, and demonstrated significant correlations with all aspects of precision, sensitivity, robustness and reproducibility. PID also showed strong correlations with conventional HER2 testing methodologies (IHC and ISH). In the neoadjuvant study, patients with a pathologic complete response (pCR) had a significantly higher PID score compared with patients who did not achieve a pCR (p = 0.011), and was significantly correlated to residual cancer burden (RCB) class (p = 0.026, R
CONCLUSIONS: Analytic testing of PID showed that it may be a viable testing methodology that could offer advantages over other experimental or conventional biomarker diagnostic methodologies. Our data also suggests that PID quantitation of HER2 protein may offer an improvement over conventional HER2 testing in the selection of patients who will be the most likely to benefit from HER2-targeted therapy. Further studies with a larger cohort are warranted.

PURPOSE OF REVIEW: The risk of cancer is higher, and its outcome is worse in patients with primary immunodeficiency (PID) than in members of the general population. Thus, the inter-relationship of malignant diseases with PIDs requires more study.
RECENT FINDINGS: Large genetic screens identified a vast number of germline mutations in childhood cancer patient samples. Although TP53 was the most frequent single gene identified as mutated, many PID disorders like DNA repair defects are among the inborn causes of childhood cancer. We provide a comprehensive analysis of compiled data from seven recent studies that focused on germline genetic landscapes and preexisting conditions in pediatric oncology. As potentially causal germline variants were identified in ≈8% of malignancies in children and adolescents, we visualized this proportion as the 'tips of the icebergs'. The results of additional network analyses showed the shared patterns of germline mutations in various malignancies and yielded a spatial distribution of the 'icebergs'.
SUMMARY: The 'iceberg map of germline mutations in childhood cancers' was created to increase the awareness of the inborn genetic underpinnings of childhood malignancies and their relationships with immunodeficiencies. Needs and perspectives of clinical immunologists and pediatric oncologists to both improve patient care and guide research at this critical interface are discussed. VIDEO ABSTRACT.

Non-small cell lung carcinoma (NSCLC) is the most common cause of cancer‑associated mortality in the world and accounts for ~85% of human lung cancers. Metastasis‑associated protein 2 (MTA2) is a component of the histone deacetylase complex and serves a role in tumor progression; however, the mechanism through which MTA2 is involved in the progression of NSCLC remains unclear. The aim of the present study was to investigate the expression and function of MTA2 and the MTA2‑mediated signaling pathway in NSCLC cells. Expression of MTA2 and its target genes was analyzed in MTA2‑overexpressing and anti‑MTA2 antibody (AbMTA2)‑treated NSCLC cells, as well as growth, migration, invasion and apoptotic‑resistance. The inhibitory effects on tumor formation were analyzed using AbMTA2‑treated NSCLC cells and in a mouse model. Histological assessment was conducted to analyze the expressions levels of extracellular signal‑regulated kinase (ERK), RAC‑α serine/threonine protein kinase (AKT) and vascular endothelial growth factor (VEGF) in experimental tumors. Results of the present study demonstrated that MTA2 was overexpressed in NSCLC cells. The growth, migration and invasion of NSCLC cells were markedly inhibited by AbMTA2. In addition, it was observed that the ERK/AKT and VEGF signaling pathways were both upregulated in MTA2‑overexpressing NSCLC cells, and downregulated following silencing of MTA2 activation. ERK and AKT phosphorylation levels were downregulated in NSCLC cells and tumors following MTA2 silencing. The in vivo study demonstrated that tumor growth was markedly inhibited following siRNA‑MTA2 treatment. In conclusion, the results of the present study suggested that MTA2 silencing may significantly inhibit the growth and aggressiveness of NSCLC cells. Results from the present study indicated that the mechanism underlying the MTA2‑mediated invasive potential of NSCLC cells involved the ERK/AKT and VEGF signaling pathways, which may be a potential therapeutic target for the treatment of NSCLC.

Early diagnosis of prostate cancer (PCa) is critical for the application of efficient treatment to PCa patients. However, the majority of PCas remains indolent from several months to several years before malignancy. Current diagnosis methods have limitations in their reliability and are inefficient in time cost. Thus, an efficient in vivo PCa cell xenograft model is highly desired for diagnostic studies in PCas. In the present study we present a standardized procedure to create a PCa cell xenograft model using zebrafish (Danio rerio) as the host. PC3-CTR cells, a cell line from adenocarcinoma with stable expression of calcitonin receptor (CRT), were subcutaneously injected into zebrafish larvae at 48 h post fertilization. The nursing conditions for the larvae were optimized with stable survival rates of post hatch and post PC3-CTR cell injection. In this system, the progression of PC3-CTR cells in vivo was evaluated by migration and proliferation of the cells. Massive migrations of PC3 cells in vivo were observed at post injection day (PID)3. The injected PC3-CTR cells eventually invaded the whole larval zebrafish at PID5. Quantification of PC3-CTR cell proliferation was done using quantitative PCR (qPCR) analysis targeting the expression profiles of two PCa housekeeping genes, TATA-binding protein (TBP) and hypoxanthine phosphoribosyltransferase 1 (HPRT1) encoding genes. The excessive proliferation of PC3 cells in vivo was detected with both qPCR assays. Expression levels of one non‑coding gene, prostate cancer associated 3 gene (pca3), and two other genes encoding transient receptor potential ion channel Melastatin 8 (trpm8) and prostate-specific membrane antigen (psma), showed a significantly enhanced aggressiveness of PC3-CTR cells in vivo. The model established in the present study provides an improved in vivo model for the diagnosis of PCas efficiently. This PCa cell xenograft model can also serve as a tool for high throughput anti-PCa drug screening in therapeutic treatments.

OBJECTIVE: Breast cancer is a severe risk to public health and has adequately convoluted pathogenesis. Therefore, the description of key molecular markers and pathways is of much importance for clarifying the molecular mechanism of breast cancer-associated fibroblasts initiation and progression. Breast cancer-associated fibroblasts gene expression dataset was downloaded from Gene Expression Omnibus database.
METHODS: A total of nine samples, including three normal fibroblasts, three granulin-stimulated fibroblasts and three cancer-associated fibroblasts samples, were used to identify differentially expressed genes (DEGs) between normal fibroblasts, granulin-stimulated fibroblasts and cancer-associated fibroblasts samples. The gene ontology (GO) and pathway enrichment analysis was performed, and protein-protein interaction (PPI) network of the DEGs was constructed by NetworkAnalyst software.
RESULTS: Totally, 190 DEGs were identified, including 66 up-regulated and 124 down-regulated genes. GO analysis results showed that up-regulated DEGs were significantly enriched in biological processes (BP), including cell-cell signalling and negative regulation of cell proliferation; molecular function (MF), including insulin-like growth factor II binding and insulin-like growth factor I binding; cellular component (CC), including insulin-like growth factor binding protein complex and integral component of plasma membrane; the down-regulated DEGs were significantly enriched in BP, including cell adhesion and extracellular matrix organization; MF, including N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase activity and calcium ion binding; CC, including extracellular space and extracellular matrix. WIKIPATHWAYS analysis showed the up-regulated DEGs were enriched in myometrial relaxation and contraction pathways. WIKIPATHWAYS, REACTOME, PID_NCI and KEGG pathway analysis showed the down-regulated DEGs were enriched endochondral ossification, TGF beta signalling pathway, integrin cell surface interactions, beta1 integrin cell surface interactions, malaria and glycosaminoglycan biosynthesis-chondroitin sulfate/dermatan sulphate. The top 5 up-regulated hub genes, CDKN2A, MME, PBX1, IGFBP3, and TFAP2C and top 5 down-regulated hub genes VCAM1, KRT18, TGM2, ACTA2, and STAMBP were identified from the PPI network, and subnetworks revealed these genes were involved in significant pathways, including myometrial relaxation and contraction pathways, integrin cell surface interactions, beta1 integrin cell surface interaction. Besides, the target hsa-mirs for DEGs were identified. hsa-mir-759, hsa-mir-4446-5p, hsa-mir-219a-1-3p and hsa-mir-26a-5p were important miRNAs in this study.
CONCLUSIONS: We pinpoint important key genes and pathways closely related with breast cancer-associated fibroblasts initiation and progression by a series of bioinformatics analysis on DEGs. These screened genes and pathways provided for a more detailed molecular mechanism underlying breast cancer-associated fibroblasts occurrence and progression, holding promise for acting as molecular markers and probable therapeutic targets.

The quantitative sensitivity and dynamic range of conventional immunohistochemistry (IHC) with 3,3'-diaminobenzidine (IHC-DAB) used in pathological diagnosis in hospitals are poor, because enzyme activity can affect the IHC-DAB chromogenic reaction. Although fluorescent IHC can effectively increase the quantitative sensitivity of conventional IHC, tissue autofluorescence interferes with the sensitivity. Here, we created new fluorescent nanoparticles called phosphor-integrated dots (PIDs). PIDs have 100-fold greater brightness and a more than 300-fold greater dynamic range than those of commercially available fluorescent nanoparticles, quantum dots, whose fluorescence intensity is comparable to tissue autofluorescence. Additionally, a newly developed image-processing method enabled the calculation of the PID particle number in the obtained image. To quantify the sensitivity of IHC using PIDs (IHC-PIDs), the IHC-PIDs method was compared with fluorescence-activated cell sorting (FACS), a method well suited for evaluating total protein amount, and the two values exhibited strong correlation (R = 0.94). We next applied IHC-PIDs to categorize the response to molecular target-based drug therapy in breast cancer patients. The results suggested that the PID particle number estimated by IHC-PIDs of breast cancer tissues obtained from biopsy before chemotherapy can provide a score for predicting the therapeutic effect of the human epidermal growth factor receptor 2-targeted drug trastuzumab.

BACKGROUND: The sensitivities and specificities of biomarkers for gastric cancer are insufficient for clinical detection, and new diagnostics are therefore urgently required.
METHODS: A discovery set of gastric cancer tissues was labeled with iTRAQ reagents, separated using SCX chromatography, and identified using LC-ESI-MS/MS. A validation set of gastric cancer tissues was used to confirm the expression levels of potential markers.
RESULTS: The present study detected metastasis-associated protein 2 (MTA2) and Histone deacetylases 1 (HDAC1) proteins that were overexpressed in gastric cancer tissues compared with that in adjacent gastric tissue. The sensitivity and specificity of MTA2 in detecting 76 cases gastric cancers were 57.9% (95% CI: 46.5%-69.3%) and 55.3% (95% CI: 43.8%-66.7%), respectively. The sensitivity and specificity of HDAC1 were 61.8% (95% CI: 50.7%-73%) and 63.2% (95% CI: 52.1%-74.3%), respectively. The co-expression of MTA2 and HDAC1 in gastric cancer achieved 65.3% sensitivity (95% CI: 51.5%-79.1%) and 65.2% specificity (95% CI: 50.9%-79.5%), which was strongly associated with lymph node metastasis and TNM staging.
CONCLUSION: The present findings indicated a tight correlation between the MTA2 and HDAC1 expression level and lymph node metastasis and TNM staging in gastric cancers. Therefore, MTA2 and HDAC1 might be predictors of lymph node metastasis phenotype and possible target molecule for anticancer drug design in human gastric cancer.

Common variable immunodeficiency (CVID) is a diagnostic category of primary immunodeficiency (PID) which may present with heterogeneous disorders including recurrent infections, autoimmunity, granulomatous diseases, lymphoid and other types of malignancies. Generally, the incidence of malignancy in CVID patients is around 1.5-20.7% and usually occurs during the 4th-6th decade of life. Non-Hodgkin lymphoma is the most frequent malignancy, followed by epithelial tumours of stomach, breast, bladder and cervix. The exact pathological mechanisms for cancer development in CVID are not fully determined; however, several mechanisms including impaired genetic stability, genetic predisposition, immune dysregulation, impaired clearance of oncogenic viruses and bacterial infections, and iatrogenic causes have been proposed to contribute to the high susceptibility of these patients to malignancies.

Purpose/aim: To focus on current molecular and genetic aspects and MTA proteins, since pancreatic cancer is a lethal malignant with poor prognosis. Early diagnosis is essential step, contributing to potential curative resection.
MATERIALS AND METHODS: A PubMed search of relevant articles published up to August 2016 was performed to identify current information about pancreatic cancer regarding molecular biomarkers, with emphasis on carcinogenesis, novel therapeutic targets, and MTA proteins.
RESULTS: Understanding the mechanisms involved in the process of carcinogenesis at the molecular level and the recognition of various oncogenes has opened new horizons for both diagnosis and targeted therapy. Metastasis associated (MTA) proteins (MTA1, MTA2, MTA3) comprise a well-established family of biomarkers. The oncogene MTA1 and its expression product MTA1 protein are the most important and adequately studied in the current research. It defines the growth, local invasiveness, lymphatic spread, and metastatic capacity of various malignancies such as colorectal or gastric cancer including also pancreatic cancer. This protein is associated with malignant potential and biological behavior. Consequently, it could contribute to cancer detection since the first stages of carcinogenesis, as well as in prediction of its malignant differentiation grade. The pre-operative information of the possibility of lymph node involvement may also affect the attempt and the extent of curative resection and lymphadenectomy.
CONCLUSIONS: Carcinogenesis and implicated oncogenes, either activators or repressors, concentrate much research interest, as well as being useful as biomarkers and for targeted therapy. MTA proteins could become useful diagnostic and prognostic biomarkers in current management of pancreatic cancer.

Recently, intriguing new roles for some small nucleolar RNA host genes (SNHGs) in cancer have emerged. In the present study, a panel of SNHGs was profiled to detect aberrantly expressed SNHGs in gastric cancer (GC). The expression of SNHG5 was significantly downregulated in GC and was significantly associated with the formation of a tumor embolus and with the tumor, node and metastasis stage. SNHG5 was a long non-coding RNA, which was a class of non-coding RNA transcripts longer than 200 nucleotides. SNHG5 suppressed GC cell proliferation and metastasis in vitro and in vivo. Furthermore, SNHG5 exerted its function through interacting with MTA2, preventing the translocation of MTA2 from the cytoplasm into the nucleus. SNHG5 overexpression led to significant increases in the acetylation levels of histone H3 and p53, indicating that SNHG5 might affect acetylation by trapping MTA2 in the cytosol, thereby interfering with the formation of the nucleosome remodeling and histone deacetylation complex. This study is the first to demonstrate that SNHG5 is a critical and powerful regulator that is involved in GC progression through trapping MTA2 in the cytosol. These results imply that SNHG5 may be a novel therapeutic target for the treatment of GC.

As a family of chromatin remodeling proteins, metastasis-associated proteins (MTAs) have shown to be the master regulators in both physiological and pathological contexts. Although MTA3 is the latest being identified in MTA family, it has started to draw as much attention as the other family members. MTA3 is expressed in various tissues and is associated with different physiological functions. In cancerous context, both MTA1 and MTA2 are generally considered as oncogenes because they are capable of enhancing metastasis. However, MTA3 appears to play more complicated roles in cancers depending on the contexts. As a tumor suppressor, MTA3 usually down-regulates Snail, the master regulator of epithelium-mesenchymal transition, and subsequently represses cancer cell invasion and migration. Additionally, MTA3 may function by enhancing cancer cell differentiation without affecting proliferation in certain cancers. On the other hand, MTA3 might function in oncogene - related properties similarly as MTA1 and MTA2. In this review, we summarize our current understanding about MTA3 in normal development, cancers as well as other human diseases by comparing the similarities and differences between MTA3 and the other members of the MTA family.

microRNAs (miRNAs) play important roles in cancer development and progression. In this study, we explored the expression and biological roles of miR-548b in human gliomas. The expression of miR-548b in human glioma tissues and cell lines was examined. Gain-of-function experiments were conducted to determine the roles of miR-548b in glioma cell growth, invasiveness, and tumorigenesis. Bioinformatic analysis and luciferase reporter assays were performed to identify direct target genes for miR-548b. miR-548b was underexpressed in human glioma tissues and cell lines. Re-expression of miR-548b significantly inhibited the proliferation and colony formation of U87 and U373 glioma cells. Enforced expression of miR-548b significantly impaired the invasiveness of glioma cells. Notably, metastasis tumor-associated protein-2 (MTA2) was a direct target of miR-548b. Overexpression of miR-548b negatively regulated endogenous MTA2 expression in U87 cells. Rescue experiments with an MTA2 construct lacking the 3'-untranslated region showed that enforced expression of MTA2 significantly restored cell proliferation and invasion in miR-548b-overexpressing cells. In-vivo studies confirmed that miR-548b overexpression retarded the growth of U87 xenograft tumors, which was accompanied by reduced expression of MTA2. In conclusion, miR-548b exerts its tumor-suppressive activity in glioma through repression of MTA2. Restoration of miR-548b may have therapeutic potential in glioma.

OBJECTIVE: Some studies suggest that pelvic inflammatory disease (PID) is a potential risk factor for ovarian cancer. However, only few studies have investigated the association between PID and risk of borderline ovarian tumors. We conducted a population-based cohort study to investigate the association between PID and risk of borderline ovarian tumors.
METHODS: Using various nationwide Danish registries we identified all women in Denmark during 1978-2012, who were born during 1940-1970 (n=1,318,925). Of these, 81,263 women were diagnosed with PID in the study period, and 2736 women had a borderline ovarian tumor (1290 serous and 1344 mucinous). Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between PID and risk of borderline tumors were estimated using Cox regression models with adjustment for potential confounders.
RESULTS: A history of PID was associated with an increased risk of borderline ovarian tumors (HR=1.39; 95% CI: 1.19-1.61). However, histotype-specific analyses revealed significant variation in risk as PID was only associated with an increased risk of serous borderline tumors (HR=1.85; 95% CI: 1.52-2.24), but not with mucinous borderline tumors (HR=1.06; 95% CI: 0.83-1.35).
CONCLUSIONS: PID is associated with an increased risk of serous borderline tumors. Further research on the potential underlying biological mechanisms and on the identification of the subset of women with PID who are at increased risk of serous borderline tumors is warranted.

BACKGROUND: Pelvic inflammatory disease (PID) has been proposed as a risk factor for ovarian cancer. However, the existing literature on the association between PID and ovarian cancer risk is inconclusive, and only few cohort studies have been conducted.
METHODS: Using nationwide Danish registries, we conducted a population-based cohort study including all women from the birth cohorts 1940 to 1970 in Denmark during 1978-2012 (n = 1,318,929) to investigate the association between PID and subsequent risk of epithelial ovarian cancer. Among women in the cohort, 81,281 women were diagnosed with PID and 5,356 women developed ovarian cancer during follow-up through 2012. Cox regression models were used to estimate HRs and 95% confidence intervals (CI) for the association between PID and ovarian cancer, both overall and according to histotype.
RESULTS: For ovarian cancer overall, we observed no association with PID (HR, 1.05; 95% CI, 0.92-1.20). However, in histotype-specific analyses, we found a statistically significantly increased risk of serous ovarian cancer among women with PID (HR, 1.19; 1.00-1.41; P = 0.047). Conversely, PID was not convincingly associated with risk of any of the other histotypes of ovarian cancer.
CONCLUSIONS: PID was associated with a modestly increased risk of serous ovarian cancer, but not other histotypes.
IMPACT: Our results indicate that PID is not a strong risk factor for ovarian cancer. Whether PID is slightly associated with risk of serous ovarian cancer has to be confirmed in other studies. Cancer Epidemiol Biomarkers Prev; 26(1); 104-9. ©2016 AACR.

Single nucleotide polymorphisms (SNPs) in pathways influencing lymph node (LN) metastasis and estrogen receptor (ER) status in breast cancer may partially explain inter-patient variability in prognosis. We examined 154 SNPs in 12 metastasis-related genes for associations with breast cancer risk, stratified by LN and ER status, in European-American (EA) and African-American (AA) women. Two-thousand six hundred and seventy-one women enrolled in the Women's Circle of Health Study were genotyped. Pathway analyses were conducted using the adaptive rank truncated product (ARTP) method, with p

The metastasis-associated (MTA) gene family is a critical component of the nucleosome remodeling and histone deacetylase complex, and plays an important role in metastatic processes. We systematically evaluated dysregulation of the MTA family to clarify their clinical significance in gastric cancer (GC). One hundred and forty-five patients who underwent surgery for GC were evaluated. We analyzed the expression levels of the MTA family (MTA1, 2 and 3) by qPCR in GC tissue, and the MTA1 protein expression in primary cancer and matched normal mucosa (NM) was measured using immunohistochemical analysis. The expression of all the MTA family members was significantly increased in a stage-dependent manner, and elevated expression of all of the MTA family members was correlated with metastatic factors and prognosis in GC patients. Multivariate analysis revealed that MTA1 overexpression was an independent risk factor for survival. Especially, elevated expression of MTA1 was significantly correlated with recurrence, and was an independent risk factor for lymph node metastasis. Immunohistochemical analysis demonstrated that MTA1 was predominantly expressed in the nuclei of primary GC cells but was not expressed in NM and in the cancer stroma. In conclusion, quantification of MTA expression may support the accurate diagnosis of disease staging and may help predict clinical outcomes.

Gastric cancer is generally associated with poor survival rates and accounts for a remarkable proportion of global cancer mortality. The prevalence of gastric carcinoma varies in different regions of world and across teh various ethnic groups. On the basis of pathological assessment, gastric cancer can be categorized as intestinal and diffuse carcinomas. The etiology is diverse, including chemical carcinogen exposure, and high salt intake Helicobacter pylori also plays a vital role in the pathogenesis of certain gastric carcinomas. The development of gastric cancer involves various alterations in mRNAs, genes (GOLPH3, MTA2) and proteins (Coronins). miRNAs, Hsamir135b, MiR21, miR106b, miR17, miR18a, MiR21, miR106b, miR17, miR18a and MiRNA375, miRNA1955p are the latest diagnostic biomarkers which can facilitate the early diagnosis of gastric carcinomas. Recent development in the treatment strategies for gastric carcinoma include the introduction of monoclonal antibodies, TKI inhibitors, inhibitors of PDGFR β, VEGFR1, VEGFR2, AntiEGFR and antiHER2 agents which can be applied along with conventional therapies.

INTRODUCTION: Here we present an unusual case of DNA ligase IV deficiency syndrome without dysmorphic facial findings and microcephaly complicated with Epstein-Barr virus-associated large B-cell lymphoma with the right lung involvement and a massive brain tumor lesion in a two-year-old female.
METHODS: PID panel was used for sequencing 55 genes. Most genes have >98% exon coverage including splicing sites. LIG4 gene has 100% exon and splicing site coverage. This was used in Ion Torrent PGM system, the library kit was made by Agilent with Haloplex technology. The sequence analysis software was Alamut, direct sequencing of LIG4 gene was performed after NGS results.
RESULT: We identified three heterozygous mutations in LIG4 gene c.2736+3delC and c.8 C>T (p.A3V) inherited from mother and c.26C>T (p.T9I) - from father after PID panel sequencing and some additional polymorphisms in ATM, NOD2 and NLRP3 genes.
CONCLUSION: This case broadens the clinical spectrum of DNA ligase IV deficiency.

BACKGROUND: Oesophageal cancer is the fourth leading cause of cancer death in China where essentially all cases are histologically oesophageal squamous cell carcinoma (ESCC). Agnostic pathway-based analyses of genome-wide association study (GWAS) data combined with tissue-specific expression quantitative trait loci (eQTL) analysis and publicly available functional data can identify biological pathways and/or genes enriched with functionally-relevant disease-associated variants.
METHOD: We used the adaptive multilocus joint test to analyse 1827 pathways containing 6060 genes using GWAS data from 1942 ESCC cases and 2111 controls with Chinese ancestry. We examined the function of risk alleles using in silico and eQTL analyses in oesophageal tissues.
RESULTS: Associations with ESCC risk were observed for 36 pathways predominantly involved in apoptosis, cell cycle regulation and DNA repair and containing known GWAS-associated genes. After excluding genes with previous GWAS signals, candidate pathways (and genes) for ESCC risk included taste transduction (KEGG_hsa04742; TAS2R13, TAS2R42, TAS2R14, TAS2R46,TAS2R50), long-patch base excision repair (Reactome_pid; POLD2) and the metabolics pathway (KEGG_hsa01100; MTAP, GAPDH, DCTD, POLD2, AMDHD1). We identified and validated CASP8 rs13016963 and IDH2 rs11630814 as eQTLs, and CASP8 rs3769823 and IDH2 rs4561444 as the potential functional variants in high-linkage disequilibrium with these single nucleotide polymorphisms (SNPs), respectively. Further, IDH2 mRNA levels were down-regulated in ESCC (tumour:normal-fold change = 0.69, P =  .75E-14).
CONCLUSION: Agnostic pathway-based analyses and integration of multiple types of functional data provide new evidence for the contribution of genes in taste transduction and metabolism to ESCC susceptibility, and for the functionality of both established and new ESCC risk-related SNPs.

We report the updated classification of primary immunodeficiencies compiled by the Primary Immunodeficiency Expert Committee (PID EC) of the International Union of Immunological Societies (IUIS). In the two years since the previous version, 34 new gene defects are reported in this updated version. For each disorder, the key clinical and laboratory features are provided. In this new version we continue to see the increasing overlap between immunodeficiency, as manifested by infection and/or malignancy, and immune dysregulation, as manifested by auto-inflammation, auto-immunity, and/or allergy. There is also an increased number of genetic defects that lead to susceptibility to specific organisms which reflects the finely tuned nature of immune defense systems. This classification is the most up to date catalogue of all known and published primary immunodeficiencies and acts as a current reference of the knowledge of these conditions and is an important aid for the genetic and molecular diagnosis of patients with these rare diseases.

There are now nearly 300 single-gene inborn errors of immunity underlying phenotypes as diverse as infection, malignancy, allergy, auto-immunity, and auto-inflammation. For each of these five categories, a growing variety of phenotypes are ascribed to Primary Immunodeficiency Diseases (PID), making PIDs a rapidly expanding field of medicine. The International Union of Immunological Societies (IUIS) PID expert committee (EC) has published every other year a classification of these disorders into tables, defined by shared pathogenesis and/or clinical consequences. In 2013, the IUIS committee also proposed a more user-friendly, phenotypic classification, based on the selection of key phenotypes at the bedside. We herein propose the revised figures, based on the accompanying 2015 IUIS PID EC classification.

Human primary immunodeficiency (PID) states, where mutations in single immune system genes predispose individuals to certain infectious agents and not others, are experiments of nature that hold important lessons for the immunologist. The number of genetically defined PIDs is rising rapidly, as is the opportunity to learn from them. Epstein-Barr virus (EBV), a human herpesvirus, has long been of interest because of its complex interaction with the immune system. Thus, it causes both infectious mononucleosis (IM), an immunopathologic disease associated with exaggerated host responses, and at least one malignancy, EBV-positive lymphoproliferative disease, when those responses are impaired. Here, we describe the full range of PIDs currently linked with an increased risk of EBV-associated disease. These provide examples where IM-like immunopathology is fatally exaggerated, and others where responses impaired at the stage of induction, expansion, or effector function predispose to malignancy. Current evidence from this rapidly moving field supports the view that lesions in both natural killer cell and T cell function can lead to EBV pathology.

The aim of our study was to assess the differential gene expression of Parkinson protein 7 (PARK7) interactome in malignant pleural mesothelioma (MPM) using data mining techniques to identify novel candidate genes that may play a role in the pathogenicity of MPM. We constructed the PARK7 interactome using the ConsensusPathDB database. We then interrogated the Oncomine Cancer Microarray database using the Gordon Mesothelioma Study, for differential gene expression of the PARK7 interactome. In ConsensusPathDB, 38 protein interactors of PARK7 were identified. In the Gordon Mesothelioma Study, 34 of them were assessed out of which SUMO1, UBC3, KIAA0101, HDAC2, DAXX, RBBP4, BBS1, NONO, RBBP7, HTRA2, and STUB1 were significantly overexpressed whereas TRAF6 and MTA2 were significantly underexpressed in MPM patients (network 2). Furthermore, Kaplan-Meier analysis revealed that MPM patients with high BBS1 expression had a median overall survival of 16.5 vs. 8.7 mo of those that had low expression. For validation purposes, we performed a meta-analysis in Oncomine database in five sarcoma datasets. Eight network 2 genes (KIAA0101, HDAC2, SUMO1, RBBP4, NONO, RBBP7, HTRA2, and MTA2) were significantly differentially expressed in an array of 18 different sarcoma types. Finally, Gene Ontology annotation enrichment analysis revealed significant roles of the PARK7 interactome in NuRD, CHD, and SWI/SNF protein complexes. In conclusion, we identified 13 novel genes differentially expressed in MPM, never reported before. Among them, BBS1 emerged as a novel predictor of overall survival in MPM. Finally, we identified that PARK7 interactome is involved in novel pathways pertinent in MPM disease.

BACKGROUND: MetastamiRs have momentous clinical relevance and have been correlated with disease progression in many tumors. In this study, we identified neuroblastoma metastamiRs exploiting unique mouse models of favorable and high-risk metastatic human neuroblastoma. Further, we related their deregulation to the modulation of target proteins and established their association with clinical outcomes.
RESULTS: Whole genome miRNA microarray analysis identified 74 metastamiRs across the manifold of metastatic tumors. RT-qPCR on select miRNAs validated profile expression. Results from bio-informatics across the ingenuity pathway, miRCancer, and literature data-mining endorsed the expression of these miRNAs in multiple tumor systems and showed their role in metastasis, identifying them as metastamiRs. Immunoblotting and TMA-IHC analyses revealed alterations in the expression/phosphorylation of metastamiRs' targets, including ADAMTS-1, AKT1/2/3, ASK1, AURKβ, Birc1, Birc2, Bric5, β-CATENIN, CASP8, CD54, CDK4, CREB, CTGF, CXCR4, CYCLIN-D1, EGFR, ELK1, ESR1, CFOS, FOSB, FRA, GRB10, GSK3β, IL1α, JUND, kRAS, KRTAP1, MCP1, MEGF10, MMP2, MMP3, MMP9, MMP10, MTA2, MYB, cMYC, NF2, NOS3, P21, pP38, PTPN3, CLEAVED PARP, PKC, SDF-1β, SEMA3D, SELE, STAT3, TLR3, TNFα, TNFR1, and VEGF in aggressive cells ex vivo and in a manifold of metastatic tumors in vivo. miRNA mimic (hsa-miR-125b, hsa-miR-27b, hsa-miR-93, hsa-miR-20a) and inhibitor (hsa-miR-1224-3p, hsa-miR-1260) approach for select miRNAs revealed the direct influence of the altered metastamiRs in the regulation of identified protein targets. Clinical outcome association analysis with the validated metastamiRs' targets corresponded strongly with poor overall and relapse-free survival.
CONCLUSIONS: For the first time, these results identified a comprehensive list of neuroblastoma metastamiRs, related their deregulation to altered expression of protein targets, and established their association with poor clinical outcomes. The identified set of distinctive neuroblastoma metastamiRs could serve as potential candidates for diagnostic markers for the switch from favorable to high-risk metastatic disease.

BACKGROUND: Laterally spreading tumors (LSTs) are generally defined as lesions >10 mm in diameter, are characterized by lateral expansion along the luminal wall with a low vertical axis. In contrast to other forms of tumor, LSTs are generally considered to have a superficial growth pattern and the potential for malignancy. We focused on this morphological character of LSTs, and analyzed the gene expression profile of LSTs.
METHODS: The expression of 168 genes in 41 colorectal tumor samples (17 LST-adenoma, 12 LST-carcinoma, 12 Ip [pedunculated type of the Paris classification)-adenoma, all of which were 10 mm or more in diameter] was analyzed by PCR array. Based on the results, we investigated the expression levels of genes up-regulated in LST-adenoma, compared to Ip-adenoma, by hierarchical and K-means clustering. To confirm the results of the array analysis, using an additional 60 samples (38 LST-adenoma, 22 Ip-adenoma), we determined the localization of the gene product by immunohistochemical staining.
RESULT: The expression of 129 genes differed in colorectal tumors from normal mucosa by PCR array analysis. As a result of K-means clustering, the expression levels of five genes, AKT1, BCL2L1, ERBB2, MTA2 and TNFRSF25, were found to be significantly up-regulated (p < 0.05) in LST-adenoma, compared to Ip-adenoma. Immunohistochemical analysis showed that the BCL2L1 protein was significantly and meaningfully up-regulated in LST-adenoma compared to Ip-adenoma (p = 0.010). With respect to apoptosis status in LST-Adenoma, it assumes that BCL2L1 is anti-apoptotic protein, the samples such as BCL2L1 positive and TUNEL negative, or BCL2L1 negative and TUNEL positive are consistent with the assumption. 63.2 % LST-adenoma samples were consistent with the assumption.
CONCLUSIONS: LSTs have an unusual profile of gene expression compared to other tumors and BCL2L1 might be concerned in the organization of LSTs.

How loss-of-function of GATA3 contributes to the development of breast cancer is poorly understood. Here, we report that GATA3 nucleates a transcription repression program composed of G9A and MTA3-, but not MTA1- or MTA2-, constituted NuRD complex. Genome-wide analysis of the GATA3/G9A/NuRD(MTA3) targets identified a cohort of genes including ZEB2 that are critically involved in epithelial-to-mesenchymal transition and cell invasion. We demonstrate that the GATA3/G9A/NuRD(MTA3) complex inhibits the invasive potential of breast cancer cells in vitro and suppresses breast cancer metastasis in vivo. Strikingly, the expression of GATA3, G9A, and MTA3 is concurrently downregulated during breast cancer progression, leading to an elevated expression of ZEB2, which, in turn, represses the expression of G9A and MTA3 through the recruitment of G9A/NuRD(MTA1).

OBJECTIVE: Metastasis-associated protein 2 is considered as an intrinsic subunit of the nucleosome remodelling and histone deacetylase complex, which contributes to the epigenetic silencing genes. More and more evidence suggests that metastasis-associated protein 2 is required to maintain the malignant phenotype, but the role of metastasis-associated protein 2 function in mediating tumour metastasis in non-small-cell lung cancer has not been explored.
METHODS: Bioinformatics was used to detect the GEO 3141 database, the online tool of Kmplot was used to confirm the high expression of metastasis-associated protein 2 in influencing 5-year overall survival. Wound-healing assay, Transwell invasion assay and Living imaging assay together showed that MTA2 shRNA inhibited cell migration and invasion in vitro and in vivo. Chromatin immunoprecipitation, quantitative chromatin immunoprecipitation and luciferase reporter assays showed metastasis-associated protein 2 binding on the promoter of the epithelial transmembrane glycoprotein (Ep-CAM) and cell adhesion molecule E-cadherin.
RESULTS: The patient samples collected in our hospital show that metastasis-associated protein 2 was expressed in aggressive lung cancer cells, and its higher expression is correlated with poor prognosis. Metastasis-associated protein 2 promoted cell migration and invasion in vitro and in vivo through binding on the promoter of Ep-CAM and E-cadherin. Luciferase reporter assays showed repressed or enhanced E-cadherin or Ep-CAM promoter-driven luciferase reporter under metastasis-associated protein 2 overexpression or depletion. The changes in the level of protein and RNA implied that suppression of downstream E-cadherin or Ep-CAM was an important mechanism by which metastasis-associated protein 2 triggered epithelial-mesenchymal transition and metastasis.
CONCLUSIONS: Together, our experiments reveal the mechanism for metastasis-associated protein 2 in facilitating invasive potential of non-small-cell lung cancer cells, suggesting that metastasis-associated protein 2 might be a potential therapeutic target for treating the metastasis of non-small-cell lung cancer.

BACKGROUND: We have preliminarily reported MTA2 expression in gastric cancer and its biological functions by using knockdown cell models, while the molecular mechanisms of MTA2 in regulating malignant behaviors are still unclear.
METHODS: MTA2 overexpression models were established by transfection assay in gastric cancer cells BGC-823 and MKN28. Cell proliferation assay, colony formation in soft agar, wound-healing assay and transwell migration assay were performed with MTA2 overexpression and negative control (NC) cells. Subcutaneous xenografts and pulmonary metastasis models by BGC-823/MTA2 and BGC-823/NC cells were used to observe the capacity of growth and metastasis in vivo. Differential gene expression in MTA2 knockdown and overexpression cells was analyzed by microarrays. IL-11, which demonstrated as differential expression in microarray, was detected by real-time PCR, western blot, ELISA and immunohistochemistry staining. Recombinant human IL-11 (rhIL-11) was administrated in cell proliferation and colony formation as rescue assay.
RESULTS: The numbers of colonies in soft agar were significantly more in BGC-823/MTA2 and MKN28/MTA2 cells, comparing with those in their NC cells. Capabilities of cell proliferation, wound-healing and cell migration were not significantly changed in MTA2 overexpression cells. The sizes of subcutaneous xenografts and pulmonary metastases of BGC-832/MTA2 cells were significantly larger than those in BGC-823/NC group. Differential expression of IL-11 was identified by genome expression microarray both in MTA2 knockdown and overexpression cells. IL-11 expression was elevated in BGC-823/MTA2 cells, whereas reduced in SGC-7901/shMTA2 cells. Administration of rhIL-11 recovered colony formation capacity of SGC-7901/shMTA2 cells.
CONCLUSIONS: MTA2 overexpression enhances colony formation and tumor growth of gastric cancer cells, but not plays important role in cancer cell migration and metastasis. IL-11 is one of the downstream effectors of MTA2 in regulating gastric cancer cells growth.

PURPOSE: Focal and temporal tumour heterogeneity can represent a major challenge for biology-guided therapies. This study proposes to investigative molecular discrepancies between primary colorectal cancer (CRC) samples and matched metastases.
EXPERIMENTAL DESIGN: Surgical samples from primary and matched metastatic tissues from 13 CRC patients along with their adjacent normal tissue were evaluated. A mutational analysis was performed using a targeted Next Generation Sequencing assay (Foundation Medicine) with a focus on known recurrent somatic mutations as surrogate of key oncogenic events. Gene expression analysis was also performed to investigate transcriptional discrepancies.
RESULTS: Among the 26 samples, 191 mutations were identified including mutations in APC (13 pts), TP53 (11 pts), and KRAS (7 pts). Global concordance rate for mutations was 78% between primary and metastatic tumours and raised to 90% for 12 known recurrent mutations in CRC. Differential gene expression analysis revealed a low number of significantly variant transcripts between primary and metastatic tumours once the tissue effect was taken into account. Only two pathways (ST_ADRENERGIC, PID_REELINPATHWAY) were differentially up-regulated in metastases among 17 variant pathways. A common profile in primary and metastatic tumours revealed conserved pathways mostly involved in cell cycle regulation. Only two pathways were significantly down regulated compared to normal control, including regulation of autophagy (KEGG_REGULATION_OF_AUTOPHAGY).
CONCLUSION: These results suggest that profiles of primary tumour can identify key alterations present in matched CRC metastases at first metastatic progression. Gene expression analysis identified mainly conserved pathways between primary tumour and matched liver metastases.