BCAR3

Gene Summary

Gene:BCAR3; BCAR3 adaptor protein, NSP family member
Aliases: NSP2, AND-34, SH2D3B
Location:1p22.1
Summary:Breast tumors are initially dependent on estrogens for growth and progression and can be inhibited by anti-estrogens such as tamoxifen. However, breast cancers progress to become anti-estrogen resistant. Breast cancer anti-estrogen resistance gene 3 was identified in the search for genes involved in the development of estrogen resistance. The gene encodes a component of intracellular signal transduction that causes estrogen-independent proliferation in human breast cancer cells. The protein contains a putative src homology 2 (SH2) domain, a hall mark of cellular tyrosine kinase signaling molecules, and is partly homologous to the cell division cycle protein CDC48. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:breast cancer anti-estrogen resistance protein 3
Source:NCBIAccessed: 01 September, 2019

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Signal Transducing Adaptor Proteins
  • Biomarkers, Tumor
  • Breast Cancer
  • Estrogen Antagonists
  • Cancer DNA
  • Virus Integration
  • Cloning, Molecular
  • Tamoxifen
  • Transforming Growth Factor beta
  • Receptors, Interleukin-1 Type I
  • Transcription
  • Young Adult
  • Oligonucleotide Array Sequence Analysis
  • Chromosome 1
  • Antineoplastic Agents, Hormonal
  • Drug Resistance
  • rac GTP-Binding Proteins
  • Single-Stranded Conformational Polymorphism
  • Amino Acid Sequence
  • Signal Transduction
  • Carrier Proteins
  • RTPCR
  • CDC42
  • BCAR1
  • Protein Biosynthesis
  • Disease Progression
  • Protein Binding
  • RT-PCR
  • Cancer Gene Expression Regulation
  • Biological Models
  • Gene Expression Profiling
  • Base Sequence
  • Messenger RNA
  • Estrogen Receptor Modulators
  • BCAR3 protein, human
  • Cell Differentiation
  • Polymerase Chain Reaction
  • Molecular Sequence Data
  • Gene Expression
  • rac1 GTP-Binding Protein
  • Transfection
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (1)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: BCAR3 (cancer-related)

Zhu X, Tan J, Liang Z, Zhou M
Comprehensive analysis of competing endogenous RNA network and 3-mRNA signature predicting survival in papillary renal cell cancer.
Medicine (Baltimore). 2019; 98(30):e16672 [PubMed] Related Publications
Long non-coding RNAs (lncRNAs) can act as competing endogenous RNAs (ceRNAs) to exert significant roles in regulating the expression of mRNAs by sequestering and binding miRNAs. To elucidate the functional roles and regulatory mechanism of lncRNAs in papillary renal cell cancer (pRCC), we conducted a comprehensive analysis of ceRNA network and constructed a mRNA signature to predict prognosis of pRCC.We collected mRNAs and lncRNAs expression profiles of 289 pRCC samples and 32 normal renal tissues, and miRNA expression profiles of 292 pRCC samples and 34 normal samples from The Cancer Genome Atlas (TCGA) database. Differential expressions of RNAs were evaluated by the "edgeR" package in R. Functional enrichment analysis of DEmRNA was performed by DAVID 6.8 and KEGG, while PPI network of top 200 DEmRNAs was conducted using the STRING database. The univariate and multivariate Cox regression were conducted to figure out the candidate DEmRNAs with predictive values in prognosis. Receiver operator characteristic (ROC) curve estimation was performed to achieve the area under the curve (AUC) of the ROC curve to judge mRNA-associated prognosic model. A ceRNA network was established relying on the basis of combination of lncRNA-miRNA interactions and miRNA-mRNA interactions.A total of 1928 DEmRNAs, 981 DElncRNAs, and 52 DEmiRNAs were identified at significance level of |log2Fold Change |>2 and adjusted P-value < .01. A 3-mRNA signatures consisting of ERG, RRM2, and EGF was constructed to predict survival in pRCC. Moreover, a pRCC-associated ceRNA network was constructed, with 57 lncRNAs, 11 miRNAs, and 28 mRNAs.Our study illustrated the regulatory mechanism of ceRNA network in papillary renal cancer. The identified mRNA signatures could be used to predict survival of pRCC.

Wang H, Guo H, Wang Z, et al.
The Diagnostic Value of Quantitative CT Analysis of Ground-Glass Volume Percentage in Differentiating Epidermal Growth Factor Receptor Mutation and Subtypes in Lung Adenocarcinoma.
Biomed Res Int. 2019; 2019:9643836 [PubMed] Free Access to Full Article Related Publications
Objective: To retrospectively investigate computed tomographic (CT) quantitative analysis of ground-glass opacity (GGO) volume percentage and morphologic features of resected lung adenocarcinomas according to epidermal growth factor receptor (
Methods: Amplification refractory mutation system was used to detect mutations in the EGFR gene. Distribution of demographics and GGO volume percentage were performed according to EGFR mutation status and subtypes.
Results: EGFR mutations were significantly more frequent in women (55.2% vs. 37.0%,
Conclusion: GGO volume percentage in adenocarcinomas with EGFR mutation was significantly higher than that in tumors without EGFR mutation, and adenocarcinomas with exon 21 mutation showed significantly higher GGO volume percentage than in tumors with exon 19 mutation and those without EGFR mutation. Our results indicate that GGO volume percentage cut-off values of more than 37.7% and 34.3% were predictors of positive exon 21 mutation and EGFR mutation, respectively.

Sadłecki P, Grabiec M, Grzanka D, et al.
Expression of zinc finger transcription factors (ZNF143 and ZNF281) in serous borderline ovarian tumors and low-grade ovarian cancers.
J Ovarian Res. 2019; 12(1):23 [PubMed] Free Access to Full Article Related Publications
Low-grade ovarian cancers represent up to 8% of all epithelial ovarian carcinomas (EOCs). Recent studies demonstrated that epithelial-mesenchymal transition (EMT) is crucial for the progression of EOCs. EMT plays a key role in cancer invasion, metastasis formation and chemotherapy resistance. An array of novel EMT transcription factors from the zinc finger protein family have been described recently, among them zinc finger protein 143 (ZNF143) and zinc finger protein 281 (ZNF281). The study included tissue specimens from 42 patients. Based on histopathological examination of surgical specimens, eight lesions were classified as serous borderline ovarian tumors (sBOTs) and 34 as low-grade EOCs. The proportions of the ovarian tumors that tested positively for ZNF143 and ZNF281 were 90 and 57%, respectively. No statistically significant differences were found in the expressions of ZNF143 and ZNF281 transcription factors in SBOTs and low-grade EOCs. Considering the expression patterns for ZNF143 and ZNF281 identified in this study, both sBOTs and low-grade EOCs might undergo a dynamic epithelial-mesenchymal interconversion. The lack of statistically significant differences in the expressions of the zinc finger proteins in sBOTs and low-grade serous EOCs might constitute an evidence for common origin of these two tumor types.

Sang M, Meng L, Ma C, et al.
Effect of AR antagonist combined with PARP1 inhibitor on sporadic triple-negative breast cancer bearing AR expression and methylation-mediated BRCA1 dysfunction.
Biomed Pharmacother. 2019; 111:169-177 [PubMed] Related Publications
Triple-negative breast cancer (TNBC) patients usually present worse clinical outcomes due to their high heterogeneity. The purpose of our study is to investigate the prognostic role of AR and BRCA1 expression in sporadic TNBC patients, and effect of AR blockade and PARP1 inhibitor for TNBC patients who characterized by positive-AR expression and BRCA1 inactivation or dysfunction. In our present study, we found that AR is expressed in 43.6% and 34.0% of TNBC tissues, when 1% or 10% staining was used as the threshold for AR positivity, respectively. When 1% staining was used as the threshold, AR expression indicates a poor disease-free survival (DFS) of TNBC patients. TNBC patients with negative BRCA1 show a poor DFS, and BRCA1 suppression is associated with the methylation status of its promoter. Interestingly, BRCA1-/AR + TNBC patients have shorter DFS than other TNBC patients regardless of the threshold for AR positivity. AR antagonists MDV3100 enhances the PARP1 inhibitor Olaparib-mediated decrease of cell viability in AR-positive/BRCA1-inactivated cells in vitro and in vivo. Our results suggested that combination of AR blockade and PARP1 inhibitor may be a potential strategy for sporadic TNBC patients who characterized by positive-AR expression and BRCA1 inactivation or dysfunction.

Cao Y, Shi C, Li J, et al.
Expression profile of long noncoding RNAs in human papillary thyroid carcinoma.
Neoplasma. 2019; 66(2):245-251 [PubMed] Related Publications
Long non-coding RNAs (lncRNAs) are strongly associated with cancer biology. The objective of this study is to investigate the expression profile of lncRNAs in human papillary thyroid carcinoma (PTC), and to understand the biological role of lncRNAs and their involvement in PTC oncogenesis. The lncRNAs and messenger RNAs (mRNAs) expression in human PTC and paired adjacent non-cancerous thyroid (NCT) tissues were studied by micro-array, and quantitative real-time polymerase chain reaction (qRT-PCR) validated five differentially expressed lncRNAs. We identified 2,925 significantly differentially expressed lncRNAs with potential roles in PTC, (absolute fold change >2.0; p<0.05). Of these, 1,922 were up-regulated and 933 down-regulated and the qRT-PCR results agreed with micro-array results. Gene ontology (GO) enrichment and pathway analysis then investigated gene function and identified significantly enriched pathways in differentially expressed mRNA's. Many of these pathways were related to cancer, including 60 genes associated with "pathways in cancer" and 34 linked to "proteoglycans in cancer". Co-expression network and target prediction analysis of lncRNAs revealed that TCONS_00020457 can have important roles in PTC. In conclusion, the results of this study indicate that lncRNAs can be important regulators in PTC tumorigenesis and provide understanding of the function and mechanism of lncRNAs related to human papillary thyroid carcinoma.

Zhang W, Lin Y, Liu X, et al.
Prediction and prognostic significance of BCAR3 expression in patients with multiple myeloma.
J Transl Med. 2018; 16(1):363 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Multiple myeloma (MM) is the plasma cell tumor, which is characterized by clonal proliferation of tumor cells, with high risk of progression to renal impairment, bone damage and amyloidosis. Although the survival rate of patients with MM has improved in the past decade, most people inevitably relapse. The treatment and prognosis of MM are still urgent problems. Breast Cancer Antiestrogen Resistance 3 (BCAR3) is a protein-coding gene that is associated with many tumors. However, there have been few studies on the relationship of BCAR3 and MM.
METHODS: We analyzed 1878 MM patients (1930 samples) from 7 independent datasets. First, we compared the BCAR3 expression level of MM patients in different stages and MM patients with different amplification of 1q21. Second, we analyzed BCAR3 expression levels in MM patients with different molecular subtypes. Finally, we explored the event-free survival rate (EFS) and overall survival rate (OS) of MM patients with high or low BCAR3 expression, including patients before and after relapse, and their therapeutic responses to bortezomib and dexamethasone.
RESULTS: The expression of BCAR3 showed a decreasing trend in stages I, II and III (P = 0.00068). With the increase of 1q21 amplification level, the expression of BCAR3 decreased (P = 0.022). Patients with high BCAR3 expression had higher EFS and OS (EFS: P < 0.0001, OS: P < 0.0001). The expression of BCAR3 gene before relapse was higher than that after relapse (P = 0.0045). BCAR3 is an independent factor affecting prognosis (EFS: P = 5.17E-03; OS: P = 3.33E-04).
CONCLUSION: We found that high expression level of BCAR3 predicted better prognosis of MM patients. Low expression of BCAR3 at diagnosis can predict early relapse. BCAR3 is an independent prognostic factor for MM. BCAR3 can be used as a potential biomarker.

Lu Y, Kweon SS, Tanikawa C, et al.
Large-Scale Genome-Wide Association Study of East Asians Identifies Loci Associated With Risk for Colorectal Cancer.
Gastroenterology. 2019; 156(5):1455-1466 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
BACKGROUND & AIMS: Genome-wide association studies (GWASs) have associated approximately 50 loci with risk of colorectal cancer (CRC)-nearly one third of these loci were initially associated with CRC in studies conducted in East Asian populations. We conducted a GWAS of East Asians to identify CRC risk loci and evaluate the generalizability of findings from GWASs of European populations to Asian populations.
METHODS: We analyzed genetic data from 22,775 patients with CRC (cases) and 47,731 individuals without cancer (controls) from 14 studies in the Asia Colorectal Cancer Consortium. First, we performed a meta-analysis of 7 GWASs (10,625 cases and 34,595 controls) and identified 46,554 promising risk variants for replication by adding them to the Multi-Ethnic Global Array (MEGA) for genotype analysis in 6445 cases and 7175 controls. These data were analyzed, along with data from an additional 5705 cases and 5961 controls genotyped using the OncoArray. We also obtained data from 57,976 cases and 67,242 controls of European descent. Variants at identified risk loci were functionally annotated and evaluated in correlation with gene expression levels.
RESULTS: A meta-analyses of all samples from people of Asian descent identified 13 loci and 1 new variant at a known locus (10q24.2) associated with risk of CRC at the genome-wide significance level of P < 5 × 10
CONCLUSIONS: We showed that most of the risk loci previously associated with CRC risk in individuals of European descent were also associated with CRC risk in East Asians. Furthermore, we identified 13 loci significantly associated with risk for CRC in Asians. Many of these loci contained genes that regulate the immune response, Wnt signaling to β-catenin, prostaglandin E2 catabolism, and cell pluripotency and proliferation. Further analyses of these genes and their variants is warranted, particularly for the 8 loci for which the lead CRC risk variants were not replicated in persons of European descent.

Bou-Dargham MJ, Liu Y, Sang QA, Zhang J
Subgrouping breast cancer patients based on immune evasion mechanisms unravels a high involvement of transforming growth factor-beta and decoy receptor 3.
PLoS One. 2018; 13(12):e0207799 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
In the era of immunotherapy and personalized medicine, there is an urgent need for advancing the knowledge of immune evasion in different cancer types and identifying reliable biomarkers that guide both therapy selection and patient inclusion in clinical trials. Given the differential immune responses and evasion mechanisms in breast cancer, we expect to identify different breast cancer groups based on their expression of immune-related genes. For that, we used the sequential biclustering method on The Cancer Genome Atlas RNA-seq breast cancer data and identified 7 clusters. We found that 77.4% of the clustered tumor specimens evade through transforming growth factor-beta (TGF-β) immunosuppression, 57.7% through decoy receptor 3 (DcR3) counterattack, 48.0% through cytotoxic T-lymphocyte-associated protein 4 (CTLA4), and 34.3% through programmed cell death-1 (PD-1). TGF-β and DcR3 are potential novel drug targets for breast cancer immunotherapy. Targeting TGF-β and DcR3 may provide a powerful approach for treating breast cancer because 57.7% of patients overexpressed these two molecules. Furthermore, triple-negative breast cancer (TNBC) patients clustered equally into two subgroups: one with impaired antigen presentation and another with high leukocyte recruitment but four different evasion mechanisms. Thus, different TNBC patients may be treated with different immunotherapy approaches. We identified biomarkers to cluster patients into subgroups based on immune evasion mechanisms and guide the choice of immunotherapy. These findings provide a better understanding of patients' response to immunotherapies and shed light on the rational design of novel combination therapies.

Mello JBH, Barros-Filho MC, Abreu FB, et al.
MicroRNAs involved in the HMGA2 deregulation and its co-occurrence with MED12 mutation in uterine leiomyoma.
Mol Hum Reprod. 2018; 24(11):556-563 [PubMed] Related Publications
STUDY QUESTION: Can the mediator complex subunit 12 (MED12) mutation and high mobility group AT-hook 2 (HMGA2) overexpression co-occurrence be explained by the alternative mechanism of HMGA2 dysregulation in uterine leiomyomas (UL)?
SUMMARY ANSWER: The co-occurrence of MED12 mutation and HMGA2 overexpression, and a negative correlation of five validated or predicted microRNAs that target HMGA2 were reported.
WHAT IS KNOWN ALREADY: The recent stratification of UL, according to recurrent and mutually exclusive genomic alterations affecting HMGA2, MED12, fumarate hydratase (FH) and collagen type IV alpha 5-alpha 6 (COL4A5-COL4A6) pointed out the involvement of distinct molecular pathways. However, the mechanisms of regulation involving these drivers are poorly explored.
STUDY DESIGN, SIZE, DURATION: A total of 78 UL and 34 adjacent normal myometrium (NM) tissues was collected from 56 patients who underwent hysterectomies at a single institution. The patients were treated at the Department of Gynecology and Obstetrics, School of Medicine, Sao Paulo State University, Botucatu, SP, Brazil, from October 1995 to February 2004.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Gene expression profiling was evaluated from fresh frozen tissues and compared with MED12 mutations at exon 2. In addition, RT-qPCR was applied to evaluate the expression levels of HMGA2 and their predictive miRNA regulators: hsa-let-7a, miR-26a, miR-26b, mir-93 and mir-106b.
MAIN RESULTS AND THE ROLE OF CHANCE: An unsupervised hierarchical clustering analysis revealed two main clusters with one of them (26 of 42 UL) showing an enrichment of MED12 mutated cases (18 of 26 UL). Increased expression levels of HMGA2 were observed in both clusters, including cases with MED12 mutation (cluster 1:18 UL). A significant HMGA2 overexpression (P < 0.001) in UL in comparison with NM was found. Five miRNAs predicted to regulate HMGA2 were significantly downregulated (P < 0.001) and negatively correlated to HMGA2 expression levels (P < 0.05) in UL.
LIMITATIONS REASONS FOR CAUTION: An in vivo functional study was not performed to validate the microRNAs and HMGA2 interaction due to technical limitations.
WIDER IMPLICATIONS OF THE FINDINGS: HMGA2 overexpression was detected in a significant number of MED12 mutated ULs, suggesting that these alterations coexist. Furthermore, five miRNAs were described as potential regulators of HMGA2 expression in UL.
LARGE-SCALE DATA: Data available in the Gene Expression Omnibus GSE42939.
STUDY FUNDING AND COMPETING INTEREST(S): This study was supported by grants from Fundação de Amparo a Pesquisa do Estado de São Paulo (# 2008/58835-2) and Conselho Nacional de Pesquisa (# 485032/2007-4), Brazil. The authors declared having no conflicts of interest.

Wu Y, Tan L, Chen J, et al.
MAD2 Combined with Mitotic Spindle Apparatus (MSA) and Anticentromere Antibody (ACA) for Diagnosis of Small Cell Lung Cancer (SCLC).
Med Sci Monit. 2018; 24:7541-7547 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
BACKGROUND MAD2 is the gene controlling mitosis. Many studies have assessed MAD2 in various types of carcinoma. Antinuclear mitotic spindle apparatus antibody (MSA) and anticentromere antibody (ACA) are related mitotic antibodies, playing roles in autoimmune diseases and carcinomas, but the expression of MAD2, MSA, and ACA in SCLC is unclear. MATERIAL AND METHODS We enrolled 70 SCLC patients, 72 non-small cell lung cancer (NSCLC) patients, and 65 pulmonary nodule (PN) patients. MAD2 expression was measured through agarose electrophoresis and qt-PCR. Antinuclear mitotic spindle apparatus antibody (MSA) and anticentromere antibody (ACA) were detected by indirect immunofluorescence (IIF). RESULTS MAD2 was found both in SCLC and NSCLC. Interestingly, there was a significant difference found between SCLC and NSCLC using qt-PCR (P<0.05). The area under the ROC curve of MAD2 expression was 0.799, with medium diagnostic value. MAD2 expression was related to age, lymphatic metastasis, and survival time, but not with sex. The positivity for MSA and ACA by IIF assay were 37.20% and 34.00%, respectively, in the SCLC group, which were higher than in the NSCLC and pulmonary nodule groups (P<0.05). The kappa values of MSA and ACA with MAD2 expression were 0.73 and 0.65, respectively, with moderate consistency. Combining MAD2 with MSA and ACA enhanced the sensitivity and specificity for diagnosing SCLC. CONCLUSIONS MAD2 expression was found to be involved in carcinogenesis and prognosis of SCLC. The combination of MAD2 with MSA and ACA is useful for early diagnosis and shows promise in treatment of SCLC.

Servín-Blanco R, Chávaro-Ortiz RM, Zamora-Alvarado R, et al.
Generation of cancer vaccine immunogens derived from major histocompatibility complex (MHC) class I molecules using variable epitope libraries.
Immunol Lett. 2018; 204:47-54 [PubMed] Related Publications
Although various immune checkpoint inhibitors (ICIs), used for the treatment of advanced cancer, showed remarkably durable tumor regression in a subset of patients, there are important limitations in a large group of non-responders, and the generation of novel immunogens capable of inducing protective cellular immune responses is a priority in cancer immunotherapy field. During the last decades, several types of vaccine immunogens have been used in numerous preclinical studies and clinical trials. However, although immunity to tumor Ags can be elicited by most vaccines tested, their clinical efficacy remains modest. Recently, we have developed an innovative vaccine concept, called Variable Epitope Libraries (VELs), with the purpose to exploit the high antigenic variability of many important pathogens and tumor cells as starting points for the construction of a new class of vaccine immunogens capable of inducing the largest possible repertoire of both B and T cells. In the present study, we decided to generate VEL immunogens derived from both classical and non-classical major histocompatibility complex (MHC) class I molecules. The MHC molecules, responsible for antigen presentation and subsequent activation of T lymphocytes, undergo multiple modifications that directly affect their proper function, resulting in immune escape of tumor cells. Two large VELs derived from multi-epitope region of H2-Kd and Qa-2 sequences (46 and 34 amino acids long, respectively), along with their wild type counterparts have been generated as synthetic peptides and tested in an aggressive 4T1 mouse model of breast cancer. Significant inhibition of tumor growth and the reduction of metastatic lesions in the lungs of immunized mice were observed. This study demonstrated for the first time the successful application of VELs carrying combinatorial libraries of epitope variants derived from MHC class I molecules as novel vaccine immunogens.

Wang X, Ding Y, Da B, et al.
Identification of potential prognostic long non‑coding RNA signatures based on a competing endogenous RNA network in lung adenocarcinoma.
Oncol Rep. 2018; 40(6):3199-3212 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
A number of experimental and computational studies have demonstrated the key roles of long non‑coding RNAs (lncRNAs) acting as competing endogenous RNAs (ceRNAs) in the tumorigenesis of lung adenocarcinoma (LUAC). However, there remains a requirement for prognostic candidate biomarkers acting as ceRNAs for the prediction of overall survival in patients with LUAC. The main goal of the present study was to identify novel lncRNAs associated with LUAC overall survival and assess their prognostic values. The study analyzed coding RNA and ncRNA expression profiles of patients with LUAC by retrieving existing RNA‑sequencing datasets from The Cancer Genome Atlas database, and 2,507 differentially expressed mRNAs, 1,633 lncRNAs and 113 miRNAs were screened from patients with LUAC compared with those of adjacent normal samples (P<0.01 and |logFC|>2). Of these LUAC‑specific RNAs, 134 lncRNAs, 21 miRNAs and 34 mRNAs were used to build an lncRNA‑mRNA‑miRNA ceRNA network, among which 8 lncRNAs and 9 mRNAs were associated with overall survival in patients with LUAC by acting as ceRNAs. Next, an lncRNA‑based prognostic signature was constructed by risk scoring approach based on the expression levels of 9 prognosis‑associated lncRNAs using Cox's regression analysis. Moreover, the prognostic capacity of the 9‑lncRNA signature was independent of known clinical prognostic factors. These results provide novel insight into the potential of lncRNA ceRNAs to be candidate biomarkers associated with LUAC overall survival.

Jeannot E, Harlé A, Holmes A, Sastre-Garau X
Nuclear factor I X is a recurrent target for HPV16 insertions in anal carcinomas.
Genes Chromosomes Cancer. 2018; 57(12):638-644 [PubMed] Related Publications
Anal carcinomas (AC) are associated with human papillomavirus (HPV) DNA sequences, but little is known about the physical state of the viral genome in carcinoma cells. To define the integration status and gene(s) targeted by viral insertions in AC, tumor DNAs extracted from 35 tumor specimen samples in patients with HPV16-associated invasive carcinoma were analyzed using the detection of integrated papillomavirus sequences-PCR approach. The genomic status at integration sites was assessed using comparative genomic hybridization-array assay and gene expression using reverse transcription quantitative PCR (RT-qPCR). HPV16 DNA was found integrated in 25/35 (71%) cases and the integration locus could be determined at the molecular level in 19 cases (29 total integration loci). HPV DNA was inserted on different chromosomes, but 5 cases harbored viral sequences at 19p13.2, within the nuclear factor I X (NFIX) locus. Viral DNA mapped between the most distal and the two proximal alternatively expressed exons of this gene in three cases (CA21, CA04, and CA35) and upstream of this gene (663 kb and 2.3 Mb) in the others. CGH arrays showed genomic gains/amplifications at the NFIX region, associated with HPV within the gene and RT-qPCR, revealed NFIX mRNA overexpression. Other genes targeted by integration were IL20RB, RPS6KA2, MSRA1, PIP5K1B, SLX4IP, CECR1, BCAR3, ATF6, CSNK1G1, APBA2, AGK, ILF3, PVT1, TRMT1, RAD51B, FASN, CCDC57, DSG3, and ZNF563. We identified recurrent targeting of NFIX by HPV16 insertion in anal carcinomas, supporting a role for this gene in oncogenesis, as reported for non-HPV tumors.

Danková Z, Braný D, Dvorská D, et al.
Methylation status of KLF4 and HS3ST2 genes as predictors of endometrial cancer and hyperplastic endometrial lesions.
Int J Mol Med. 2018; 42(6):3318-3328 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Endometrial carcinoma is one of the most common tumours in developed countries. In addition to the active role of genetic factors, epigenetic changes also have an important effect. The present study analysed the methylation status of kruppel like factor 4 (KLF4) and heparan sulfate‑glucosamine 3‑sulfotransferase 2 (HS3ST2) genes in three endometrial tissue types for carcinoma prediction. The sample comprised 91 women with histologically‑confirmed endometrial carcinoma (64.16±9.64 years old), 36 women with hyperplasia (53.39±9.64 years old) and 45 with no signs or symptoms of malignancy (48.53±11.11 years old). The CpG dinucleotide methylation levels were examined by quantitative pyrosequencing, and the discrimination accuracy of the model was calculated using the Random Forest classification algorithm of the area under the ROC curve (AUC). The mean values of KLF4 and HS3ST2 methylation indices were 23.83±11.39 and 8.52±2.57 in the control samples; 30.40±8.52 and 33.76±20.66 in hyperplasia and 34.72±10.79 and 34.49±18.39 in the cancerous tissues. Multinomial logistic regression indicated that the HS3ST2 CpG1 methylation status is a predictor of hyperplasia (P<0.05) and that the KLF4 CpG2 dinucleotide can predict carcinoma formation (P<0.001). The AUC value of 0.95 indicates high discrimination accuracy of the CpG nucleotides methylation status model between the controls and the two other diagnoses. The results of the present study establish the likelihood that aberrations in KLF4 and HS3ST2 gene methylation levels are important in the development of endometrial hyperplasia and carcinoma, with hyperplasia an intermediate step between healthy and tumour tissues.

Wei XQ, Ma Y, Chen Y, et al.
Laparoscopic surgery for early cervical squamous cell carcinoma and its effect on the micrometastasis of cancer cells.
Medicine (Baltimore). 2018; 97(34):e11921 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
The aim of this study was to evaluate the effect of laparoscopic radical hysterectomy on expressions of circulating tumor cells (CTCs) of cytokeratin 19 (CK19), cytokeratin 20 (CK20), and squamous cell carcinoma antigen (SCC-Ag) mRNA.We collect 78 patients with stage IA2-IIA1 cervical cancer who underwent radical hysterectomy by laparotomy or laparoscopy in our study, and 34 uterine fibroids patients and 32 healthy subjects were recruited as the positive control group and negative control group, respectively. Blood samples were taken from early-stage primary cervical squamous cell carcinoma patients. Real-time reverse transcription polymerase chain reaction (RT-PCR) was used to amplify peripheral blood CK19, CK20 and SCC-Ag from total RNA. We measured the expression of CK19, CK20, and SCC-Ag before laparoscopic radical hysterectomy, 24 hours and 30 days after surgery. Meanwhile, the expression of these markers was compared between laparoscopic and laparotomy groups.The expressions of CK19, CK20, and SCC-Ag in the experimental group before surgery were (0.0035 ± 0.0018), (1.06 ± 0.49), and (1.48 ± 0.46), respectively, and the positive rates were 32.1%, 33.3%, and 35.9%, respectively. The expression levels of CK19, CK20, and SCC-Ag in the experimental group before surgery was significantly higher than the positive and negative control groups, and there were no significant differences between the positive and negative control groups. The expressions and positive rates of CK19, CK20, and SCC-Ag before laparoscopic radical hysterectomy were significantly lower than the stage at 24 hours after surgery (P < .05), but higher than the stage at 30 days after surgery (P > .05). There were no significant differences in CK19, CK20, and SCC-Ag expressions before surgery, 24 hours and 30 days after surgery between laparoscopic group and laparotomy group (P > .05).Both laparotomy and laparoscopic radical mastectomy tend to increase the expression of CTCs in peripheral blood, and the expressions have no differences between these 2 groups. So, the use of CK19, CK20, and SCC-Ag expression levels from peripheral blood from early stage cervical cancer radical patients before hysterectomy can aid to overcome the lack of radiographic examination and tumor markers measurement, and provide clues for postoperative treatment and prognosis determination.

Lee J, Kim DM, Lee A
Prognostic Role and Clinical Association of Tumor-Infiltrating Lymphocyte, Programmed Death Ligand-1 Expression with Neutrophil-Lymphocyte Ratio in Locally Advanced Triple-Negative Breast Cancer.
Cancer Res Treat. 2019; 51(2):649-663 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
PURPOSE: Tumor-infiltrating lymphocyte (TIL), programmed death-ligand 1 (PD-L1) expression and neutrophil-to-lymphocyte ratio (NLR) is associated to immunogenicity and prognosis of breast cancer. We analyzed baseline NLR, changes of NLR, TIL, and PD-L1 during neoadjuvant chemotherapy (NAC) and their clinical implication in triple-negative breast cancer (TNBC).
Materials and Methods: Between January 2008 to December 2015, 358 TNBC patients were analyzed. Baseline NLR, 50 paired NLR (initial diagnosis, after completion of NAC) and 34 paired tissues (initial diagnosis, surgical specimen after completion of NAC) were collected. Changes of TIL, CD4, CD8, forkhead box P3 (FOXP3), and PD-L1 expression were assessed with immunohistochemical stain.
RESULTS: Low NLR (≤ 3.16) was associated to superior survival (overall survival: 41.83 months vs. 36.5 months, p=0.002; disease-free survival [DFS]: 37.85 months vs. 32.14 months, p=0.032). Modest NLR change after NAC (-30% < NLR change < 100%) showed prolonged DFS (38.37 months vs. 22.37 months, p=0.015). During NAC, negative or negative conversion of tumor PD-L1 expression was associated to poor DFS (34.77 months vs. 16.03 months, p=0.037), and same or increased TIL showed trends for superior DFS, but without statistical significance. Positive tumor PD-L1 expression (H-score ≥ 5) in baseline or post- NAC tissue was associated to superior DFS (57.6 months vs. 12.5 months, p=0.001 and 53.3 months vs. 18.9 months, p=0.040). Positive stromal PD-L1 expression in baseline was also associated to superior DFS (50.2 months vs. 20.4 months, p=0.002).
CONCLUSION: In locally advanced TNBC, baseline NLR, changes of NLR during NAC was associated to survival. Baseline PD-L1 expression and changes of PD-L1 expression in tumor tissue during NAC also showed association to prognosis.

Fawzy MS, Badran DI, Al Ageeli E, et al.
Longevity-Related Gene Transcriptomic Signature in Glioblastoma Multiforme.
Oxid Med Cell Longev. 2018; 2018:8753063 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Glioblastoma multiforme (GBM) (grade IV astrocytoma) has been assumed to be the most fatal type of glioma with low survival and high recurrence rates, even after prompt surgical removal and aggressive courses of treatment. Transcriptional reprogramming to stem cell-like state could explain some of the deregulated molecular signatures in GBM disease. The present study aimed to quantify the expression profiling of longevity-related transcriptional factors

Faias S, Duarte M, Albuquerque C, et al.
Clinical Impact of KRAS and GNAS Analysis Added to CEA and Cytology in Pancreatic Cystic Fluid Obtained by EUS-FNA.
Dig Dis Sci. 2018; 63(9):2351-2361 [PubMed] Related Publications
BACKGROUND: Pancreatic cysts are common incidental findings with malignant potential, raising diagnostic and treatment dilemmas.
AIMS: To determine the added value of KRAS and GNAS mutation analysis on cyst classification and decision making.
METHODS: We analyzed 52 frozen samples of pancreatic cystic fluid obtained by EUS-FNA between 2008 and 2014. In addition to cytology and CEA, mutations of GNAS (exons 8 and 9) and KRAS (exons 2 and 3) genes were analyzed using Sanger sequencing.
RESULTS: There were 52 patients, 67% females, with a mean age of 59 ± 15 years (29-91). Cysts were classified as mucinous in 21 patients (40%) (14 low-risk, seven malignant) and non-mucinous in 31 patients (60%). After EUS-FNA, 11 patients had surgery, six had chemotherapy or palliation, one had endoscopic drainage, and 34 are on follow-up after a mean of 57 months. KRAS mutation was detected in nine and GNAS in two samples. Patients harboring cysts with KRAS mutations were older (p = 0.01), cysts were more commonly mucinous (p = 0.001) and malignant (p = 0.01). KRAS mutations were present in both low-risk and malignant mucinous lesions. For identifying mucinous lesions, CEA > 192 ng/mL performed better (AUC ROC = 93%), whereas for malignant/high-risk mucinous lesions, EUS imaging had the best accuracy (AUC ROC = 88%). After molecular analysis, a modification in cyst classification occurred in ten patients, but was correct in only two, a pseudocyst re-classified as IPMN and a malignant cyst as a non-mucinous cyst.
CONCLUSIONS: In this cohort of patients with pancreatic cysts, KRAS and GNAS mutations had no significant diagnostic benefit in comparison with conventional testing.

Berardi R, Torniai M, Partelli S, et al.
Impact of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) single nucleotide polymorphisms on outcome in gastroenteropancreatic neuroendocrine neoplasms.
PLoS One. 2018; 13(5):e0197035 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Angiogenesis represents a key event in cancer development, leading to local invasion e metastatization, and might be considered a basic feature in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) with a high expression of angiogenic molecules. We aimed to analyze the prognostic and predictive role of angiogenic factors in GEP-NENs through the analysis of single nucleotide polymorphisms (SNPs) of VEGF-A, VEGFR2 and VEGFR3. The genomic DNA of 58 consecutive patients with GEP-NENs treated at our Institution was extracted from peripheral blood. Two SNPs were identified respectively in VEGF-A (rs2010963G>C, rs699947A>C), VEGFR-2 (rs2305948C>T, rs1870377T>A), and VEGFR-3 (rs307821T>C, rs307826C>A) gene. Gene polymorphisms were determined by Real-Time PCR using TaqMan assays. Median age was 57 years (range 24-79 years); 32 patients were male and 77.5% of NENs were localized in the pancreas. The allele frequency of VEGFR-2 rs2305948T and of VEGF-A rs2010963C showed a trend of higher frequency than in general population (12.1% vs. 8.0% and 34.5% vs. 31.2%, respectively). Three out SNPs (VEGF-A rs699947C, VEGF-A rs2010963GC and VEGFR-3 rs307821C) showed a correlation with an increased risk of disease relapse. Moreover median PFS changes according to the presence of 0-1 SNPs (20.7% of cases; 61.9 months), 2 SNPs (25.9%; 49.2 months) and 3 SNPs (53.4%; 27.8 months) (p = 0.034). Results suggest, for the first time, that specific SNPs in VEGF-A and VEGFR-3 correlate with poor prognosis in GEP-NENs. The identification of this new prognostic factor might be helpful in order to optimize the management of these heterogeneous neoplasms.

Sharma S, Mazumdar S, Italiya KS, et al.
Cholesterol and Morpholine Grafted Cationic Amphiphilic Copolymers for miRNA-34a Delivery.
Mol Pharm. 2018; 15(6):2391-2402 [PubMed] Related Publications
miR-34a is a master tumor suppressor playing a key role in the several signaling mechanisms involved in cancer. However, its delivery to the cancer cells is the bottleneck in its clinical translation. Herein we report cationic amphiphilic copolymers grafted with cholesterol (chol), N, N-dimethyldipropylenetriamine (cation chain) and 4-(2-aminoethyl)morpholine (morph) for miR-34a delivery. The copolymer interacts with miR-34a at low N/P ratios (∼2/1) to form nanoplexes of size ∼108 nm and a zeta potential ∼ +39 mV. In vitro studies in 4T1 and MCF-7 cells indicated efficient transfection efficiency. The intracellular colocalization suggested that the copolymer effectively transported the FAM labeled siRNA into the cytoplasm within 2 h and escaped from the endo-/lysosomal environment. The developed miR-34a nanoplexes inhibited the breast cancer cell growth as confirmed by MTT assay wherein 28% and 34% cancer cell viability was observed in 4T1 and MCF-7 cells, respectively. Further, miR-34a nanoplexes possess immense potential to induce apoptosis in both cell lines.

Lin Y, Seger N, Tsagkozis P, et al.
Telomerase promoter mutations and copy number alterations in solitary fibrous tumours.
J Clin Pathol. 2018; 71(9):832-839 [PubMed] Related Publications
AIMS: Solitary fibrous tumour (SFT) is an infrequently metastasising mesenchymal tumour defined by the
METHODS: We analysed the
RESULTS: Activating -124 C>T (n=12) or -148 C>T (n=2) mutations were found in 33% of the tumours and associated with older age (P=0.006), necrosis (P=0.009), higher mitotic rate (P=0.003), nuclear atypia (P=0.002), malignant histological diagnosis (P=0.04) and worse progression-free survival (P=0.023). We also observed frequent (24%)
CONCLUSIONS: Activating

Hsiao CL, Liu LC, Shih TC, et al.
The Association of
In Vivo. 2018 May-Jun; 32(3):487-491 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
BACKGROUND/AIM: The family of matrix metalloproteinases (MMPs) are responsible for the homeostasis of extracellular matrix components and their genetic polymorphisms may be associated with cancer susceptibility. The serum levels of MMP-1 have been reported to be lower in breast cancer patients than healthy subjects. In the current study, we aimed at investigating the contribution of a polymorphism in the promoter region of MMP-1 to breast cancer in Taiwan.
MATERIALS AND METHODS: The MMP-1 rs1799705 polymorphic genotypes were genotyped among 1,232 breast cancer patients and 1,232 healthy controls by the typical polymerase chain reaction-restriction fragment length polymorphism methodology.
RESULTS: The percentages of 2G/2G, 1G/2G, and 1G/1G for MMP1 -1607 genotypes were 35.4, 40.6 and 24.0% in the breast cancer group and 34.1, 43.6, and 22.3% in the healthy control group (p trend=0.3025), respectively. The odds ratios (ORs) after adjusting for age, smoking and alcohol drinking status for those carrying 1G/2G and 1G/1G genotypes at MMP1 -1607 were 0.93 (95%CI=0.76-1.11, p=0.2390) and 1.01 (95%CI=0.77-1.23, p=0.7377), respectively, compared to those carrying the wild-type 2G/2G genotype. Supporting this finding, the adjusted OR for those carrying the 1G allele at MMP-1 -1607 was 1.03 (95%CI=0.91-1.18, p=0.8860), compared to those carrying the wild-type 2G allele. Our findings suggest that the polymorphic genotypes at MMP1 promoter -1607 investigated in the current study, may not play a major role in determining cancer susceptibility to breast cancer in Taiwan. Other early diagnostic and predictive markers are urgently needed for personalized and precise breast cancer detection and therapy.

Liu X, Jin G, Qian J, et al.
Digital gene expression profiling analysis and its application in the identification of genes associated with improved response to neoadjuvant chemotherapy in breast cancer.
World J Surg Oncol. 2018; 16(1):82 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
BACKGROUND: This study aimed to screen sensitive biomarkers for the efficacy evaluation of neoadjuvant chemotherapy in breast cancer.
METHODS: In this study, Illumina digital gene expression sequencing technology was applied and differentially expressed genes (DEGs) between patients presenting pathological complete response (pCR) and non-pathological complete response (NpCR) were identified. Further, gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were then performed. The genes in significant enriched pathways were finally quantified by quantitative real-time PCR (qRT-PCR) to confirm that they were differentially expressed. Additionally, GSE23988 from Gene Expression Omnibus database was used as the validation dataset to confirm the DEGs.
RESULTS: After removing the low-quality reads, 715 DEGs were finally detected. After mapping to KEGG pathways, 10 DEGs belonging to the ubiquitin proteasome pathway (HECTD3, PSMB10, UBD, UBE2C, and UBE2S) and cytokine-cytokine receptor interactions (CCL2, CCR1, CXCL10, CXCL11, and IL2RG) were selected for further analysis. These 10 genes were finally quantified by qRT-PCR to confirm that they were differentially expressed (the log
CONCLUSION: Our results suggested that these 10 genes belonging to these two pathways might be useful as sensitive biomarkers for the efficacy evaluation of neoadjuvant chemotherapy in breast cancer.

Koenig AB, Barajas JM, Guerrero MJ, Ghoshal K
A Comprehensive Analysis of Argonaute-CLIP Data Identifies Novel, Conserved and Species-Specific Targets of miR-21 in Human Liver and Hepatocellular Carcinoma.
Int J Mol Sci. 2018; 19(3) [PubMed] Article available free on PMC after 01/04/2020 Related Publications
MicroRNAs are ~22 nucleotide RNAs that regulate gene expression at the post-transcriptional level by binding messenger RNA transcripts. miR-21 is described as an oncomiR whose steady-state levels are commonly increased in many malignancies, including hepatocellular carcinoma (HCC). Methods known as cross-linking and immunoprecipitation of RNA followed by sequencing (CLIP-seq) have enabled transcriptome-wide identification of miRNA interactomes. In our study, we use a publicly available Argonaute-CLIP dataset (GSE97061), which contains nine HCC cases with matched benign livers, to characterize the miR-21 interactome in HCC. Argonaute-CLIP identified 580 miR-21 bound target sites on coding transcripts, of which 332 were located in the coding sequences, 214 in the 3'-untranslated region, and 34 in the 5'-untranslated region, introns, or downstream sequences. We compared the expression of miR-21 targets in 377 patients with liver cancer from the data generated by The Cancer Genome Atlas (TCGA) and found that mRNA levels of 402 miR-21 targets are altered in HCC. Expression of three novel predicted miR-21 targets (CAMSAP1, DDX1 and MARCKSL1) correlated with HCC patient survival. Analysis of RNA-seq data from SK-Hep1 cells treated with a miR-21 antisense oligonucleotide (GSE65892) identified RMND5A, an E3 ubiquitin ligase, as a strong miR-21 candidate target. Collectively, our analysis identified novel miR-21 targets that are likely to play a causal role in hepatocarcinogenesis.

Xie H, Xue YQ, Liu P, et al.
Multi-parameter gene expression profiling of peripheral blood for early detection of hepatocellular carcinoma.
World J Gastroenterol. 2018; 24(3):371-378 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
AIM: In our previous study, we have built a nine-gene (
METHODS: Logistic regression analysis, discriminant analysis, classification tree analysis, and artificial neural network were used for the multi-parameter gene expression analysis method. One hundred and three patients with early HCC and 54 age-matched healthy normal controls were used to build a diagnostic model. Fifty-two patients with early HCC and 34 healthy people were used for validation. The area under the curve, sensitivity, and specificity were used as diagnostic indicators.
RESULTS: Artificial neural network of the total nine genes had the best diagnostic value, and the AUC, sensitivity, and specificity were 0.943, 98%, and 85%, respectively. At last, 52 HCC patients and 34 healthy normal controls were used for validation. The sensitivity and specificity were 96% and 86%, respectively.
CONCLUSION: Multi-parameter analysis methods may increase the diagnostic value compared to single factor analysis and they may be a trend of the clinical diagnosis in the future.

Fei HJ, Chen SC, Zhang JY, et al.
Identification of significant biomarkers and pathways associated with gastric carcinogenesis by whole genome-wide expression profiling analysis.
Int J Oncol. 2018; 52(3):955-966 [PubMed] Related Publications
The incidence of gastric cancer (GC) is extremely high in East Asia. GC is also one of the most common and lethal forms of cancer from a global perspective. However, to date, we have not been able to determine one or several genes as biomarkers in the diagnosis of GC and have also been unable to identify the genes which are important in the therapy of GC. In this study, we analyzed all genome-wide expression profiling arrays uploaded onto the Gene Expression Omnibus (GEO) database to filtrate the differentially expressed genes (DEGs) between normal stomach tissues and GC tissues. GSE13911, GSE19826 and GSE79973 were based on the GPL570 platform, and GSE29272 was based on the GPL96 platform. We screened out the DEGs from the two platforms and by selecting the intersection of these two platforms, we identified the common DEGs in the sequencing data from different laboratories. Finally, we obtained 3 upregulated and 34 downregulated DEGs in GC from 384 samples. As the number of downregulated DEGs was greater than that of the upregulated DEGs, functional analysis and pathway enrichment analysis were performed on the downregulated DEGs. Through our analysis, we identified the most significant genes associated with GC, such as secreted phosphoprotein 1 (SPP1), sulfatase 1 (SULF1), thrombospondin 2 (THBS2), ATPase H+/K+ transporting beta subunit (ATP4B), gastric intrinsic factor (GIF) and gastrokine 1 (GKN1). The prognostic power of these genes was corroborated in the Oncomine database and by Kaplan-Meier plotter (KM-plotter) analysis. Moreover, gastric acid secretion, collecting duct acid secretion, nitrogen metabolism and drug metabolism were significantly related to GC. Thus, these genes and pathways may be potential targets for improving the diagnosis and clinical effects in patients with GC.

Trabzonlu L, Muezzinoglu B, Corakci A
BCL-2 and PAX2 Expressions in EIN which Had Been Previously Diagnosed as Non-Atypical Hyperplasia.
Pathol Oncol Res. 2019; 25(2):471-476 [PubMed] Related Publications
The relationship between PAX2 and another anti-apoptotic gene, BCL-2, has been shown in a limited number of studies. The aims of this study are to investigate the value of PAX2 and BCL-2 expressions in lesions which have been defined as nonatypical hyperplasia in terms of detecting EIN and to evaluate the relations of these proteins in EIN. For this purpose, 108 cases of non-atypical endometrial hyperplasia diagnosed from 2006 to 2011 were re-evaluated. Immunohistochemical studies with PAX2 and BCL-2 were performed in 20 cases with EIN and 34 cases with benign hyperplasia. The mean BCL-2 immunohistochemistry scores of benign hyperplasia and EIN cases were 4.06 ± 1.04 and 4.63 ± 2.03, respectively. The mean BCL-2 score of EIN cases was significantly higher than benign hyperplasia (p = 0.021). The mean PAX2 scores of benign hyperplasia and EIN cases were 4.32 ± 1.07 and 2.19 ± 2.34, respectively. The mean PAX2 scores of EIN cases were significantly lower than benign hyperplasia (p = 0.001). BCL-2 expression was increased compared to normal endometrium in 66.7% of EIN cases, and PAX2 expression was decreased in 73.3%. Consistent with this, in 60% of cases, BCL-2 expression was increased compared to normal endometrium, while PAX2 expression was decreased. BCL-2 and PAX2 protein expression changes occur in early phases of endometrial tumorigenesis. These changes are often seen as a simultaneous increase in BCL-2 expression and decrease in PAX2 expression.

Nakagomi H, Mochizuki H, Inoue M, et al.
Combined annotation-dependent depletion score for BRCA1/2 variants in patients with breast and/or ovarian cancer.
Cancer Sci. 2018; 109(2):453-461 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Utility of combined annotation-dependent depletion (CADD) score was recently reported to rank pathogenicity as C-scores ranging 1-99 for both confirmed deleterious mutation. Using C-scores for BRCA1/2 variants, we tried to constitute the classification system for variant of uncertain significance (VUS), which had been a major problem of genetic testing for hereditary breast and/or ovarian cancer. We analyzed BRCA1/2 genes for 283 patients with breast and/or ovarian cancer. The deleterious mutation and missesne mutations, minor variant, and wild type of BRCA1 and -2 were 5, 27, 251 and 15, 85, 183, respectively. Meanwhile, the variants with C-score ≥10 were involved in 19/283 (6.7%) in BRCA1 and 34/283 (12%) in BRCA2. All deleterious mutations were included in this group. Frequency of personal history and family history of ovarian cancer were significantly high, and frequency of serous adenocarcinoma of ovary and triple negative breast cancer was relatively high in the group with deleterious mutations. Similar findings were seen in patients with variants of C-score ≥10. According to the C-score and population frequency, we could define VUS for 11 patients out of 283 patients (3.9 CADD is useful to classify the variant of BRCA1/2 and selecting the patient who needs further segregation studies.

Wang CC, Huang CY, Jhuang YL, et al.
Biological significance of TERT promoter mutation in papillary urothelial neoplasm of low malignant potential.
Histopathology. 2018; 72(5):795-803 [PubMed] Related Publications
AIMS: Mutations in FGFR3 and the promoter region of the telomerase reverse transcriptase (TERT) gene have been found frequently in urothelial carcinoma of the urinary bladder. However, related data for papillary urothelial neoplasm of low malignant potential (PUNLMP) are limited. In this study, we investigated the mutation status of the TERT promoter, FGFR3 and HRAS in low-grade papillary urothelial neoplasms and evaluated their prognostic significance.
METHODS AND RESULTS: The cases included in this study comprised 21 inverted papillomas, 30 PUNLMPs and 34 low-grade non-invasive papillary urothelial carcinomas (NIPUCs). TERT promoter mutations were observed in 10 (33%) PUNLMPs and 17 (50%) low-grade NIPUCs, but not in any inverted papilloma. FGFR3 mutations were observed more frequently in PUNLMP and low-grade NIPUC than in inverted papillomas (P = 0.009), whereas the opposite trend was noted for HRAS mutations (P < 0.001). Regarding the clinical outcome, TERT promoter mutation was associated with a higher recurrence rate in PUNLMP (P = 0.024) but not in low-grade NIPUC (P = 0.530). Notably, PUNLMP cases with TERT promoter mutations had a similar recurrence rate to that in low-grade NIPUC cases (P = 0.487).
CONCLUSIONS: Our results suggest that the status of the TERT promoter mutation may serve as a biomarker of prognostic stratification in patients with PUNLMP.

Li D, You Y, Bi FF, et al.
Autophagy is activated in the ovarian tissue of polycystic ovary syndrome.
Reproduction. 2018; 155(1):85-92 [PubMed] Related Publications
The importance of autophagy in polycystic ovary syndrome (PCOS)-related metabolic disorders is increasingly being recognized, but few studies have investigated the role of autophagy in PCOS. Here, transmission electron microscopy demonstrated that autophagy was enhanced in the ovarian tissue from both humans and rats with PCOS. Consistent with this, ovarian granulosa cells from PCOS rats showed increases in the autophagy marker protein light chain 3B (LC3B), whereas levels of the autophagy substrate SQSTM1/p62 were decreased. In addition, the ratio of LC3-II/LC3-I was markedly elevated in human PCOS ovarian tissue compared with normal ovarian tissue. Real-time PCR arrays indicated that 7 and 34 autophagy-related genes were down- and up-regulated in human PCOS , Signal-Net, and regression analysis suggested that there are a wide range of interactions among these 41 genes, and a potential network based on

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