Gene Summary

Gene:PITX2; paired like homeodomain 2
Aliases: RS, RGS, ARP1, Brx1, IDG2, IGDS, IHG2, PTX2, RIEG, ASGD4, IGDS2, IRID2, Otlx2, RIEG1
Summary:This gene encodes a member of the RIEG/PITX homeobox family, which is in the bicoid class of homeodomain proteins. The encoded protein acts as a transcription factor and regulates procollagen lysyl hydroxylase gene expression. This protein plays a role in the terminal differentiation of somatotroph and lactotroph cell phenotypes, is involved in the development of the eye, tooth and abdominal organs, and acts as a transcriptional regulator involved in basal and hormone-regulated activity of prolactin. Mutations in this gene are associated with Axenfeld-Rieger syndrome, iridogoniodysgenesis syndrome, and sporadic cases of Peters anomaly. A similar protein in other vertebrates is involved in the determination of left-right asymmetry during development. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:pituitary homeobox 2
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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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.

  • Polymerase Chain Reaction
  • Gene Expression Profiling
  • Cyclin D2
  • Transcription Factors
  • Homeodomain Proteins
  • Breast Cancer
  • Neoplasm Proteins
  • Cell Differentiation
  • DNA Methylation
  • Disease Progression
  • Risk Factors
  • Prostate Cancer
  • Cancer DNA
  • Oligonucleotide Array Sequence Analysis
  • Wnt Proteins
  • Thyroid Cancer
  • Neoplasm Recurrence, Local
  • Tamoxifen
  • Reproducibility of Results
  • Ovarian Cancer
  • MicroRNAs
  • Cell Proliferation
  • Genetic Markers
  • Cancer Gene Expression Regulation
  • Randomized Controlled Trials
  • Messenger RNA
  • Signal Transduction
  • Gene Expression
  • Neoplasm Invasiveness
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Whole Exome Sequencing
  • CpG Islands
  • Adenocarcinoma
  • Proportional Hazards Models
  • Cancer Screening
  • Biomarkers, Tumor
  • Promoter Regions
  • Chromosome 4
  • Staging
  • Epigenetics
  • Prostatectomy
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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: PITX2 (cancer-related)

Böhm J, Muenzner JK, Caliskan A, et al.
Loss of enhancer of zeste homologue 2 (EZH2) at tumor invasion front is correlated with higher aggressiveness in colorectal cancer cells.
J Cancer Res Clin Oncol. 2019; 145(9):2227-2240 [PubMed] Related Publications
PURPOSE: Enhancer of zeste homolog 2 (EZH2) is associated with epigenetic gene silencing and aggressiveness in many tumor types. However, the prognostic impact of high EZH2 expression is controversially discussed for colorectal cancer. For this reason, we immunohistochemically analyzed EZH2 expression in 105 specimens from colon cancer patients separately for tumor center and invasion front.
METHODS: All sections from tissue microarrays were evaluated manually and digitally using Definiens Tissue Studio software (TSS). To mirror-image the EZH2 status at the tumor invasion front, we treated HCT116 colon cancer cells with the EZH2 inhibitor 3-Deazaneplanocin A (DZNep) and studied the growth of in ovo xenografts in the chorioallantoic membrane (CAM) assay.
RESULTS: We showed a significant decrease in EZH2 expression and the repressive H3K27me3 code at the tumor invasion front as supported by the TSS-constructed heatmaps. Loss of EZH2 at tumor invasion front, but not in tumor center was correlated with unfavorable prognosis and more advanced tumor stages. The observed cell cycle arrest in vitro and in vivo was associated with higher tumor aggressiveness. Xenografts formed by DZNep-treated HCT116 cells showed loosely packed tumor masses, infiltrative growth into the CAM, and high vessel density.
CONCLUSION: The differences in EZH2 expression between tumor center and invasion front as well as different scoring and cutoff values can most likely explain controversial literature data concerning the prognostic value of EZH2. Epigenetic therapies using EZH2 inhibitors have to be carefully evaluated for each specific tumor type, since alterations in cell differentiation might lead to unfavorable results.

Yari K, Jalilvand A
Comment on: 'A 40-bp insertion/deletion polymorphism in the constitutive promoter of MDM2 confers risk for hepatocellular carcinoma in a Chinese population'.
Gene. 2019; 712:143965 [PubMed] Related Publications
Recently, we read the published article in GENE. Dong et al. presented the evaluation of the MDM2 40-bp insertion/deletion status in Hepatocellular carcinoma patients (Dong et al., 2012). The authors stated that the insertion allele showed a 521-bp band and the deletion allele showed a 481-bp band on agarose gel electrophoresis. While it seems that these reported sizes for insertion and deletion alleles of MDM2 are incorrect. Our analysis using the primers indicated that the length of insertion and deletion fragments will be 481 and 441 bps, respectively. Actually, 40-bp is added to the fragment length instead of reducing the 40-bp. In the 'UCSC In-Silico PCR' tool, the length of the amplified fragment using mentioned primers is 481-bp including the sequence of 40-bp insertion allele (5'-(A)

Nam KJ, Park H, Ko ES, et al.
Radiomics signature on 3T dynamic contrast-enhanced magnetic resonance imaging for estrogen receptor-positive invasive breast cancers: Preliminary results for correlation with Oncotype DX recurrence scores.
Medicine (Baltimore). 2019; 98(23):e15871 [PubMed] Free Access to Full Article Related Publications
To evaluate the ability of a radiomics signature based on 3T dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) to distinguish between low and non-low Oncotype DX (OD) risk groups in estrogen receptor (ER)-positive invasive breast cancers.Between May 2011 and March 2016, 67 women with ER-positive invasive breast cancer who performed preoperative 3T MRI and OD assay were included. We divided the patients into low (OD recurrence score [RS] <18) and non-low risk (RS ≥18) groups. Extracted radiomics features included 8 morphological, 76 histogram-based, and 72 higher-order texture features. A radiomics signature (Rad-score) was generated using the least absolute shrinkage and selection operator (LASSO). Univariate and multivariate logistic regression analyses were performed to investigate the association between clinicopathologic factors, MRI findings, and the Rad-score with OD risk groups, and the areas under the receiver operating characteristic curves (AUC) were used to assess classification performance of the Rad-score.The Rad-score was constructed for each tumor by extracting 10 (6.3%) from 158 radiomics features. A higher Rad-score (odds ratio [OR], 65.209; P <.001), Ki-67 expression (OR, 17.462; P = .007), and high p53 (OR = 8.449; P = .077) were associated with non-low OD risk. The Rad-score classified low and non-low OD risk with an AUC of 0.759.The Rad-score showed the potential for discrimination between low and non-low OD risk groups in patients with ER-positive invasive breast cancers.

Zhao J, Lee EE, Kim J, et al.
Transforming activity of an oncoprotein-encoding circular RNA from human papillomavirus.
Nat Commun. 2019; 10(1):2300 [PubMed] Free Access to Full Article Related Publications
Single-stranded circular RNAs (circRNAs), generated through 'backsplicing', occur more extensively than initially anticipated. The possible functions of the vast majority of circRNAs remain unknown. Virus-derived circRNAs have recently been described in gamma-herpesviruses. We report that oncogenic human papillomaviruses (HPVs) generate circRNAs, some of which encompass the E7 oncogene (circE7). HPV16 circE7 is detectable by both inverse RT-PCR and northern blotting of HPV16-transformed cells. CircE7 is N

Kesarwani P, Prabhu A, Kant S, Chinnaiyan P
Metabolic remodeling contributes towards an immune-suppressive phenotype in glioblastoma.
Cancer Immunol Immunother. 2019; 68(7):1107-1120 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
Glioblastoma (GBM) is one of the most aggressive tumors. Numerous studies in the field of immunotherapy have focused their efforts on identifying various pathways linked with tumor-induced immunosuppression. Recent research has demonstrated that metabolic reprogramming in a tumor can contribute towards immune tolerance. To begin to understand the interface between metabolic remodeling and the immune-suppressive state in GBM, we performed a focused, integrative analysis coupling metabolomics with gene-expression profiling in patient-derived GBM (n = 80) and compared them to low-grade astrocytoma (LGA; n = 28). Metabolic intermediates of tryptophan, arginine, prostaglandin, and adenosine emerged as immuno-metabolic nodes in GBM specific to the mesenchymal and classical molecular subtypes of GBM. Integrative analyses emphasized the importance of downstream metabolism of several of these metabolic pathways in GBM. Using CIBERSORT to analyze immune components from the transcriptional profiles of individual tumors, we demonstrated that tryptophan and adenosine metabolism resulted in an accumulation of Tregs and M2 macrophages, respectively, and was recapitulated in mouse models. Furthermore, we extended these findings to preclinical models to determine their potential utility in defining the biologic and/or immunologic consequences of the identified metabolic programs. Collectively, through integrative analysis, we uncovered multifaceted ways by which metabolic reprogramming may contribute towards immune tolerance in GBM, providing the framework for further investigations designed to determine the specific immunologic consequence of these metabolic programs and their therapeutic potential.

Pires LV, Yi Y, Cheng JC, et al.
Lapatinib Inhibits Amphiregulin-induced BeWo Choriocarcinoma Cell Proliferation by Reducing ERK1/2 and AKT Signaling Pathways.
Anticancer Res. 2019; 39(5):2377-2383 [PubMed] Related Publications
BACKGROUND: Human choriocarcinoma is the most aggressive type of gestational trophoblastic neoplasia. The expression of epidermal growth factor receptor (EGFR) in choriocarcinomas is significantly higher than those of trophoblastic cells in healthy placentas. Lapatinib is a potent EGFR and human epidermal growth factor receptor 2 (HER2) inhibitor that inhibits cell proliferation and induces apoptosis in various human cancer cells. Amphiregulin (AREG) is the most abundant EGFR ligand in amniotic fluid during human pregnancy.
AIM: To explore the role of AREG in human choriocarcinoma cell proliferation.
MATERIALS AND METHODS: The effect of lapatinib and AREG on cell proliferation was examined by the MTT assay. Western blots were used to investigate EGFR and HER2 expression, and the activation of caspase-3, extracellular signal-regulated kinases 1/2 (ERK1/2) and phosphatidylinositol 3-kinase /protein kinase B (PI3K/AKT) signaling pathways.
RESULTS: Treatment with lapatinib reduced BeWo cell proliferation by inducing apoptosis. Moreover, AREG treatment stimulated BeWo cell proliferation by activating ERK1/2 and PI3K/AKT signaling pathways, which was blocked by lapatinib.
CONCLUSION: Targeting EGFR/HER2 might be a useful therapeutic strategy for human choriocarcinoma.

García-Sancha N, Corchado-Cobos R, Pérez-Losada J, Cañueto J
MicroRNA Dysregulation in Cutaneous Squamous Cell Carcinoma.
Int J Mol Sci. 2019; 20(9) [PubMed] Article available free on PMC after 01/07/2020 Related Publications
Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans and it can be locally invasive and metastatic to distant sites. MicroRNAs (miRNAs or miRs) are endogenous, small, non-coding RNAs of 19-25 nucleotides in length, that are involved in regulating gene expression at a post-transcriptional level. MicroRNAs have been implicated in diverse biological functions and diseases. In cancer, miRNAs can proceed either as oncogenic miRNAs (onco-miRs) or as tumor suppressor miRNAs (oncosuppressor-miRs), depending on the pathway in which they are involved. Dysregulation of miRNA expression has been shown in most of the tumors evaluated. MiRNA dysregulation is known to be involved in the development of cutaneous squamous cell carcinoma (CSCC). In this review, we focus on the recent evidence about the role of miRNAs in the development of CSCC and in the prognosis of this form of skin cancer.

Stojanović S, Najman S
The Effect of Conditioned Media of Stem Cells Derived from Lipoma and Adipose Tissue on Macrophages' Response and Wound Healing in Indirect Co-culture System In Vitro.
Int J Mol Sci. 2019; 20(7) [PubMed] Article available free on PMC after 01/07/2020 Related Publications
Immunomodulatory and wound healing activities of adipose-derived stem cells (ADSCs) have been reported in various in vitro and in vivo experimental models suggesting their beneficial role in regenerative medicine and treatments of inflammatory-related disorders. Lipoma-derived stem cells (LDSCs) were reported as a potential tool in regenerative medicine due to the similarity with ADSCs but we have previously shown that LDSCs have different differentiation capacity than ADSCs despite a similar mesenchymal phenotype. To further analyze the potential differences and/or similarities between those two stem cell types, in the present study we examined the macrophages (MΦs)' response, immunomodulatory and wound healing effect of conditioned media (CM) of LDSCs and ADSCs in indirect co-culture system in vitro. We confirmed similar mesenchymal phenotype and stemness state of LDSCs and ADSCs but indicated differences in expression of some inflammatory-related genes. Anti-inflammatory potential of CM of LDSCs and ADSCs, with pronounced effect of LDSCs, in unstimulated RAW 264.7 MΦs was evaluated by decrease in

Jiang R, Hu C, Li Q, et al.
Sodium new houttuyfonate suppresses metastasis in NSCLC cells through the Linc00668/miR-147a/slug axis.
J Exp Clin Cancer Res. 2019; 38(1):155 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
BACKGROUND: As most lung cancer patients present with invasive, metastatic disease, it is vital to investigate anti-metastatic treatments for non-small cell lung cancer (NSCLC). Houttuynia cordata is commonly used as a Chinese anticancer medicine in the clinic, and sodium new houttuyfonate (SNH), a main compound of this herb, has long been found to have antibiotic effects, although its anticancer effects have not been investigated. Here, we tried to address this lack of research from the perspective of the competing endogenous RNA (ceRNA) theory.
METHODS: The effects of SNH on NSCLC cells were analysed with Cell Counting Kit-8 assays and colony formation assays. In addition, transwell assays and wound healing assays were used to determine the effects of SNH on migration and invasion in NSCLC cells. The levels of key genes and proteins were examined by quantitative real-time PCR, western blotting, immunofluorescence staining and IHC staining. Through transcriptome screening and digital gene expression profiling, Linc00668 was identified to be regulated by SNH. Dual-luciferase reporter assays and RNA immunoprecipitation assays verified the binding efficiency between miR-147a and Linc00668 or Slug.
RESULTS: In the present study, SNH regulated NSCLC cells in multiple ways, the most prominent of which was suppressing the expression of Linc00668, which was indicated to promote migration and invasion in NSCLC cells. Functional studies demonstrated that Linc00668 acted as a ceRNA by sponging miR-147a to further regulate Slug mRNA levels, thereby influencing the progression of the epithelial-mesenchymal transition. Consistently, the results of in vivo animal models showed that SNH depressed Linc00668 and suppressed the metastasis of NSCLC.
CONCLUSIONS: SNH suppressed metastasis of NSCLC cells and the mechanism may involve with the Linc00668/miR-147a/Slug axis.

Kubatka P, Uramova S, Kello M, et al.
Anticancer Activities of
Int J Mol Sci. 2019; 20(7) [PubMed] Article available free on PMC after 01/07/2020 Related Publications
Naturally-occurring mixtures of phytochemicals present in plant foods are proposed to possess tumor-suppressive activities. In this work, we aimed to evaluate the antitumor effects of

Gharbaran R, Zhang B, Valerio L, et al.
Effects of vitamin D3 and its chemical analogs on the growth of Hodgkin's lymphoma, in vitro.
BMC Res Notes. 2019; 12(1):216 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
OBJECTIVE: Vitamin D receptor (VDR) activities have been noted for a number of B cell malignancies which showed varying sensitivities to vitamin D3 (1,25-dihydroxyvitamin D3, VD3, calcitriol) and its synthetic analogs. The objective of this study was to address the potential effects of VD3 and vitamin D3 analogs (VDAs) on the growth of Hodgkin's lymphoma (HL), a malignant pathology of B cell origin, in vitro.
RESULTS: Immunofluorescence staining showed the expression of VDR by primary Hodgkin's (H) and Reed-Sternberg (RS)-HRS-tumor cells in HL histological sections. Western blot analyses revealed expression of VDR in the HL cell lines Hs445, HDLM2, KMH2, and L428. One-way analysis of variance (ANOVA) on data obtained from water-soluble tetrazolium 1 (WST-1) cell proliferation assay showed decreased cell growth in HDLM2 and L428, 72 h after treatment with 10 µM of either VD3 of VDAs. Western blot analyses showed that treatment of L428 cells with the VDAs (calcipotriol and EB1089) resulted in modest increases in nuclear accumulation of VDR (nuVDR) compared to either dimethyl sulfoxide (DMSO) or VD3 treatments. nuVDR for DMSO control and VD3 was comparable. These results suggest that VD3 or VDAs may affect growth of HL.

Márton É, Lukács J, Penyige A, et al.
Circulating epithelial-mesenchymal transition-associated miRNAs are promising biomarkers in ovarian cancer.
J Biotechnol. 2019; 297:58-65 [PubMed] Related Publications
Ovarian cancer is the fifth most common cause of cancer death among women that is mostly due to the difficulty of early diagnosis. Circulating miRNAs proved to be reliable biomarkers in various cancers. We screened 9 miRNAs, which are involved in epithelial-mesenchymal transition, in the plasma samples of patients with malignant (n = 28) or non-malignant (n = 12) ovarian tumors and disease-free healthy volunteers (n = 60) by qRT-PCR. The expression levels of miR200a, miR200b, miR200c, miR141, miR429, miR203a, miR34b (p < 0.001) and miR34a (p < 0.01) were significantly higher in the malignant samples than in healthy controls. MiR203a, miR141 (p < 0.01), miR200a and miR429 (p < 0.05) levels were also higher in malignant compared to non-malignant samples. ROC-AUC was the highest in the case of miR200c: 0.861 (95%CI = 0.776-0.947). Spearman's rank correlation analysis revealed positive correlation between the plasma levels of the studied miRNAs that was the highest between miR200b and miR200c (r

Asiaf A, Ahmad ST, Malik AA, et al.
Association of Protein Expression and Methylation of DAPK1 with Clinicopathological Features in Invasive Ductal Carcinoma Patients from Kashmir
Asian Pac J Cancer Prev. 2019; 20(3):839-848 [PubMed] Related Publications
Aims: Death-associated protein kinase-1 (DAPK1) is a pro-apoptotic Ser/Thr kinase that participates in cell apoptosis and tumor suppression. DAPK1 is frequently lost in many different tumor types including breast cancer. The aim of this study was to evaluate the promoter methylation status of DAPK1 and a possible correlation with the expression of DAPK1 and standard clinicopathological features in invasive ductal breast carcinoma patients (IDC). Methods: Methylation Specific PCR (MSP) was carried out to investigate the promoter methylation status of DAPK1 from 128 breast cancer patients. The effect of promoter methylation on protein expression was evaluated by immunohistochemistry (n=128) and western blotting (n=56). Results: We found significant difference in DAPK1 promoter methylation frequency among breast tumors when compared with the corresponding normal tissues. Hypermethylation of DAPK1 is significantly correlated with the loss of DAPK1 protein expression (P < .001, rs= -0.361). The loss of DAPK1 protein was significantly associated with estrogen receptor (ER) negativity (p= 0.003), triple negative breast cancer (TNB) (p= 0.024) and advanced tumor stages (P = 0.001). Moreover, age at diagnosis (p= 0.041), tumor stage (p= 0.034), ER negativity (p= 0.004) and TNB cancers (p=0.003) correlated significantly with the hypermethylation of the DAPK1 promoter. Coclusion: This study indicates that DAPK1 is methylated in IDC and promoter hypermethylation could be attributed to silencing of DAPK1 gene expression in breast cancer. Thus, we consider DAPK1 inactivation by promoter hypermethylation likely plays a role in the development and progression of breast cancer.

Buendia Duque M, Pinheiro KV, Thomaz A, et al.
Combined Inhibition of HDAC and EGFR Reduces Viability and Proliferation and Enhances STAT3 mRNA Expression in Glioblastoma Cells.
J Mol Neurosci. 2019; 68(1):49-57 [PubMed] Related Publications
Changes in expression of histone deacetylases (HDACs), which epigenetically regulate chromatin structure, and mutations and amplifications of the EGFR gene, which codes for the epidermal growth factor receptor (EGFR), have been reported in glioblastoma (GBM), the most common and malignant type of brain tumor. There are likely interplays between HDACs and EGFR in promoting GBM progression, and HDAC inhibition can cooperate with EGFR blockade in reducing the growth of lung cancer cells. Here, we found that either HDAC or EGFR inhibitors dose-dependently reduced the viability of U87 and A-172 human GBM cells. In U87 cells, the combined inhibition of HDACs and EGFR was more effective than inhibiting either target alone in reducing viability and long-term proliferation. In addition, HDAC or EGFR inhibition, alone or combined, led to G0/G1 cell cycle arrest. The EGFR inhibitor alone or combined with HDAC inhibition increased mRNA expression of the signal transducer and activator of transcription 3 (STAT3), which can act either as an oncogene or a tumor suppressor in GBM. These data provide early evidence that combining HDAC and EGFR inhibition may be an effective strategy to reduce GBM growth, through a mechanism possibly involving STAT3.

Martinelli AHS, Lopes FC, John EBO, et al.
Modulation of Disordered Proteins with a Focus on Neurodegenerative Diseases and Other Pathologies.
Int J Mol Sci. 2019; 20(6) [PubMed] Article available free on PMC after 01/07/2020 Related Publications
Intrinsically disordered proteins (IDPs) do not have rigid 3D structures, showing changes in their folding depending on the environment or ligands. Intrinsically disordered proteins are widely spread in eukaryotic genomes, and these proteins participate in many cell regulatory metabolism processes. Some IDPs, when aberrantly folded, can be the cause of some diseases such as Alzheimer's, Parkinson's, and prionic, among others. In these diseases, there are modifications in parts of the protein or in its entirety. A common conformational variation of these IDPs is misfolding and aggregation, forming, for instance, neurotoxic amyloid plaques. In this review, we discuss some IDPs that are involved in neurodegenerative diseases (such as beta amyloid, alpha synuclein, tau, and the "IDP-like" PrP), cancer (p53, c-Myc), and diabetes (amylin), focusing on the structural changes of these IDPs that are linked to such pathologies. We also present the IDP modulation mechanisms that can be explored in new strategies for drug design. Lastly, we show some candidate drugs that can be used in the future for the treatment of diseases caused by misfolded IDPs, considering that cancer therapy has more advanced research in comparison to other diseases, while also discussing recent and future developments in this area of research. Therefore, we aim to provide support to the study of IDPs and their modulation mechanisms as promising approaches to combat such severe diseases.

Ohe R, Meng HX, Ye Aung N, et al.
Differential expression of estrogen receptor-α on follicular dendritic cells from patients with grade 1-2 and grade 3 follicular lymphoma.
Hematol Oncol. 2019; 37(2):151-159 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
Hormone therapy has been used for patients with estrogen receptor alpha (ERα)-positive breast cancers. Recently, some studies reported the expression of ERα on neoplastic cells from B-cell lymphomas. However, there has been only one report of ERα expression on the follicular dendritic cells (FDCs) that structurally and functionally support the microenvironment of follicular lymphomas (FLs). The objective of this study was to investigate the frequency of ERα expression on FDCs in nonneoplastic reactive lymphoid tissues and to compare the frequency of ERα expression on FDCs in the axillary lymph nodes between patients with and without antiestrogen therapy and among patients with grades 1-3 of FL. Reverse transcription-polymerase chain reaction was performed to detect ERα mRNA in FL. In nonneoplastic germinal centers (GCs) from patients with tonsillitis or reactive lymphadenitis, ERα was expressed in the light zone. ERα-positive cells strongly correlated with the width of GCs (r

Wang Y, Liu G, Ren L, et al.
Long non-coding RNA TUG1 recruits miR‑29c‑3p from its target gene RGS1 to promote proliferation and metastasis of melanoma cells.
Int J Oncol. 2019; 54(4):1317-1326 [PubMed] Related Publications
Melanoma is an aggressive type of skin cancer, characterized by high mortality rates worldwide. Therefore, the identification of new diagnostic markers and therapeutic targets for melanoma is imperative. Accumulating evidence has demonstrated that long non-coding RNAs (lncRNAs) play important roles in tumor initiation and progression. It was recently reported that the expression of lncRNA taurine upregulated 1 (TUG1) was relatively higher in cancer compared with that in normal cells, and that TUG1 promoted the progression of various cancers. However, the pattern of expression and mechanism of action of TUG1 in melanoma remain unclear. The aim of the present study was to investigate whether TUG1 expression is relatively higher in melanoma tissues and whether this expression is correlated with poor overall survival. Knockdown of TUG1 was found to suppress melanoma cell growth and metastasis and induce cell apoptosis. By contrast, the overexpression of TUG1 promoted the growth and metastasis of melanoma cells, and inhibited their apoptosis. In addition, the results of the present study indicated that TUG1 sequestered endogenous miR‑29c‑3p and that it was able to suppress its expression. Furthermore, it was observed that miR‑29c‑3p could reverse the promoting effect of TUG1 on melanoma progression, which may be associated with the positive regulation of regulator of G-protein signaling 1 (RGS1), a target gene of miR‑29c‑3p. Taken together, the data of the present study demonstrated that TUG1 promoted proliferation and invasion and suppressed apoptosis in melanoma cells by regulating miR‑29c‑3p and its target gene, RGS1. Therefore, lncRNA TUG1 appears to be a promising diagnostic marker for melanoma patients.

Jovanović N, Mitrović T, Cvetković VJ, et al.
The Impact of
Medicina (Kaunas). 2019; 55(2) [PubMed] Article available free on PMC after 01/07/2020 Related Publications

Olsson-Brown A, Piskilidis P, O'Hagan J, et al.
The impact of the 21-gene recurrence score (Oncotype DX) on concordance of adjuvant therapy decision making as measured by the Liverpool Systemic Therapy Adjuvant Decision Tool.
Breast. 2019; 44:94-100 [PubMed] Related Publications
PURPOSE: The 21-gene recurrence score (Oncotype DX) (RS) informs systemic therapy decision making in ER-positive HER2-negative early breast cancer (BC). To date no study has described the more nuanced discussions that take place regarding systemic therapy or the impact of the RS on concordance in such decision making. Here we utilized a novel decision making tool to assess the impact of the RS on decision making as well as concordance of treatment recommendations.
PATIENTS AND METHODS: The clinicopathological information (CPI) of 50 BCs without and with the RS were presented to a panel of breast oncologists in a simulated MDT. The Liverpool Adjuvant Systemic Therapy Decision Tool (LASTDT) was developed and used to categorize treatment recommendations. Outcome measures included the impact of the RS on decisiveness and concordance in decision making and its impact on treatment recommendations.
RESULTS: Availability of the RS increased definitive decision making from 8% (4/50) to 56% (28/50) [χ
CONCLUSIONS: The RS improves certainty of decision making as well as concordance amongst oncologists. This provides evidence that the availability of the RS can improve consistency of decision making amongst oncologists and thus helps to ensure patients are managed consistently. This is particularly important when patients are managed in a loco-regional, multidisciplinary team manner where heterogeneous decisions can lead to disparity in care.

Schreuder K, Kuijer A, Bentum S, et al.
Use and Impact of the 21-Gene Recurrence Score in Relation to the Clinical Risk of Developing Metastases in Early Breast Cancer Patients in the Netherlands.
Public Health Genomics. 2018; 21(1-2):85-92 [PubMed] Related Publications
BACKGROUND: The nationwide use of the 21-gene recurrence score (21-RS) and implications regarding chemotherapy administration in relation to clinical risk in early breast cancer patients are investigated.
METHODS: Breast cancer patients surgically treated between 2014 and 2016 were selected from the Netherlands Cancer Registry and categorized as having a clinical low, intermediate, or high risk of developing metastases. Deployment of the 21-RS is advocated in patients with an intermediate risk of developing metastases. The use and impact of the 21-RS test result on chemotherapy administration were assessed in relation to the clinical risk as well as patient and tumor characteristics; χ2 tests were used for analysis.
RESULTS: Of all patients, 20,488 were considered as clinical low-, 4,309 as intermediate-, and 15,266 as high-risk patients. The 21-RS was deployed in 0.1% (n = 23), 3.2% (n = 137), and 0.6% (n = 90) of these categories, respectively. In the clinical intermediate-risk group, the 21-RS assigned 73.7, 13.1, and 13.1% of patients to the genomic low-, intermediate-, and high-risk category, respectively. Adherence to the 21-RS was 95.6% in these patients.
CONCLUSION: In the Netherlands, the 21-RS test is applied both inside and outside the guideline-directed area. In case of discordance between the genomic and clinical risk, patients were treated in line with the result of the 21-RS.

Jevrić M, Matić IZ, Krivokuća A, et al.
Association of uPA and PAI-1 tumor levels and 4G/5G variants of PAI-1 gene with disease outcome in luminal HER2-negative node-negative breast cancer patients treated with adjuvant endocrine therapy.
BMC Cancer. 2019; 19(1):71 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
BACKGROUND: The aim of this study was to evaluate the prognostic potential of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) tumor tissue levels and examine the association between these biomarkers and classical prognostic factors in early node-negative luminal breast cancer patients. The clinical value of 4G/5G variants of PAI-1 gene was evaluated.
PATIENTS AND METHODS: This study involved 81 node-negative, estrogen receptor-positive and/or progesterone receptor-positive and human epidermal growth factor receptor 2-negative operable breast cancer patients who underwent radical surgical resection and received adjuvant endocrine therapy. Determination of uPA and PAI-1 concentrations in the breast cancer tissue extracts was performed using FEMTELLE® uPA/PAI-1 ELISA. An insertion (5G)/deletion (4G) polymorphism at position - 675 of the PAI-1 gene was detected by PCR-RFLP analysis.
RESULTS: Our research showed that patients with uPA tumor tissue levels higher than 3 ng/mg of protein had significantly reduced disease-free survival (DFS) and overall survival (OS) when compared to patients with uPA tumor tissue levels lower or equal to 3 ng/mg of protein. Patients with PAI-1 tumor tissue levels higher than 14 ng/mg of protein had significantly decreased OS in comparison with patients with PAI-1 tumor tissue levels lower or equal to 14 ng/mg of protein. ROC analysis confirmed the uPA and PAI-1 discriminative potential for the presence/absence of relevant events in these patients and resulted in higher cut-off values (5.65 ng/mg of protein for uPA and 27.10 ng/mg of protein for PAI-1) than standard reference cut-off values for both biomarkers. The prognostic importance of uPA and PAI-1 ROC cut-off values was confirmed by the impact of uPA higher than 5.65 ng/mg of protein and PAI-1 higher than 27.10 ng/mg of protein on poorer DFS, OS and event-free survival (EFS). We observed that patients with dominant allele in PAI-1 genotype (heterozygote and dominant homozygote, - 675 4G/5G and - 675 5G/5G) had significantly increased DFS, OS and EFS when compared with patients with recessive homozygote genotype (- 675 4G/4G).
CONCLUSION: Our study indicates that uPA and PAI-1 tumor tissue levels and 4G/5G variants of PAI-1 gene might be of prognostic significance in early node-negative luminal HER2-negative breast cancer patients treated with adjuvant endocrine therapy.

Jiang Q, Xie M, He M, et al.
PITX2 methylation: a novel and effective biomarker for monitoring biochemical recurrence risk of prostate cancer.
Medicine (Baltimore). 2019; 98(1):e13820 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
AIMS: Prostate cancer is one of the most common malignancies in men. Biochemical recurrence (BCR) and progression following curative treatment pose a significant public health challenge. Thus, it is essential to explore effective biomarkers for disease progression monitoring and risk stratification. The promoter region of the paired-like homeodomain transcription factor 2 (PITX2) gene has been found to be frequently methylated in prostate cancer. However, the prognostic role of PITX2 methylation in prostate cancer and which patients most likely to be recommended for PITX2 methylation tests to assess BCR risk remain controversial. Therefore, a systematic review was performed to explore the relationship of PITX2 methylation with the BCR risk of prostate cancer.
METHODS: The PubMed, EMBASE, and Cochrane Library databases were systematically searched for eligible studies. Seven studies with a total of 2185 patients were included. Pooled hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were calculated.
RESULTS: The overall HR was 2.71 (95% CI, 2.21-3.31), suggesting that PITX2 methylation has an adverse impact on BCR of prostate cancer. The pooled estimate of 5-year BCR-free survival for patients with a high methylation status was significantly lower than that for patients with a low methylation status (71% vs 90%; odds ratio [OR] = 3.50; 95% CI, 2.67-4.60, P = .000). A subgroup analysis was conducted according to detection method; the combined HRs were 2.68 (95% CI, 2.02-3.55) for quantitative methylation-specific PCR (qMSP) and 3.29 (95% CI, 2.31-4.68) for microarray EpiChip. In subgroups defined by region, Gleason score, pathological stage, surgical margin status and ethnicity, high methylation status was also associated with BCR of prostate cancer.
CONCLUSIONS: As an effective biomarker, PITX2 methylation is feasible for individualized BCR risk assessment of prostate cancer following radical prostatectomy.

Dinkelborg PH, Wang M, Gheorghiu L, et al.
A common Chk1-dependent phenotype of DNA double-strand break suppression in two distinct radioresistant cancer types.
Breast Cancer Res Treat. 2019; 174(3):605-613 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
PURPOSE: Triple-negative breast cancers (TNBC) are often resistant to treatment with ionizing radiation (IR). We sought to investigate whether pharmacologic inhibition of Chk1 kinase, which is commonly overexpressed in TNBC, preferentially sensitizes TNBC cells to IR.
METHODS: Ten breast cancer cell lines were screened with small molecule inhibitors against Chk1 and other kinases. Chk1 inhibition was also tested in isogenic KRAS mutant or wild-type cancer cells. Cellular radiosensitization was measured by short-term and clonogenic survival assays and by staining for the DNA double-strand break (DSB) marker γ-H2AX. Radiosensitization was also assessed in breast cancer biopsies using an ex vivo assay. Aurora B kinase-dependent mitosis-like chromatin condensation, a marker of radioresistance, was detected using a specific antibody against co-localized phosphorylation of serine 10 and trimethylation of lysine 9 on histone 3 (H3K9me3/S10p). Expression of CHEK1 and associated genes was evaluated in TNBC and lung adenocarcinoma.
RESULTS: Inhibition of Chk1 kinase preferentially radiosensitized TNBC cells in vitro and in patient biopsies. Interestingly, TNBC cells displayed lower numbers of IR-induced DSBs than non-TNBC cells, correlating with their observed radioresistance. We found that Chk1 suppressed IR-induced DSBs in these cells, which was dependent on H3K9me3/S10p-a chromatin mark previously found to indicate radioresistance in KRAS mutant cancers. Accordingly, the effects of Chk1 inhibition in TNBC were reproduced in KRAS mutant but not wild-type cells. We also observed co-expression of genes in this Chk1 chromatin pathway in TNBC and KRAS mutant lung cancers.
CONCLUSIONS: Chk1 promotes an unexpected, common phenotype of chromatin-dependent DSB suppression in radioresistant TNBC and KRAS mutant cancer cells, providing a direction for future investigations into overcoming the treatment resistance of TNBC.

Thriveni K, Raju A, Ramaswamy G, Krishnamurthy S
Impact of gene polymorphism of TNF-
Indian J Cancer. 2018 Apr-Jun; 55(2):179-183 [PubMed] Related Publications
AIM: Inflammation plays a lead role in the tumor microenvironment and promotes metastasis. Single-nucleotide polymorphism (SNP) in the tumor necrosis factor (TNF) gene locus may alter the expression of genes and proteins. The objective of the study is to find the distribution of genetic polymorphism in the sites of TNF-α -308G>A and TNF- β +252A>G in breast cancer and evaluate polymorphism effects on plasma levels.
MATERIALS AND METHODS: The study group consisted of 109 invasive ductal primary breast cancer patients and 75 age-matched healthy female controls. Plasma cytokine concentrations were measured by the MILLIPLEX
RESULTS: Odds ratio with 95% confidence interval showed that these polymorphisms were not a causative risk factor, and both polymorphisms were consistent with Hardy-Weinberg equilibrium. Plasma TNFα and TNFβ median concentrations were significantly higher in cases when compared to controls (P < 0.01). When plasma TNFα levels were grouped under polymorphic subtypes, patients with mutant TNF- α -308A allele showed significantly higher values (P < 0.001). In addition, plasma TNFα values were significantly elevated in mutant TNF-β +252G allele (P < 0.01).
CONCLUSION: This study demonstrated that there is no significant association between SNPs and breast cancer susceptibility in South Indian population. However, plasma TNFα level is significantly elevated with mutant-recessive TNF-α -308 A and TNF-β +252 G alleles of patients.

Lu K, Li H, Wu Z, et al.
Predictive of 21-gene recurrence score assay in non-estrogen receptor-positive and lymph node-negative breast cancer.
J BUON. 2018 Sep-Oct; 23(5):1297-1301 [PubMed] Related Publications
PURPOSE: The 21-gene recurrence score (RS) assay predicts relapse of estrogen receptor-positive and lymph node-negative breast cancer more accurately than traditional markers; however, whether this assay can be regarded as a molecular marker of other types of breast cancer is unclear. We aimed to identify the effect of 21-gene recurrence score assay in non-estrogen receptor-positive and lymph node-negative breast cancer.
METHODS: We analyzed 21-gene expression by quantitative real-time PCR (qRT-PCR) in 100 cases of breast cancer tissues and followed up for 5 years to investigate the prognostic significance in non-estrogen receptor-positive and lymph node-negative breast cancer. Also, the correlation between RS and the clinicopathological features were analyzed. Adjuvant online (AOL) database was used for the analyses in the present study.
RESULTS: The cases were classified as RS low (n=52), moderate (n=22) and high (n=26) risk. The RS based on the21-gene assay was not correlated with age, tumor size, histological grade, and lymph node and estrogen receptor/progesterone receptor (ER/PR) status; however, there was significant correlation with Her-2 status. The 5-year recurrence rates were 1.92%, 4.55% and 15.38% in the low, moderate and high-risk groups, respectively. In addition, there was significant difference between the low-high groups (p<0.05). Furthermore, the consistency of the prognosis predicted by the AOL system was 56% and 59% in the RS moderate-high risk and low risk groups, respectively.
CONCLUSIONS: The 21-gene RS assay was a prognostic indicator for patients with non-ER-positive and lymph node-negative breast cancer. In addition, our results coincided with those obtained using the AOL system.

Barbosa TC, Lopes BA, Blunck CB, et al.
A novel PAX5 rearrangement in TCF3-PBX1 acute lymphoblastic leukemia: a case report.
BMC Med Genomics. 2018; 11(1):122 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
BACKGROUND: Chromosome translocations are a hallmark of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Additional genomic aberrations are also crucial in both BCP-ALL leukemogenesis and treatment management. Herein, we report the phenotypic and molecular cytogenetic characterization of an extremely rare case of BCP-ALL harboring two concomitant leukemia-associated chromosome translocations: t(1;19)(q23;q13.3) and t(9;17)(p13;q11.2). Of note, we described a new rearrangement between exon 6 of PAX5 and a 17q11.2 region, where intron 3 of SPECC1 is located. This rearrangement seems to disrupt PAX5 similarly to a PAX5 deletion. Furthermore, a distinct karyotype between diagnosis and relapse samples was observed, disclosing a complex clonal evolution during leukemia progression.
CASE PRESENTATION: A 16-year-old boy was admitted febrile with abdominal and joint pain. At clinical investigation, he presented with anemia, splenomegaly, low white blood cell count and 92% lymphoblast. He was diagnosed with pre-B ALL and treated according to high risk GBTLI-ALL2009. Twelve months after complete remission, he developed a relapse in consequence of a high central nervous system and bone marrow infiltration, and unfortunately died.
CONCLUSIONS: To our knowledge, this is the first report of a rearrangement between PAX5 and SPECC1. The presence of TCF3-PBX1 and PAX5-rearrangement at diagnosis and relapse indicates that both might have participated in the malignant transformation disease maintenance and dismal outcome.

Tevis SE, Bassett R, Bedrosian I, et al.
OncotypeDX Recurrence Score Does Not Predict Nodal Burden in Clinically Node Negative Breast Cancer Patients.
Ann Surg Oncol. 2019; 26(3):815-820 [PubMed] Related Publications
BACKGROUND: OncotypeDX recurrence score (RS)
METHODS: Patients with invasive breast cancer who underwent sentinel lymph node dissection from 2010 to 2015 were identified from a prospectively maintained database. Patients were excluded if they were clinically node positive or if they received neoadjuvant chemotherapy. RS was classified as low (< 18), intermediate (18-30), or high (> 30). The association between RS, lymph node burden, and disease recurrence was evaluated. Statistical analyses were performed in R version 3.4.0; p < 0.05 was considered significant.
RESULTS: A positive SLN was found in 168 (15%) of 1121 patients. Completion axillary lymph node dissection was performed in 84 (50%) of SLN-positive patients. The remaining 84 (50%) patients had one to two positive SLNs and did not undergo further axillary surgery. RS was low in 58.5%, intermediate in 32.6%, and high in 8.9%. RS was not associated with a positive SLN, number of positive nodes, maximum node metastasis size, or extranodal extension. The median follow-up was 23 months. High RS was not associated with locoregional recurrence (p = 0.07) but was significantly associated with distant recurrence (p = 0.0015).
CONCLUSIONS: OncotypeDX RS is not associated with nodal burden in women with clinically node-negative breast cancer, suggesting that RS is not useful to guide decisions regarding extent of axillary surgery for these patients.

Pease AM, Riba LA, Gruner RA, et al.
Oncotype DX
Ann Surg Oncol. 2019; 26(2):366-371 [PubMed] Related Publications
METHODS: The National Cancer Database was used to identify all patients with T1-T3, ER-positive, HER2-negative primary invasive breast cancer diagnosed from 2010 to 2015 who had Oncotype DX recurrence scores (RS) and received NCT. RS were classified as low, intermediate, or high. Unadjusted and adjusted regression analyses were performed to determine the association between pathologic complete response (pCR) and RS.
RESULTS: A total of 989 patients (mean age, 54.6 years) with available RS who underwent NCT were identified. RS were low in 227 (23.0%) patients, intermediate in 450 (45.5%) patients, and high in 312 (31.5%) patients. Most patients had a T1 (431 [43.6%]) or T2 tumor (451 [45.6%]). Most had N0 disease (757 [76.5%]). Tumor grades were 1 (123 [12.4%]), 2 (517 [52.3%]), or 3 (349 [35.3%]). pCR was achieved by 42 (4.3%) patients. Adjusted multivariable analysis showed a significant association between pCR and high RS (odds ratio 4.87; 95% confidence interval 2.01-11.82).
CONCLUSIONS: High Oncotype DX RS was associated with pCR after NCT in this national cohort of ER-positive, HER2-negative patients. Oncotype DX testing could help to identify patients most suited for NCT and should be considered for incorporation into the multidisciplinary decision-making process.

Yang X, Shen H, Buckley B, et al.
NTRK1 is a positive regulator of YAP oncogenic function.
Oncogene. 2019; 38(15):2778-2787 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Multiple cancer signalling networks take part in regulatory crosstalks with the Hippo tumour suppressor pathway through the transcriptional cofactor Yes-associated protein (YAP). Nevertheless, how YAP is controlled by pathway crosstalks in tumourigenesis remains poorly understood. Here, we performed a targeted kinase inhibitor screen in human cancer cells to identify novel Hippo pathway regulators. Notably, we identified the nerve growth factor (NGF) receptor tyrosine kinase (NTRK1), a molecule not previously associated with Hippo signalling. NTRK1 inhibition decreased YAP-driven transcription, cancer cell proliferation and migration. Furthermore, using a complementary functional genomics approach and mouse xenograft models, we show that NTRK1 regulates YAP oncogenic activity in vivo. Mechanistically, NTRK1 inhibition was found to induce large suppressor kinase 1 (LATS1) phosphorylation and to control YAP subcellular localization. Taken together, these results provide compelling evidence of crosstalks between the NGF-NTRK1 and Hippo cancer pathways.

Xu JL, Bai J, Jiao JF, et al.
Meta-analysis on the association between xeroderma pigmentosum Group A A23G polymorphism and esophageal cancer in a Chinese population.
J Cancer Res Ther. 2018; 14(Supplement):S1173-S1177 [PubMed] Related Publications
Aim of the Study: Several studies have evaluated the correlation between xeroderma pigmentosum Group A (XPA) A23G polymorphism (rs 1800975) and esophageal cancer in Chinese people. However, the results are inconsistent. To assess the effects of XPA A23G variants on the risk for development of esophageal cancer in the Chinese population, a meta-analysis was performed.
Materials and Methods: Studies were identified using PubMed and Chinese databases through December 2015. The associations were assessed with pooled odds ratios (ORs) and 95% confidence intervals (95% CIs).
Results: This meta-analysis identified seven studies including 1514 esophageal cancer cases and 2120 controls. In the overall analysis, no significant association between XPA A23G polymorphism and esophageal cancer was found in the Chinese population. In the subgroup analyses by geographic area(s) and source of controls, significant results were only found in studies with hospital-based controls (GG vs. AA: OR = 0.42, 95% CI = 0.28-0.62; GG vs. AA + AG: OR = 0.55, 95% CI = 0.39-0.78; GG + AG vs. AA: OR = 0.54, 95% CI = 0.40-0.72; G vs. A: OR = 0.61, 95% CI = 0.50-0.75).
Conclusions: This meta-analysis suggested that XPA A23G gene polymorphism may be one low-penetrant risk factor for esophageal cancer in Chinese individuals.

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