PAX2

Gene Summary

Gene:PAX2; paired box 2
Aliases: FSGS7, PAPRS
Location:10q24.31
Summary:PAX2 encodes paired box gene 2, one of many human homologues of the Drosophila melanogaster gene prd. The central feature of this transcription factor gene family is the conserved DNA-binding paired box domain. PAX2 is believed to be a target of transcriptional supression by the tumor suppressor gene WT1. Mutations within PAX2 have been shown to result in optic nerve colobomas and renal hypoplasia. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Dec 2014]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:paired box protein Pax-2
Source:NCBIAccessed: 31 August, 2019

Ontology:
What does this gene/protein do?
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Contents

Gene Summary

Cancer Overview

Specific Cancers (3)

Useful Links

Latest Publications
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 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.

  • Messenger RNA
  • Neoplastic Cell Transformation
  • Cystadenocarcinoma, Serous
  • Renal Cell Carcinoma
  • Kidney Cancer
  • Ovarian Cancer
  • Chromosome 10
  • DNA-Binding Proteins
  • Transforming Growth Factor beta
  • p53 Protein
  • Gene Expression Profiling
  • Base Sequence
  • Western Blotting
  • RTPCR
  • Kidney
  • Trans-Activators
  • Fallopian tube cancer
  • siRNA
  • Immunohistochemistry
  • FISH
  • Transcription Factors
  • WT1
  • Molecular Sequence Data
  • Cell Proliferation
  • PTEN
  • Biomarkers, Tumor
  • Endometrial Cancer
  • Promoter Regions
  • Zinc Fingers
  • Paired Box Transcription Factors
  • Oligonucleotide Array Sequence Analysis
  • DNA Mutational Analysis
  • Mutation
  • Cancer Gene Expression Regulation
  • PAX8 Transcription Factor
  • Cell Differentiation
  • Gene Expression
  • Phenotype
  • PAX2 Transcription Factor
  • Nuclear Proteins
Tag cloud generated 31 August, 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.

Entity Topic PubMed Papers
Kidney CancerPAX2 and Kidney Cancer View Publications40
Fallopian tube cancerPAX2 and Fallopian tube cancer View Publications10
-PAX2 and Precancerous Conditions View Publications4
Ovarian CancerPAX2 and Ovarian Cancer View Publications17
Endometrial CancerPAX2 and Endometrial Cancer View Publications10

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

Latest Publications: PAX2 (cancer-related)

Jester R, Znoyko I, Garnovskaya M, et al.
Expression of renal cell markers and detection of 3p loss links endolymphatic sac tumor to renal cell carcinoma and warrants careful evaluation to avoid diagnostic pitfalls.
Acta Neuropathol Commun. 2018; 6(1):107 [PubMed] Free Access to Full Article Related Publications
Endolymphatic sac tumor (ELST) is a rare neoplasm arising in the temporal petrous region thought to originate from endolymphatic sac epithelium. It may arise sporadically or in association with Von-Hippel-Lindau syndrome (VHL). The ELST prevalence in VHL ranges from 3 to 16% and may be the initial presentation of the disease. Onset is usually in the 3rd to 5th decade with hearing loss and an indolent course. ELSTs present as locally destructive lesions with characteristic computed tomography imaging features. Histologically, they show papillary, cystic or glandular architectures. Immunohistochemically, they express keratin, EMA, and variably S100 and GFAP. Currently it is recommended that, given its rarity, ELST needs to be differentiated from other entities with similar morphologic patterns, particularly other VHL-associated neoplasms such as metastatic clear cell renal cell carcinoma (ccRCC). Nineteen ELST cases were studied. Immunohistochemistry (18/19) and single nucleotide polymorphism microarray testing was performed (12/19). Comparison with the immunophenotype and copy number profile in RCC is discussed. Patients presented with characteristic bone destructive lesions in the petrous temporal bones. Pathology of tumors showed characteristic ELST morphology with immunoexpression of CK7, GFAP, S100, PAX-8, PAX-2, CA-9 in the tumor cells. Immunostaines for RCC, CD10, CK20, chromogranin A, synaptophysin, TTF-1, thyroglobulin, and transthyretin were negative in the tumor cells. Molecular testing showed loss of 3p and 9q in 66% (8/12) and 58% (7/12) cases, respectively. Immunoreactivity for renal markers in ELST is an important diagnostic caveat and has not been previously reported. In fact, renal markers are currently recommended in order to rule out metastatic RCC although PAX gene complex and CA-9 have been implicated in the development of the inner ear. Importantly copy number assessment of ELST has not been previously reported. Loss of 3p (including the VHL locus) in ELST suggests similar mechanistic origins as ccRCC.
Related: Cytokines Kidney Cancer

Hart MR, Anderson DJ, Porter CC, et al.
Activating PAX gene family paralogs to complement PAX5 leukemia driver mutations.
PLoS Genet. 2018; 14(9):e1007642 [PubMed] Free Access to Full Article Related Publications
PAX5, one of nine members of the mammalian paired box (PAX) family of transcription factors, plays an important role in B cell development. Approximately one-third of individuals with pre-B acute lymphoblastic leukemia (ALL) acquire heterozygous inactivating mutations of PAX5 in malignant cells, and heterozygous germline loss-of-function PAX5 mutations cause autosomal dominant predisposition to ALL. At least in mice, Pax5 is required for pre-B cell maturation, and leukemic remission occurs when Pax5 expression is restored in a Pax5-deficient mouse model of ALL. Together, these observations indicate that PAX5 deficiency reversibly drives leukemogenesis. PAX5 and its two most closely related paralogs, PAX2 and PAX8, which are not mutated in ALL, exhibit overlapping expression and function redundantly during embryonic development. However, PAX5 alone is expressed in lymphocytes, while PAX2 and PAX8 are predominantly specific to kidney and thyroid, respectively. We show that forced expression of PAX2 or PAX8 complements PAX5 loss-of-function mutation in ALL cells as determined by modulation of PAX5 target genes, restoration of immunophenotypic and morphological differentiation, and, ultimately, reduction of replicative potential. Activation of PAX5 paralogs, PAX2 or PAX8, ordinarily silenced in lymphocytes, may therefore represent a novel approach for treating PAX5-deficient ALL. In pursuit of this strategy, we took advantage of the fact that, in kidney, PAX2 is upregulated by extracellular hyperosmolarity. We found that hyperosmolarity, at potentially clinically achievable levels, transcriptionally activates endogenous PAX2 in ALL cells via a mechanism dependent on NFAT5, a transcription factor coordinating response to hyperosmolarity. We also found that hyperosmolarity upregulates residual wild type PAX5 expression in ALL cells and modulates gene expression, including in PAX5-mutant primary ALL cells. These findings specifically demonstrate that osmosensing pathways may represent a new therapeutic target for ALL and more broadly point toward the possibility of using gene paralogs to rescue mutations driving cancer and other diseases.
Related: Acute Lymphocytic Leukemia (ALL)

Maliszewska-Olejniczak K, Brodaczewska KK, Bielecka ZF, Czarnecka AM
Three-Dimensional Cell Culture Model Utilization in Renal Carcinoma Cancer Stem Cell Research.
Methods Mol Biol. 2018; 1817:47-66 [PubMed] Related Publications
Specific 3D conditions of cancer cell lines have been optimized over last years, with growing significance of serum-free and xeno-free culture variants. The choice of proper culture media enables cancer stem cells proliferation in primary and stable cell lines. To obtain renal cell cancer stem-like phenotype, we employed media dedicated for mesenchymal cells and adult stem cells. Developed RCC cell line 3D culture system enables effective drug testing, including tyrosine kinase inhibitor anti-cancer cell toxicity. To induce formation of 3D spheroids by RCC cell lines, StemXvivo and NutriStem media must be used. Usage of laminin- or poly-D-lysine coated plates enhances also the formation of spheroids in 3D-promoting media. Seeding is optimal with Caki-1 or ACHN cell lines as well as 786-O or HKCSC cells. Our bio-mimic 3D RCC cell culture model promotes cell viability and stem-related gene expression including E-cadherin, N-cadherin, HIF1, HIF2, VEGF, Sox2, Pax2, and Nestin. 3D spheroid formation ability and spheroid volume increase are disturbed upon drug treatment. Untreated 3D structures reach ~100 μm in diameter at the end of 14-day long experiment. Sorter-based cell cycle analysis and Ki-67 staining should be conducted to verify specific toxicity. We suggest that due to the more complex architecture 3D RCC culture is more relevant to investigate the in vivo-like tumor drug response.
Related: Kidney Cancer

Jahangiri R, Mosaffa F, Gharib M, et al.
PAX2 expression is correlated with better survival in tamoxifen-treated breast carcinoma patients.
Tissue Cell. 2018; 52:135-142 [PubMed] Related Publications
PAX2 (paired box gene 2) is a transcription factor, which is involved in both cell proliferation and carcinogenesis. This study aimed to investigate PAX2 expression in tamoxifen resistant (TAM-R) and tamoxifen sensitive (TAM-S) breast carcinoma patients and analyze its correlation with clinicopathological characteristics and survival. Immunohistochemical analysis was performed to evaluate PAX2 protein expression in 36 TAM-R and 36 TAM-S formalin-fixed paraffin-embedded (FFPE) breast tumor tissues. Data analysis indicated that PAX2 expression was significantly higher in TAM-S group in comparison to TAM-R (P = 0.014). Overexpression of PAX2 was significantly correlated with perineural invasion (PNI) (P = 0.025). Kaplan-Meier survival analysis showed significant association between high expression of PAX2 and better disease-free survival (P < 0.001) and also overall survival (P = 0.031). Multivariate cox regression analysis demonstrated that patients with increased expression of PAX2 have a trend toward improved disease free survival (OR = 0.065, 95% CI: 0.009-0.476; P = 0.007) and overall survival (OR = 0.147, 95% CI: 0.020-1.105; P = 0.062). Our data suggested that high expression of PAX2 could be associated with better survival in estrogen receptor positive tamoxifen-treated breast carcinoma patients.
Related: Breast Cancer

Grimley E, Dressler GR
Are Pax proteins potential therapeutic targets in kidney disease and cancer?
Kidney Int. 2018; 94(2):259-267 [PubMed] Free Access to Full Article Related Publications
Pax genes encode developmental regulators that are expressed in a variety of tissues and control critical events in morphogenesis. In the kidney, Pax2 and Pax8 are expressed in embryonic development and in specific renal diseases associated with aberrant epithelial cell proliferation. Prior genetic and cell biological studies suggest that reducing the activity of Pax proteins in renal cancer or in polycystic kidney disease can slow the progression of these conditions. The Pax proteins may be critical for providing tissue and locus specificity to recruit epigenetic modifiers that control gene expression and chromatin structure. Although they are nuclear, targeting Pax proteins to inhibit function may be feasible with small molecules. Such inhibition of Pax protein function may provide novel therapies for subsets of renal disorders that are tissue- and cell type-specific and avoid systemic effects on non-Pax-expressing cells and tissues. Given the paucity of effective treatments for renal cancer and cystic disease, the Pax family of proteins represents new pharmaceutical targets that merit exploration and further development.
Related: Kidney Cancer PAX8

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.
Related: Endometrial (Uterus) Cancer Endometrial Cancer

Lu Y, Li W
Functional characterization of E2F3b in human HepG2 liver cancer cell line.
J Cell Biochem. 2018; 119(4):3429-3439 [PubMed] Related Publications
E2F3 is a transcription factor that has been shown to be overexpressed in hepatocellular carcinoma (HCC). It is well-known that the E2F3 gene encodes two proteins E2F3a and E2F3b. Therefore, the functions of the two distinct isoforms need to be clarified separately. To characterize the function of E2F3b in HCC, the effects of ectopic expression of E2F3b on cell proliferation, cell cycle, apoptosis and gene expression were investigated. E2F3b promoted G1/S phase transition and markedly increased cell proliferation, but had minor effect on apoptosis. Microarray analyses identified 366 differentially expressed genes (171 upregulated and 195 downregulated) in E2F3b- overexpressing cells. Differential expression of 16 genes relevant to cell cycle and cell proliferation were further verified by real-time PCR. Six genes, including CDC2, CCNE1, ARF, MAP4K2, MUSK, and PAX2 were confirmed to be upregulated by more than twofold; one gene, CCNA2 was validated to be downregulated by more than twofold. We also confirmed that E2F3b increased the protein levels of both cyclin E and Arf but did not affect cyclin D1 protein. These results suggest that E2F3b functions as an important promoter for cell proliferation and plays important roles in transcriptional regulation in HepG2 liver cancer cells.
Related: Apoptosis E2F3 Liver Cancer

Giagulli C, D'Ursi P, He W, et al.
A single amino acid substitution confers B-cell clonogenic activity to the HIV-1 matrix protein p17.
Sci Rep. 2017; 7(1):6555 [PubMed] Free Access to Full Article Related Publications
Recent data highlight the presence, in HIV-1-seropositive patients with lymphoma, of p17 variants (vp17s) endowed with B-cell clonogenicity, suggesting a role of vp17s in lymphomagenesis. We investigated the mechanisms responsible for the functional disparity on B cells between a wild-type p17 (refp17) and a vp17 named S75X. Here, we show that a single Arginine (R) to Glycine (G) mutation at position 76 in the refp17 backbone (p17R76G), as in the S75X variant, is per se sufficient to confer a B-cell clonogenic potential to the viral protein and modulate, through activation of the PTEN/PI3K/Akt signaling pathway, different molecules involved in apoptosis inhibition (CASP-9, CASP-7, DFF-45, NPM, YWHAZ, Src, PAX2, MAPK8), cell cycle promotion and cancer progression (CDK1, CDK2, CDK8, CHEK1, CHEK2, GSK-3 beta, NPM, PAK1, PP2C-alpha). Moreover, the only R to G mutation at position 76 was found to strongly impact on protein folding and oligomerization by altering the hydrogen bond network. This generates a conformational shift in the p17 R76G mutant which enables a functional epitope(s), masked in refp17, to elicit B-cell growth-promoting signals after its interaction with a still unknown receptor(s). Our findings offer new opportunities to understand the molecular mechanisms accounting for the B-cell growth-promoting activity of vp17s.
Related: Signal Transduction

Knutson TP, Truong TH, Ma S, et al.
Posttranslationally modified progesterone receptors direct ligand-specific expression of breast cancer stem cell-associated gene programs.
J Hematol Oncol. 2017; 10(1):89 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Estrogen and progesterone are potent breast mitogens. In addition to steroid hormones, multiple signaling pathways input to estrogen receptor (ER) and progesterone receptor (PR) actions via posttranslational events. Protein kinases commonly activated in breast cancers phosphorylate steroid hormone receptors (SRs) and profoundly impact their activities.
METHODS: To better understand the role of modified PRs in breast cancer, we measured total and phospho-Ser294 PRs in 209 human breast tumors represented on 2754 individual tissue spots within a tissue microarray and assayed the regulation of this site in human tumor explants cultured ex vivo. To complement this analysis, we assayed PR target gene regulation in T47D luminal breast cancer models following treatment with progestin (promegestone; R5020) and antiprogestins (mifepristone, onapristone, or aglepristone) in conditions under which the receptor is regulated by Lys388 SUMOylation (K388 intact) or is SUMO-deficient (via K388R mutation to mimic persistent Ser294 phosphorylation). Selected phospho-PR-driven target genes were validated by qRT-PCR and following RUNX2 shRNA knockdown in breast cancer cell lines. Primary and secondary mammosphere assays were performed to implicate phospho-Ser294 PRs, epidermal growth factor signaling, and RUNX2 in breast cancer stem cell biology.
RESULTS: Phospho-Ser294 PR species were abundant in a majority (54%) of luminal breast tumors, and PR promoter selectivity was exquisitely sensitive to posttranslational modifications. Phospho-PR expression and target gene programs were significantly associated with invasive lobular carcinoma (ILC). Consistent with our finding that activated phospho-PRs undergo rapid ligand-dependent turnover, unique phospho-PR gene signatures were most prevalent in breast tumors clinically designated as PR-low to PR-null (luminal B) and included gene sets associated with cancer stem cell biology (HER2, PAX2, AHR, AR, RUNX). Validation studies demonstrated a requirement for RUNX2 in the regulation of selected phospho-PR target genes (SLC37A2). In vitro mammosphere formation assays support a role for phospho-Ser294-PRs via growth factor (EGF) signaling as well as RUNX2 as potent drivers of breast cancer stem cell fate.
CONCLUSIONS: We conclude that PR Ser294 phosphorylation is a common event in breast cancer progression that is required to maintain breast cancer stem cell fate, in part via cooperation with growth factor-initiated signaling pathways and key phospho-PR target genes including SLC37A2 and RUNX2. Clinical measurement of phosphorylated PRs should be considered a useful marker of breast tumor stem cell potential. Alternatively, unique phospho-PR target gene sets may provide useful tools with which to identify patients likely to respond to selective PR modulators that block PR Ser294 phosphorylation as part of rational combination (i.e., with antiestrogens) endocrine therapies designed to durably block breast cancer recurrence.
Related: Breast Cancer

Martin-Montalvo A, Lorenzo PI, López-Noriega L, Gauthier BR
Targeting pancreatic expressed PAX genes for the treatment of diabetes mellitus and pancreatic neuroendocrine tumors.
Expert Opin Ther Targets. 2017; 21(1):77-89 [PubMed] Related Publications
INTRODUCTION: Four members of the PAX family, PAX2, PAX4, PAX6 and PAX8 are known to be expressed in the pancreas. Accumulated evidences indicate that several pancreatic expressed PAX genes play a significant role in pancreatic development/functionality and alterations in these genes are involved in the pathogenesis of pancreatic diseases. Areas covered: In this review, we summarize the ongoing research related to pancreatic PAX genes in diabetes mellitus and pancreatic neuroendocrine tumors. We dissect the current knowledge at different levels; from mechanistic studies in cell lines performed to understand the molecular processes controlled by pancreatic PAX genes, to in vivo studies using rodent models that over-express or lack specific PAX genes. Finally, we describe human studies associating variants on pancreatic-expressed PAX genes with pancreatic diseases. Expert opinion: Based on the current literature, we propose that future interventions to treat pancreatic neuroendocrine tumors and diabetes mellitus could be developed via the modulation of PAX4 and/or PAX6 regulated pathways.
Related: Cancer of the Pancreas Pancreatic Cancer

Jia N, Wang J, Li Q, et al.
DNA methylation promotes paired box 2 expression via myeloid zinc finger 1 in endometrial cancer.
Oncotarget. 2016; 7(51):84785-84797 [PubMed] Free Access to Full Article Related Publications
This work investigated the role of paired box 2 (PAX2) in endometrial cancer and its epigenetic regulation mechanism. Endometrial cancer tissues and cell lines exhibited increased PAX2 expression compared with hyperplasia, normal endometrium and endometrial epithelial cells. Knock-down of PAX2 resulted in reduced cell viability, invasion and migration, and PAX2 overexpression caused the opposite effects. Increased methylation of the PAX2 promoter was observed in both cancer tissues and cell lines and was positively correlated with PAX2 expression. After 5-Aza-CdR treatment, PAX2 mRNA and protein were down-regulated, and PAX2 methylation was decreased. Deletion analysis confirmed that a repressive transcriptional regulatory region of the PAX2 promoter coincided with the hypermethylated region identified in MassARRAY analysis. Binding sites of myeloid zinc finger 1 (MZF1) are predicted in the defined region. Knock-down of MZF1 up-regulated the transcriptional activity and protein level of PAX2 after 5-Aza-CdR treatment, which indicated that MZF1 may act as a repressive transcription factor when the PAX2 promoter is unmethylated. In conclusion, PAX2 is involved in the carcinogenesis of endometrial cancer by stimulating cell growth and promoting cell motility. The overexpression of PAX2 in endometrial cancer is regulated by promoter hypermethylation and the transcription factor MZF1.
Related: Azacitidine Endometrial (Uterus) Cancer Endometrial Cancer

Yu L, Li J, Xu S, et al.
An Xp11.2 translocation renal cell carcinoma with SMARCB1 (INI1) inactivation in adult end-stage renal disease: a case report.
Diagn Pathol. 2016; 11(1):98 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Xp11.2 translocation/transcription factor E3 (TFE3) rearrangement renal cell carcinoma (RCC) is a rare subtype of RCC with limited clinical and pathological data.
CASE PRESENTATION: Here we present an unusual high-grade Xp11.2 translocation RCC with a rhabdoid feature and SMARCB1 (INI1) inactivation in a 40-year-old man with end-stage kidney disease. The histological examination of the dissected left renal tumor showed an organoid architecture of the eosinophilic or clear neoplastic cells with necrosis and high mitotic activity. In some areas, non-adhesive tumor cells with eccentric nuclei were observed. Immunohistochemically (IHC), the tumor cells are positive for TFE3 and the renal tubular markers (PAX2 and PAX8), and completely negative for SMARCB1, an oncosuppressor protein. Break-apart florescence in situ hybridization and reverse transcription polymerase chain reaction confirmed TFE3 rearrangement on Xp11.2 and the presence of ASPSCR1-TFE3 fusion gene. DNA sequencing revealed a frameshift mutation in exon 4 of SMARCB1 gene.
CONCLUSION: It is important to recognize this rare RCC with both TFE3 rearrangement and SMARCB1 inactivation, as the prognosis and therapeutic strategies, particularly targeted therapies for such tumors, might be different.
Related: Chromosome X FISH Kidney Cancer ASPSCR1 SMARCB1

Koppens MA, Bounova G, Cornelissen-Steijger P, et al.
Large variety in a panel of human colon cancer organoids in response to EZH2 inhibition.
Oncotarget. 2016; 7(43):69816-69828 [PubMed] Free Access to Full Article Related Publications
EZH2 inhibitors have gained great interest for their use as anti-cancer therapeutics. However, most research has focused on EZH2 mutant cancers and recently adverse effects of EZH2 inactivation have come to light. To determine whether colorectal cancer cells respond to EZH2 inhibition and to explore which factors influence the degree of response, we treated a panel of 20 organoid lines derived from human colon tumors with different concentrations of the EZH2 inhibitor GSK126. The resulting responses were associated with mutation status, gene expression and responses to other drugs. We found that the response to GSK126 treatment greatly varied between organoid lines. Response associated with the mutation status of ATRX and PAX2, and correlated with BIK expression. It also correlated well with response to Nutlin-3a which inhibits MDM2-p53 interaction thereby activating p53 signaling. Sensitivity to EZH2 ablation depended on the presence of wild type p53, as tumor organoids became resistant when p53 was mutated or knocked down. Our exploratory study provides insight into which genetic factors predict sensitivity to EZH2 inhibition. In addition, we show that the response to EZH2 inhibition requires wild type p53. We conclude that a subset of colorectal cancer patients may benefit from EZH2-targeting therapies.
Related: TP53 BIK EZH2 ATRX

Lin Z, Zhao J, Wang X, et al.
Overexpression of microRNA-497 suppresses cell proliferation and induces apoptosis through targeting paired box 2 in human ovarian cancer.
Oncol Rep. 2016; 36(4):2101-7 [PubMed] Related Publications
MicroRNAs are a class of endogenous, small non-coding RNAs which are tightly involved in evolution and progression of human cancers. MicroRNA-497 has been reported as tumor-suppressor in various human cancer. However, the role of miR-497 in ovarian cancer is still poorly known. We investigated the expression level and cellular function of miR-497 in human ovarian cancer. In this study, the expression of miR-497 in ovarian cancer tissues and SKOV3 cells was detected by quantitative reverse‑transcription polymerase chain reaction (qRT-PCR). CCK-8 assay was used to analysis the cell proliferation. Transwell assay was performed to analysis cell migration and invasion. Cell apoptosis was evaluated by flow cytometry. Luciferase assay was performed to verify a putative target site of miR-497 in the 3'UTR of PAX2 mRNA. The results showed that miR-497 was markedly decreased in ovarian cancer tissues and SKOV3 cells. Moreover, overexpression of miR-497 in SKOV3 cells induced PAX2 protein expression and resulted in inhibition of cell proliferation, migration and invasion, and induction of cell apoptosis. In addition, we confirmed that PAX2 is a direct target gene of miR-497. Furthermore, Silencing of PAX2 by RNA interference suppressed cell proliferation and promoted cell apoptosis in vitro. Taken together, our study rationally present that miR-497 has a potential role as a useful diagnostic and therapeutic biomarker for human ovarian cancer.
Related: Apoptosis MicroRNAs Ovarian Cancer

Muscat A, Popovski D, Jayasekara WS, et al.
Low-Dose Histone Deacetylase Inhibitor Treatment Leads to Tumor Growth Arrest and Multi-Lineage Differentiation of Malignant Rhabdoid Tumors.
Clin Cancer Res. 2016; 22(14):3560-70 [PubMed] Related Publications
PURPOSE: Malignant rhabdoid tumor (MRT) and atypical teratoid rhabdoid tumors (ATRT) are rare aggressive undifferentiated tumors primarily affecting the kidney and CNS of infants and young children. MRT are almost exclusively characterized by homozygous deletion or inactivation of the chromatin remodeling gene SMARCB1 SMARCB1 protein loss leads to direct impairment of chromatin remodeling and we have previously reported a role for this protein in histone acetylation. This provided the rationale for investigating the therapeutic potential of histone deactylase inhibitors (HDACi) in MRT.
EXPERIMENTAL DESIGN: Whereas previously HDACis have been used at doses and schedules that induce cytotoxicity, in the current studies we have tested the hypothesis, both in vitro and in vivo, that sustained treatment of human MRT with low-dose HDACi can lead to sustained cell growth arrest and differentiation.
RESULTS: Sustained low-dose panobinostat (LBH589) treatment led to changes in cellular morphology associated with a marked increase in the induction of neural, renal, and osteoblast differentiation pathways. Genome-wide transcriptional profiling highlighted differential gene expression supporting multilineage differentiation. Using mouse xenograft models, sustained low-dose LBH589 treatment caused tumor growth arrest associated with tumor calcification detectable by X-ray imaging. Histological analysis of LBH589-treated tumors revealed significant regions of ossification, confirmed by Alizarin Red staining. Immunohistochemical analysis showed increased TUJ1 and PAX2 staining suggestive of neuronal and renal differentiation, respectively.
CONCLUSIONS: Low-dose HDACi treatment can terminally differentiate MRT tumor cells and reduce their ability to self-renew. The use of low-dose HDACi as a novel therapeutic approach warrants further investigation. Clin Cancer Res; 22(14); 3560-70. ©2016 AACR.
Related: Apoptosis Malignant Rhabdoid Tumour

Kuroda N, Agatsuma Y, Tamura M, et al.
Sporadic renal hemangioblastoma with CA9, PAX2 and PAX8 expression: diagnostic pitfall in the differential diagnosis from clear cell renal cell carcinoma.
Int J Clin Exp Pathol. 2015; 8(2):2131-8 [PubMed] Free Access to Full Article Related Publications
To date, 13 cases of sporadic renal hemangioblastoma have been reported. In this article, we report such a case that might cause the diagnostic pitfall. A 37-year-old Japanese was found to have a renal mass by periodic medical check-up. He underwent radical nephrectomy. Macroscopically, the tumor was well-defined without fibrous capsule and the cut surface of the tumor exhibited light brown to gray-tan color without hemorrhage or necrosis. Microscopically, the tumor was made up of large polygonal to short spindle cells with eosinophilic cytoplasm with occasional vacuolization and abundant arborizing capillary network. Immunohistochemically, neoplastic cells showed diffuse positivity for inhibin-alpha, S-100 protein, vimentin, CA9, PAX2 and PAX8, but negativity for cytokeratin CAM5.2, alpha smooth muscle actin, Melanosome, Melan A, TFE3 and cathepsin K. In genetic analyses, this tumor showed no changes of VHL gene mutation, hypermethylation and loss of heterozygosity of chromosome 3p. Additionally, G-band karyotype and array comparative genomic hybridization studies showed a normal chromosome. In conclusion, the positivity for CA9, PAX2 and PAX8 in sporadic renal hemangioblastoma may cause the critical diagnostic pitfall in the differential diagnosis from clear cell renal cell carcinoma. Pathologists need to pay attention to systemic evaluation including macroscopic, microscopic and immunohistochemical findings. In some cases, molecular genetic study may be necessary.
Related: Kidney Cancer PAX8

Liu P, Gao Y, Huan J, et al.
Upregulation of PAX2 promotes the metastasis of esophageal cancer through interleukin-5.
Cell Physiol Biochem. 2015; 35(2):740-54 [PubMed] Related Publications
BACKGROUND/AIMS: This study investigated the clinical relevance and biological function of paired box gene 2 (PAX2) in esophageal squamous cell carcinoma (ESCC).
METHODS/RESULTS: Results showed that PAX2 expression was significantly increased in tumor tissues and that its expression correlated with the ESCC stage (P = 0.001), lymph node metastasis (pN, P = 0.019) and lymphatic invasion (P = 0.005) in 120 ESCC tissue specimens by immunohistochemistry. Furthermore, PAX2 overexpression resulted in markedly reduced cell proliferation but increased metastasis capacity in ESCC TE-1 and Eca-109 cells. Knockdown of PAX2 expression with a short hairpin RNA confirmed a role in the promotion of metastasis in ESCC cells. mRNA microarray screening revealed that PAX2 overexpression affected multiple genes that function in multiple pathways. Interleukin-5 (IL-5), which was induced by PAX2 and has been shown to promote tumor metastasis, was further studied in greater detail. Two PAX2 binding sites were identified in the IL-5 promoter, and PAX2 was observed to stimulate IL-5 promoter activity and IL-5 expression in esophageal cancer cells. Chromatin immunoprecipitation (ChIP) confirmed the direct binding of PAX2 in the IL-5 promoter. The expression of PAX2 mRNA significantly correlated with that of IL-5 in normal esophageal and ESCC tissues.
CONCLUSION: These findings demonstrate that PAX2 is overexpressed in esophageal carcinoma and IL-5 is identified as PAX2's effector for metastasis.
Related: Cancer of the Esophagus Esophageal Cancer

Roma AA, Masand RP
Different staining patterns of ovarian Brenner tumor and the associated mucinous tumor.
Ann Diagn Pathol. 2015; 19(1):29-32 [PubMed] Related Publications
The association of ovarian Brenner tumors and adjacent mucinous tumors is well known but not completely understood. In this study, we analyzed immunohistochemical markers on Brenner tumors and their associated mucinous tumor to explore Mullerian as well as Wolffian and germ cell derivation and determine if the mucinous component is independent or related to the Brenner tumor. Of 32 consecutive cases of Brenner tumors, 8 were identified with significant mucinous component, and 7 additional cases included foci of mucinous epithelium within the Brenner transitional nests. All Brenner tumors were diffusely positive for GATA3 and negative for Paired box gene 8, PAX2, and Sal-like protein 4. Interestingly, the areas of mucinous epithelium as well as mucinous tumors, intermixed and adjacent to the Brenner tumor, were negative for all 4 markers; however, occasional basal-like cells retained expression of GATA3. The immunoprofile of mucinous tumors associated with Brenner tumors shares the lack of Mullerian markers PAX2 and Paired box gene 8 with the Brenner tumor but differs in the expression of GATA3 only in the Brenner tumor component.
Related: GATA3 PAX8

Liu F, Zhang R, Wang ZY, et al.
Malignant perivascular epithelioid cell tumor (PEComa) of cervix with TFE3 gene rearrangement: a case report.
Int J Clin Exp Pathol. 2014; 7(9):6409-14 [PubMed] Free Access to Full Article Related Publications
In this study, we reported the first PEComa arising within the cervix with TFE3 gene rearrangement and aggressive biological behavior. Morphologically, the tumor showed infiltrative growth into the surrounding parenchyma. The majority of tumor cells were arrayed in sheets, alveolar structures, or nests separated by delicate fibrovascular septa. There was marked intratumoral hemorrhage, necrosis, and stromal calcifications. The tumor cells had abundant clear cytoplasm, focally containing finely granular dark brown pigment, morphologically considered to be melanin. Immunohistochemically, the tumor cells demonstrated moderately (2+) or strongly (3+) positive staining for TFE3, HMB45, and Melan A but negative for CKpan, SMA, S100, PAX8, and PAX2. The presence of Ki-67 protein demonstrated a moderate proliferation rate, with a few Ki-67-positive nuclei. Using a recently developed TFE3 split FISH assay, the presence of TFE3 rearrangement was demonstrated. All these clinicopathologic features are suggestive of TFE3-rearranged PEComas of the cervix. Our results both expand the known characteristics of primary cervix PEComas and add to the data regarding TFE3 rearrangement-associated PEComas.
Related: FISH Cervical Cancer

Zhao H, Zhao Y, Jiang G, et al.
Dishevelled-3 activates p65 to upregulate p120-catenin transcription via a p38-dependent pathway in non-small cell lung cancer.
Mol Carcinog. 2015; 54 Suppl 1:E112-21 [PubMed] Related Publications
Dishevelled-3 (Dvl-3) and p120-catenin (p120ctn) have abnormal expression in non-small cell lung cancer (NSCLC), which is associated with poor prognosis. Dvl-3 upregulates p120ctn transcription in NSCLC cells, but the mechanism is unknown. Here we transiently transfected Dvl-3 cDNA to NSCLC cells. Dvl-3 transfection is sufficient for induction of p38 signaling. In turn, Dvl-3 induces p38-mediated activation of the p65 so as to facilitate its nuclear translocation. Treatment with SB203580 (p38 inhibitor) or BAY 11-7082 (IκB-α phosphorylation inhibitor) suppresses Dvl-3 induced activation of p65. The results further show that active p65 interacts with PAX2 promoter to increase the expression of PAX2 and then PAX2 binds to p120ctn promoter so as to upregulate p120ctn gene transcription. Moreover, Dvl-3 transfection enhanced the binding of active p65 to Sp1 so as to decrease the binding of Sp1 to p120ctn promoter. The above-mentioned effects are linked to biological behavior of non-small cell lung cancer cells. These findings confirm that p38 and PAX2 are important for the Dvl-3 induced upregulation of p120ctn. Dvl-3 activates a p38 → p65 → PAX2 → p120ctn pathway to affect biological behavior of NSCLC cells.
Related: Non-Small Cell Lung Cancer Lung Cancer

Ito S, Ueda T, Ueno A, et al.
Paired box 2 upregulates androgen receptor gene expression in androgen-independent prostate cancer.
FEBS J. 2014; 281(19):4506-18 [PubMed] Related Publications
Androgen-independent prostate cancer is known as a hormone-refractory disease. Although the androgen receptor (AR) is considered to be a key regulator of androgen-independent prostate cancer progression, the mechanism through which AR gene expression is regulated is not well understood. In the present study, we showed that the AR gene was upregulated by paired box 2 (PAX2) in androgen-independent prostate cancer. When PAX2 upregulated AR gene expression, a decrease in DNA methylation of the AR gene locus was also observed. PAX2 was highly expressed and promoted cell growth in an androgen-independent prostate cancer cell line (22Rv1). The cell growth inhibition by PAX2 knockdown was rescued by AR overexpression in 22Rv1 cells. In a mouse xenograft model of androgen-independent prostate cancer, PAX2 knockdown inhibited tumor growth and AR gene expression and also increased DNA methylation of the AR gene. Consistent with this, AR and PAX2 expression levels were positively correlated in prostate cancer patients. These findings suggested that PAX2 promoted cancer cell growth in androgen-independent prostate cancer by regulating AR gene expression through an epigenetic mechanism.
Related: Prostate Cancer

Ning G, Bijron JG, Yamamoto Y, et al.
The PAX2-null immunophenotype defines multiple lineages with common expression signatures in benign and neoplastic oviductal epithelium.
J Pathol. 2014; 234(4):478-87 [PubMed] Free Access to Full Article Related Publications
The oviducts contain high-grade serous cancer (HGSC) precursors (serous tubal intraepithelial neoplasia or STINs), which are γ-H2AX(p) - and TP53 mutation-positive. Although they express wild-type p53, secretory cell outgrowths (SCOUTs) are associated with older age and serous cancer; moreover, both STINs and SCOUTs share a loss of PAX2 expression (PAX2(n) ). We evaluated PAX2 expression in proliferating adult and embryonic oviductal cells, normal mucosa, SCOUTs, Walthard cell nests (WCNs), STINs, and HGSCs, and the expression of genes chosen empirically or from SCOUT expression arrays. Clones generated in vitro from embryonic gynaecological tract and adult Fallopian tube were Krt7(p) /PAX2(n) /EZH2(p) and underwent ciliated (PAX2(n) /EZH2(n) /FOXJ1(p) ) and basal (Krt7(n) /EZH2(n) /Krt5(p) ) differentiation. Similarly, non-ciliated cells in normal mucosa were PAX2(p) but became PAX2(n) in multi-layered epithelium undergoing ciliated or basal (WCN) cell differentiation. PAX2(n) SCOUTs fell into two groups: type 1 were secretory or secretory/ciliated with a 'tubal' phenotype and were ALDH1(n) and β-catenin(mem) (membraneous only). Type 2 displayed a columnar to pseudostratified (endometrioid) phenotype, with an EZH2(p) , ALDH1(p) , β-catenin(nc) (nuclear and cytoplasmic), stathmin(p) , LEF1(p) , RCN1(p) , and RUNX2(p) expression signature. STINs and HGSCs shared the type 1 immunophenotype of PAX2(n) , ALDH1(n) , β-catenin(mem) , but highly expressed EZH2(p) , LEF1(p) , RCN1(p) , and stathmin(p) . This study, for the first time, links PAX2(n) with proliferating fetal and adult oviductal cells undergoing basal and ciliated differentiation and shows that this expression state is maintained in SCOUTs, STINs, and HGSCs. All three entities can demonstrate a consistent perturbation of genes involved in potential tumour suppressor gene silencing (EZH2), transcriptional regulation (LEF1), regulation of differentiation (RUNX2), calcium binding (RCN1), and oncogenesis (stathmin). This shared expression signature between benign and neoplastic entities links normal progenitor cell expansion to abnormal and neoplastic outgrowth in the oviduct and exposes a common pathway that could be a target for early prevention.
Related: Fallopian Tube Cancer

Fan R
PAX immunoreactivity in poorly differentiated small round cell tumors of childhood.
Fetal Pediatr Pathol. 2014; 33(4):244-52 [PubMed] Related Publications
Paired box (PAX) gene antibodies have made it into the mainstream of tumor diagnosis in the recent years. We report the immunoreactivity expression patterns of three PAX genes (PAX2, PAX5 and PAX8) in poorly differentiated small round cell tumors of childhood for possible useful diagnostic applications. We collected and analyzed 123 cases of poorly differentiated small round cell tumors of childhood for their PAX immunoexpression patterns. The results indicated that PAX2 was strongly positive in all alveolar rhabdomyosarcomas and in two-thirds of the kidney clear cell sarcomas, and displayed variable expression in one-half of the embryonal rhabdomyosarcomas. PAX8 immunoexpression was noticed in five and three cases of alveolar rhabdomyosarcomas and embryonal rhabdomyosarcomas, respectively. About one-third of malignant rhabdoid tumors were PAX2-positive and PAX8-positive. All of the Ewing sarcoma and neuroblastoma cases stained negative with all three PAX stains.
Related: Childhood Brain Tumours Childhood Brain Tumors Kidney Cancer Cancer Prevention and Risk Reduction Children's Cancer Web: Home Page Neuroblastoma Malignant Rhabdoid Tumour Ewing's Sarcoma PAX8

Eneman B, Mekahli D, Audrezet MP, et al.
An unusual presentation of Denys-Drash syndrome due to bigenic disease.
Pediatrics. 2014; 133(1):e252-6 [PubMed] Related Publications
We report a case of Denys-Drash syndrome (DDS) in a 3-month-old girl presenting with bilateral renal cortical cysts mimicking polycystic kidney disease. Genetic analysis revealed a de novo heterozygous missense mutation c.1186G>A (p.Asp396Asn) in the WT1 gene, confirming the diagnosis of DDS. Because multiple renal cysts have never been reported in DDS, we explored several genes responsible for these renal manifestations, such as HNF-1β, PAX2, PKD1, and PKD2. Remarkably, we identified a heterozygous missense variant c.12439A>G (p.Lys4147Glu) in the PKD1 gene. The same variant was found in the patient's mother, who had no renal cysts, and in the grandfather, who had several renal cysts. Mutation prediction programs classified the c.12439A>G variant as being "likely pathogenic." We hypothesize that the severe cystic phenotype in the index patient could be due to the WT1 mutation, enhancing pathogenicity of the "hypomorph" PKD1 allele. A possible role for Wilms tumor suppressor 1 (WT1) in renal cyst development should be considered. From a conceptual point of view, this case shows that an unusual presentation of a known genetic syndrome might point to bigenic inheritance, with unexpected interference of mutated genes causing an uncommon clinical phenotype.
Related: Denys-Drash Syndrome

Gnemmi V, Leroy X, Triboulet JP, et al.
Pancreatic metastases of renal clear cell carcinoma: a clinicopathological study of 11 cases with special emphasis on the usefulness of PAX2 and mesothelin for the distinction from primary ductal adenocarcinoma of the pancreas.
Anal Quant Cytopathol Histpathol. 2013; 35(3):157-62 [PubMed] Related Publications
OBJECTIVE: To determine whether PAX2 and mesothelin immunohistochemistry add additional diagnostic value in discriminating between pancreatic metastasis of renal clear cell carcinoma (PMRCC) and primary ductal adenocarcinoma of the pancreas (PDAC).
STUDY DESIGN: We retrospectively collected tissue from PMRCC and PDAC. Eleven cases of PMRCC registered at Lille University Hospitals from 2001 to 2010 were included. Eleven cases of PDAC were randomly selected from our files. A comparative immunohistochemical study with anti-PAX2, anti-mesothelin, and the classical renal antibodies anti-CD10 and anti-vimentin was performed on PMRCC and PDAC.
RESULTS: We found that PMRCC displays a clinical presentation that might mimic primary pancreatic tumor, as PMRCC presented as a solitary mass in 8 cases and appeared a long time after diagnosis of a renal tumor (12.8 years, mean for metachronous metastasis). By immunohistochemistry we observed that PAX2, mesothelin, CD10 and vimentin stainings were noted in 10/11 (91%), 0/11 (0%), 11/11 (100%) and 7/11 cases (64%), respectively, among 11 PMRCC cases. All PDACs displayed diffuse mesothelin (100%) expression without PAX2 and vimentin (0%) staining, whereas CD10 was noted in 4/11 cases (36%).
CONCLUSION: These data suggest that in difficult diagnostic cases both PAX2 and mesothelin immunohistochemical study may be useful in discriminating between PMRCC and primary pancreatic carcinoma.

Hsieh CH, Chen HC, Chang YH, et al.
Co-existence of epithelioid and fibroblastoid subsets in a sarcomatoid renal carcinoma cell line revealed by clonal studies.
Anticancer Res. 2013; 33(11):4875-89 [PubMed] Related Publications
BACKGROUND: The biology of sarcomatoid renal cell carcinoma (RCC) and its conversion from and to the clear cell RCC are not fully-understood. We aimed to analyze the sarcomatoid RCC cell line, RCC52, derived from a lymph node metastatic lesion consisting mostly of sarcomatoid RCC cells with occasional clear cell areas.
MATERIALS AND METHODS: Representative clonal epithelioid and fibroblastoid sublines isolated from the RCC52 cell line were analyzed alongside the parental line. Cytofluorometric and western blot analyses were used for phenotypic study. Xenotransplantation and in vitro invasive assays were used to determine tumorigenicity and invasiveness. Immunohistology in conjunction with antibodies to paired box gene-2 (PAX2) were used to determine if xenografts or tumor biopsies had the clear cell component.
RESULTS: RCC52 cells grown as monolayers in vitro were all PAX2-negative, and consisted mostly of epithelioid cells and partly of fibroblastoid cells as noted in a previous study, confirming the co-existence of these two cell types in the in vitro growth of exclusive sarcomatoid RCC cells. Immunohistology revealed that the parental line and all epithelioid sublines tested were able to develop into solid tumors consisting mostly of sarcomatoid cells with PAX2-positive clear cells in some areas. The RCC stem cell marker CD105 was selectively expressed by a small proportion of the epithelioid, but not fibroblastoid, sublines, which was in line with the tumorigenic property of the epithelioid sublines containing cancer stem cells (CSCs). In contrast, only fibroblastoid sublines exhibited migratory/invasive properties, as determined by in vitro assays.
CONCLUSION: Our findings confirm the presence of two distinct subsets in the RCC52 line, and suggest the epithelioid subset being able to de-differentiate to clear cells, albeit partially, and harboring CSCs as an emerging therapeutic target in order to achieve effective treatment of this malignancy.
Related: Kidney Cancer Soft Tissue Sarcomas

Gojis O, Kubecova M, Rosina J, et al.
Expression of selected proteins in breast cancer brain metastases.
Folia Histochem Cytobiol. 2013; 51(3):213-8 [PubMed] Related Publications
The aim of the study was to assess the immunohistochemical (IHC) profiles of SRC3, Pax2, ER, PgR, Her2, EGFR, CK5/6, and Ki67 proteins in breast-cancer brain metastasis. The study utilized tumor samples from 30 metastatic patients and calculated correlations between all IHC variables. In fourteen cases, primary breast cancers paired with secondary deposits were analyzed. We evaluated the association between IHC status in the primary and secondary deposits, grade, and histotype of the tumors. The examination of the metastatic deposits in all 30 patients resulted in positive detection in the following cases: SRC3 in 20 cases (66.6%), Pax2 in 22 (73.3%), ER in 22 (73.3%), PgR in 25 (83.3%), Her2 in 10 (33.3%), EGFR in 12 (40%), CK5/6 in 7 (23.3%), and Ki67 in 23 (76.6%). Grade 2 was found in 13.3% of all patients, and grade 3 in 86.7%. SRC3 and Pax2 were positive in both G2 and G3. Invasive lobular carcinoma and invasive ductal carcinoma were diagnosed in 23.3% and 76.7% of cases, respectively. There were no differences between the IHC expression of the studied proteins in either grading or histotype of the tumors. In the IHC profiles, which included SRC3, Pax2, ER, PgR, Her2, CK5/6, Ki67, and EGFR, we found no statistically significant differences between the primary cancer and the brain metastasis. In our study of metastatic breast carcinoma deposits, there was no correlation between SRC3, Pax2 status and histotype, and tumor grade. The IHC status of the paired primary and metastatic deposits did not differ in a statistically significant manner.
Related: Breast Cancer MKI67

Jiang JG, Rao Q, Xia QY, et al.
Sporadic hemangioblastoma of the kidney with PAX2 and focal CD10 expression: report of a case.
Int J Clin Exp Pathol. 2013; 6(9):1953-6 [PubMed] Free Access to Full Article Related Publications
In this study, we presented an additional case of renal hemangioblastoma, which demonstrates PAX2 and focal CD10 expression. Histologically, the tumor consisted of sheets of oval or polygonal cells and a prominent vascular network. The tumor cells varied in size, and possessed pale or eosinophilic cytoplasm that sometimes contained sharply delineated fine vacuoles. The tumor cell nuclei with inconspicuous nucleoli showed moderate nuclear atypia and pleomorphism. Focal areas of stromal hyalinization and sclerosis were detected. On account of its strong or moderate immunoreactivity for the a-inhibin, S100, NSE, and EGFR, the diagnosis of renal hemangioblastoma was established. For further evidence of VHL deficiency, the tumor was subjected to VHL sequence analysis of all three exons and fluorescence in situ hybridization (FISH) detection for chromosome 3p deletion. None of the VHL gene mutations and chromosome 3p deletion was detected in the tumor. Because of several shared morphological and immunophenotypic features, renal hemangioblastoma may be underrecognized and should be included in the differential diagnosis of primary renal tumors, in particular clear cell renal cell carcinoma. The unexpected positive staining of PAX2 and CD10 in renal hemangioblastoma should be particular concerned. Using a combination of immunoprofile may be helpful to the differential diagnosis of these renal tumors.
Related: Chromosome 3 FISH Kidney Cancer VHL

Crum CP, Herfs M, Ning G, et al.
Through the glass darkly: intraepithelial neoplasia, top-down differentiation, and the road to ovarian cancer.
J Pathol. 2013; 231(4):402-12 [PubMed] Free Access to Full Article Related Publications
It is currently hoped that deaths from extra-uterine high-grade serous cancer (HGSC) will be reduced via opportunistic salpingectomy in healthy women. Accumulated data implicate the fimbria as a site of origin and descriptive molecular pathology and experimental evidence strongly support a serous carcinogenic sequence in the Fallopian tube. Both direct and indirect ('surrogate') precursors suggest that the benign tube undergoes important biological changes after menopause, acquiring abnormalities in gene expression that are often shared with malignancy, including PAX2, ALDH1, LEF1, RCN1, RUNX2, beta-catenin, EZH2, and others. However, the tube can be linked to only some HGSCs, recharging arguments that nearby peritoneum/ovarian surface epithelium (POSE) also hosts progenitors to this malignancy. A major sticking point is the difference in immunophenotype between POSE and Müllerian epithelium, essentially requiring mesothelial to Müllerian differentiation prior to or during malignant transformation to HGSC. However, emerging evidence implicates an embryonic or progenitor phenotype in the adult female genital tract with the capacity to differentiate, normally or during neoplastic transformation. Recently, a putative cell of origin for cervical cancer has been identified in the squamo-columnar (SC) junction, projecting a model whereby Krt7+ embryonic progenitors give rise to immunophenotypically distinct progeny under stromal influences via 'top down' differentiation. Similar differentiation can be seen in the endometrium with a parallel in juxtaposed mesothelial and Müllerian differentiation in the ovary. Abrupt mesothelial-Müllerian transitions remain to be proven, but would explain the rapid evolution, short asymptomatic interval, and absence of a defined epithelial starting point in many HGSCs. Resolving this question will require accurately distinguishing progenitor from progeny tumour cells in HGSC and pinpointing where initial transformation and trans-differentiation occur, whether in the tube or POSE. Both will be critical to expectations from prophylactic salpingectomy and future approaches to pelvic serous cancer prevention.
Related: Fallopian Tube Cancer Ovarian Cancer Cervical Cancer

Pan Z, Grizzle W, Hameed O
Significant variation of immunohistochemical marker expression in paired primary and metastatic clear cell renal cell carcinomas.
Am J Clin Pathol. 2013; 140(3):410-8 [PubMed] Related Publications
OBJECTIVES: To compare the immunohistochemical expression of diagnostic markers in primary clear cell renal cell carcinomas (RCCs) and their matched metastases.
METHODS: Tissue microarrays were constructed from 15 pairs of primary and metastatic clear cell RCCs and then evaluated for the immunohistochemical expression of renal cell carcinoma antigen (RCCA), kidney-specific cadherin, carbonic anhydrase IX (CAIX), and paired box genes 2 (PAX2) and 8 (PAX8).
RESULTS: There was significantly higher overall marker expression in metastatic tumors compared to their matched primaries (P < .001). Individually, there was greater CAIX, PAX2, and PAX8 expression and lower RCCA expression in metastatic tumors. Most importantly, a significant proportion of originally RCCA-positive tumors lost such expression in metastases.
CONCLUSIONS: Metastatic RCCs have significantly higher expression of PAX2 and PAX8 compared to primary RCCs. RCCA is not very reliable in this diagnostic setting, both because of its lower overall sensitivity and loss of expression in metastatic RCCs.
Related: Kidney Cancer PAX8

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Cite this page: Cotterill SJ. PAX2, Cancer Genetics Web: http://www.cancer-genetics.org/PAX2.htm Accessed:

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