MDM4

Gene Summary

Gene:MDM4; MDM4, p53 regulator
Aliases: HDMX, MDMX, MRP1
Location:1q32
Summary:This gene encodes a nuclear protein that contains a p53 binding domain at the N-terminus and a RING finger domain at the C-terminus, and shows structural similarity to p53-binding protein MDM2. Both proteins bind the p53 tumor suppressor protein and inhibit its activity, and have been shown to be overexpressed in a variety of human cancers. However, unlike MDM2 which degrades p53, this protein inhibits p53 by binding its transcriptional activation domain. This protein also interacts with MDM2 protein via the RING finger domain, and inhibits the latter's degradation. So this protein can reverse MDM2-targeted degradation of p53, while maintaining suppression of p53 transactivation and apoptotic functions. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Feb 2011]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:protein Mdm4
HPRD
Source:NCBIAccessed: 06 August, 2015

Ontology:

What does this gene/protein do?
Show (16)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 06 August 2015 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.

Tag cloud generated 06 August, 2015 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
Breast CancerMDM4 and Breast Cancer View Publications28
Soft Tissue SarcomaMDM4 and Soft Tissue Sarcoma View Publications17
RetinoblastomaMDM4 and Retinoblastoma
The penetrance of the RB1 mutation in retinoblastoma is thought to be dependent on concurrent genetic modifiers, in particular MDM2 and MDM4. de Oliveira Reis AH et al, 2012 reported findings that suggest that MDM2 and MDM4 polymorphisms may influence development and survival in Retinoblastoma.
View Publications13
Brain Tumours, ChildhoodMDM4 and Brain Tumours View Publications12

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

Latest Publications: MDM4 (cancer-related)

Grawenda AM, Møller EK, Lam S, et al.
Interaction between p53 mutation and a somatic HDMX biomarker better defines metastatic potential in breast cancer.
Cancer Res. 2015; 75(4):698-708 [PubMed] Related Publications
TP53 gene mutation is associated with poor prognosis in breast cancer, but additional biomarkers that can further refine the impact of the p53 pathway are needed to achieve clinical utility. In this study, we evaluated a role for the HDMX-S/FL ratio as one such biomarker, based on its association with other suppressor mutations that confer worse prognosis in sarcomas, another type of cancer that is surveilled by p53. We found that HDMX-S/FL ratio interacted with p53 mutational status to significantly improve prognostic capability in patients with breast cancer. This biomarker pair offered prognostic utility that was comparable with a microarray-based prognostic assay. Unexpectedly, the utility tracked independently of DNA-damaging treatments and instead with different tumor metastasis potential. Finally, we obtained evidence that this biomarker pair might identify patients who could benefit from anti-HDM2 strategies to impede metastatic progression. Taken together, our work offers a p53 pathway marker, which both refines our understanding of the impact of p53 activity on prognosis and harbors potential utility as a clinical tool.

Park YH, Jung HH, Do IG, et al.
A seven-gene signature can predict distant recurrence in patients with triple-negative breast cancers who receive adjuvant chemotherapy following surgery.
Int J Cancer. 2015; 136(8):1976-84 [PubMed] Related Publications
The aim of this study was to investigate candidate genes that might function as biomarkers to differentiate triple negative breast cancers (TNBCs) among patients, who received adjuvant chemotherapy after curative surgery. We tested whether the results of a NanoString expression assay that targeted 250 prospectively selected genes and used mRNA extracted from formalin-fixed, paraffin-embedded would predict distant recurrence in patients with TNBC. The levels of expression of seven genes were used in a prospectively defined algorithm to allocate each patient to a risk group (low or high). NanoString expression profiles were obtained for 203 tumor tissue blocks. Increased expressions of the five genes (SMAD2, HRAS, KRT6A, TP63 and ETV6) and decreased expression of the two genes (NFKB1 and MDM4) were associated favorable prognosis and were validated with cross-validation. The Kaplan-Meier estimates of the rates of distant recurrence at 10 years in the low- and high-risk groups according to gene expression signature were 62% [95% confidence interval (CI), 48.6-78.9%] and 85% (95% CI, 79.2-90.7%), respectively. When adjusting for TNM stage, the distant recurrence-free survival (DRFS)s in the low-risk group was significantly longer than that in the high-risk group (p <0.001) for early stage (I and II) and advanced stage (III) tumors. In a multivariate Cox regression model, the gene expression signature provided significant predictive power jointly with the TNM staging system. A seven-gene signature could be used as a prognostic model to predict DRFS in patients with TNBC who received curative surgery followed by adjuvant chemotherapy.

Ling X, Xu C, Fan C, et al.
FL118 induces p53-dependent senescence in colorectal cancer cells by promoting degradation of MdmX.
Cancer Res. 2014; 74(24):7487-97 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
Anticancer agent FL118 was recently identified in screening of small-molecule inhibitors of human survivin expression. Although FL118 is a camptothecin analogue, its antitumor potency is much superior to other FDA-approved camptothecin analogues (irinotecan and topotecan). The mechanism of action (MOA) underlying the antitumor effects of FL118 remains to be fully elucidated. Here, we report that FL118 activates tumor suppressor p53 as a novel MOA in p53 wild-type cancer cells. Our studies show that this MOA involves an induction of proteasomal degradation of MdmX, a critical negative regulator of p53, in a manner largely independent of ATM-dependent DNA damage signaling pathway but dependent on E3-competent Mdm2. FL118 inhibits p53 polyubiquitination and monoubiquitination by Mdm2-MdmX E3 complex in cells and in cell-free systems. In contrast, FL118 stimulates Mdm2-mediated MdmX ubiquitination. Coimmunoprecipitation revealed that FL118 slightly decreases Mdm2-p53 interactions and moderately increases Mdm2-MdmX interactions, suggesting a change of targeting specificity of Mdm2-MdmX E3 complex from p53 to MdmX, resulting in accelerated MdmX degradation. As a result, p53 ubiquitination by Mdm2-MdmX E3 complex is reduced, which in turn activates p53 signaling. Activation of the p53 pathway by FL118 induces p53-dependent senescence in colorectal cancer cells. However, in the absence of p53 or in the presence of MdmX overexpression, FL118 promotes p53-independent apoptosis. These two distinct cellular consequences collectively contribute to the potent effects of FL118 to inhibit clonogenic potential of colon cancer cells. This study identifies a potential application of FL118 as an MdmX inhibitor for targeted therapies.

Zawacka-Pankau J, Selivanova G
Pharmacological reactivation of p53 as a strategy to treat cancer.
J Intern Med. 2015; 277(2):248-59 [PubMed] Related Publications
It has been confirmed through studies using the technique of unbiased sequencing that the TP53 tumour suppressor is the most frequently inactivated gene in cancer. This finding, together with results from earlier studies, provides compelling evidence for the idea that p53 ablation is required for the development and maintenance of tumours. Genetic reconstitution of the function of p53 leads to the suppression of established tumours as shown in mouse models. This strongly supports the notion that p53 reactivation by small molecules could provide an efficient strategy to treat cancer. In this review, we summarize recent advances in the development of small molecules that restore the function of mutant p53 by different mechanisms, including stabilization of its folding by Apr-246, which is currently being tested in a Phase II clinical trial. We discuss several classes of compounds that reactivate wild-type p53, such as Mdm2 inhibitors, which are currently undergoing clinical testing, MdmX inhibitors and molecules targeting factors upstream of Mdm2/X or p53 itself. Finally, we consider the clinical applications of compounds targeting p53 and the p53 pathway.

Kong LY, Wei J, Haider AS, et al.
Therapeutic targets in subependymoma.
J Neuroimmunol. 2014; 277(1-2):168-75 [PubMed] Related Publications
Subependymomas are usually treated with surgical resection; however, no standard, defined alternative medical therapy is recommended for patients who are not surgical candidates, owing to a paucity of molecular, immunological, and genetic characterization. To address this, an ex vivo functional analysis of the immune microenvironment in subependymoma was conducted, a subependymoma cytokine/chemokine microarray was constructed for the evaluation of operational immune and molecular pathways, and a subependymoma cell line was derived and used to test a variety of cytotoxic agents that target operational pathways identified in subependymoma. We found that immune effectors are detectable within the microenvironment of subependymoma; however, marked immune suppression is not observed. The subependymoma tissue microarrays demonstrated tumor expression of p53, MDM2, HIF-1α, topoisomerase II-β, p-STAT3, and nucleolin, but not EGFRvIII, EphA2, IL-13RA2, CMV, CTLA-4, FoxP3, PD-1, PD-L1, EGFR, PDGF-α, PDGF-β, PDGFR-α, PDGFR-β, PTEN, IGFBP2, PI3K, MDM4, IDH1, mTOR, or Jak2. A topoisomerase inhibitor (WP744, IC50=0.83 μM) and a p-STAT3/HIF-1α inhibitor (WP1066, IC50=3.15 μM) demonstrated a growth inhibition of the subependymoma cell proliferation. Cumulatively, these data suggest that those agents that interfere with oncogenes operational in subependymoma may have clinical impact.

Duffy MJ, Synnott NC, McGowan PM, et al.
p53 as a target for the treatment of cancer.
Cancer Treat Rev. 2014; 40(10):1153-60 [PubMed] Related Publications
TP53 (p53) is the most frequently mutated gene in cancer, being altered in approximately 50% of human malignancies. In most, if not all, cancers lacking mutation, wild-type (WT) p53 is inactivated by interaction with cellular (MDM2/MDM4) or viral proteins, leading to its degradation. Because of its near universal alteration in cancer, p53 is an attractive target for the development of new targeted therapies for this disease. However, until recently, p53 was widely regarded as ‘‘undruggable’’. This situation has now changed, as several compounds have become available that can restore wild-type properties to mutant p53 (e.g., PRIMA-1 and PRIMA-1MET). Other compounds are available that prevent the binding of MDM2/MDM4 to WT p53, thereby blocking its degradation (e.g., nutlins). Anti-mutant p53 compounds are potentially most useful in cancers with a high prevalence of p53 mutations. These include difficult-totreat tumors such as high grade serous ovarian cancer, triple-negative breast cancer and squamous lung cancer. MDM2/4 antagonists, on the other hand, are likely to be efficacious in malignancies in which MDM2 or MDM4 is overexpressed such as sarcomas, neuroblastomas and specific childhood leukemias. Presently, early clinical trials are ongoing evaluating the anti-mutant p53 agent, PRIMA-1MET, and specific MDM2–p53 nutlin antagonists.

Ling S, Tian Y, Zhang H, et al.
Metformin reverses multidrug resistance in human hepatocellular carcinoma Bel‑7402/5‑fluorouracil cells.
Mol Med Rep. 2014; 10(6):2891-7 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
Metformin exhibits anti‑proliferative effects in tumor cells in vitro and in vivo. The present study investigated the ability of metformin to reverse multidrug resistance (MDR) in human hepatocellular carcinoma Bel‑7402/5‑fluorouracil (5‑Fu; Bel/Fu) cells. The synergistic anti‑proliferative effect of metformin combined with 5‑Fu was evaluated using a Cell Counting kit‑8 assay. The variation in apoptotic rates and cell cycle distribution were evaluated using a flow cytometric assay and variations in target gene and protein expression were monitored using reverse transcription‑polymerase chain reaction and western blot analysis. The results demonstrated that metformin had a synergistic anti‑proliferative effect with 5‑Fu in the Bel/Fu cells. The variations in the number of apoptotic cells and distribution of the cell cycle were consistent with the variability in cell viability. Metformin targeted the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway, suppressed the expression of hypoxia‑inducible factor‑1α (HIF‑1α) and transcriptionally downregulated the expression of multidrug resistance protein 1/P‑glycoprotein (P‑gp) and multidrug resistance‑associated protein 1 (MRP1). Collectively, these findings suggested that metformin may target the AMPK/mTOR/HIF‑1α/P‑gp and MRP1 pathways to reverse MDR in hepatocellular carcinoma.

Warta R, Theile D, Mogler C, et al.
Association of drug transporter expression with mortality and progression-free survival in stage IV head and neck squamous cell carcinoma.
PLoS One. 2014; 9(9):e108908 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
Drug transporters such as P-glycoprotein (ABCB1) have been associated with chemotherapy resistance and are considered unfavorable prognostic factors for survival of cancer patients. Analyzing mRNA expression levels of a subset of drug transporters by quantitative reverse transcription polymerase chain reaction (qRT-PCR) or protein expression by tissue microarray (TMA) in tumor samples of therapy naïve stage IV head and neck squamous cell carcinoma (HNSCC) (qRT-PCR, n = 40; TMA, n = 61), this in situ study re-examined the significance of transporter expression for progression-free survival (PFS) and overall survival (OS). Data from The Cancer Genome Atlas database was used to externally validate the respective findings (n = 317). In general, HNSCC tended to lower expression of drug transporters compared to normal epithelium. High ABCB1 mRNA tumor expression was associated with both favorable progression-free survival (PFS, p = 0.0357) and overall survival (OS, p = 0.0535). Similar results were obtained for the mRNA of ABCC1 (MRP1, multidrug resistance-associated protein 1; PFS, p = 0.0183; OS, p = 0.038). In contrast, protein expression of ATP7b (copper transporter ATP7b), mRNA expression of ABCG2 (BCRP, breast cancer resistance protein), ABCC2 (MRP2), and SLC31A1 (hCTR1, human copper transporter 1) did not correlate with survival. Cluster analysis however revealed that simultaneous high expression of SLC31A1, ABCC2, and ABCG2 indicates poor survival of HNSCC patients. In conclusion, this study militates against the intuitive dogma where high expression of drug efflux transporters indicates poor survival, but demonstrates that expression of single drug transporters might indicate even improved survival. Prospectively, combined analysis of the 'transportome' should rather be performed as it likely unravels meaningful data on the impact of drug transporters on survival of patients with HNSCC.

Fan C, Wei J, Yuan C, et al.
The functional TP53 rs1042522 and MDM4 rs4245739 genetic variants contribute to Non-Hodgkin lymphoma risk.
PLoS One. 2014; 9(9):e107047 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
As a heterogeneous kind of malignances, Non-Hodgkin lymphoma (NHL) is the most common hematologic cancer worldwide with the significantly increased morbidity in China. Accumulated evidences demonstrated that oncoprotein MDM4 plays a crucial role in the TP53 tumor suppressor signaling pathway. An rs4245739 A>C polymorphism locating in the MDM4 3'-untranslated region creates a miR-191 target site and results in allele-specific MDM4 expression. In this study, we examined the association between this polymorphism as well as the TP53 Arg72Pro (rs1042522 G>C) genetic variant and Non-Hodgkin Lymphoma (NHL) risk in a Chinese Han population. Genotypes were determined in 200 NHL cases and 400 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression. We found significantly increased NHL risk among carriers of the TP53 72Pro allele compared with those with the 72Arg allele (P = 0.002 for the Pro/Pro genotype). We also observed a significantly decreased NHL risks among carriers of the MDM4 rs4245739 C allele compared with those with the A allele in Chinese (P = 0.014 for the AC genotype). Stratified analyses revealed the associations between these SNPs and NHL risk are especially noteworthy in young or male individuals. Additionally, the associations are much pronounced in NHL patients with B-cell lymphomas or grade 3 or 4 disease. Our results indicate that the TP53 Arg72Pro and the MDM4 rs4245739 polymorphisms contribute to NHL susceptibility and support the hypothesis that genetic variants in the TP53 pathway genes can act as important modifiers of NHL risk.

Zhang Q, Zeng SX, Lu H
Targeting p53-MDM2-MDMX loop for cancer therapy.
Subcell Biochem. 2014; 85:281-319 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
The tumor suppressor p53 plays a central role in anti-tumorigenesis and cancer therapy. It has been described as "the guardian of the genome", because it is essential for conserving genomic stability by preventing mutation, and its mutation and inactivation are highly related to all human cancers. Two important p53 regulators, MDM2 and MDMX, inactivate p53 by directly inhibiting its transcriptional activity and mediating its ubiquitination in a feedback fashion, as their genes are also the transcriptional targets of p53. On account of the importance of the p53-MDM2-MDMX loop in the initiation and development of wild type p53-containing tumors, intensive studies over the past decade have been aiming to identify small molecules or peptides that could specifically target individual protein molecules of this pathway for developing better anti-cancer therapeutics. In this chapter, we review the approaches for screening and discovering efficient and selective MDM2 inhibitors with emphasis on the most advanced synthetic small molecules that interfere with the p53-MDM2 interaction and are currently on Phase I clinical trials. Other therapeutically useful strategies targeting this loop, which potentially improve the prospects of cancer therapy and prevention, will also be discussed briefly.

Zhang ZD, Li Y, Fan Q, et al.
Annexin A2 is implicated in multi-drug-resistance in gastric cancer through p38MAPK and AKT pathway.
Neoplasma. 2014; 61(6):627-37 [PubMed] Related Publications
Studies have shown that Annexin A2 (ANXA2) is related with tumor proliferation, apoptosis, differentiation, invasion, migration, and drug resistance. The purpose of this study was to investigate the role and its mechanisms of ANXA2 in multi-drug-resistance (MDR) in gastric cancer. ANXA2 expression in both gastric cancer tissues and cell lines were detected by quantitative real-time PCR (RT-qPCR) and Western blotting. The cell proliferation was measured by SRB assay. The pool of siRNA against ANXA2 was designed and synthesized and then transfected into resistant gastric cancer SGC7901/DDP cells. ANXA2 expression was detected by RT-qPCR and Western blotting. Drug sensitivities of SGC7901/DDP cells to P-gp-related drug (doxorubicin) and P-gp-non-related drugs (5-FU and cisplatin) were measured by SRB assay. Expression of MDR-related genes and phosphorylation of AKT and MAPKs were also detected by RT-qPCR and Western blotting. Results showed that ANXA2 expression was significantly higher in gastric specimens than that in normal tissues, and negatively correlated with the differentiation level of gastric cancer. In addition, ANXA2 expression level was higher in SGC7901/DDP cells than that in parent SGC7901 cells. After knock-down ANXA2 expression using ANXA2 small interfering RNA, the drug sensitivity of SGC7901/DDP cells to doxorubicin, 5-FU and DDP increased. Delivery of ANXA2 siRNA significantly downregulated the expression of P-gp, MRP1 and Bcl-2, while markedly upregulated Bax in SGC7901/DDP cells. However, several other MDR factors such as GST-π, TOPO-I and TOPO-II had no obvious changes. Additionally, phosphorylation of P38MAPK and AKT, but not ERK1/2 or JNKs was specifically decreased in SGC7901/DDP cells after ANXA2 siRNA delivery. Importantly, P38MAPK and AKT inhibitor increased the drug sensitivity of SGC701/DDP cells in a similar way as ANXA2 siRNAs does. ANXA2 is involved in gastric cancer MDR through regulating p38MAPK and AKT pathways as well as certain MDR factors.

Zhu H, Chen X, Chen B, et al.
Activating transcription factor 4 mediates a multidrug resistance phenotype of esophageal squamous cell carcinoma cells through transactivation of STAT3 expression.
Cancer Lett. 2014; 354(1):142-52 [PubMed] Related Publications
Multidrug resistance (MDR) is a major challenge to the clinical treatment of esophageal cancer. The stress response gene activating transcription factor 4 (ATF4) is involved in homeostasis and cellular protection. However, relatively little is known about the expression and function of ATF4 in esophageal squamous cell carcinoma (ESCC) MDR. In this study, we investigate the potential role and mechanisms of ATF4 in ESCC MDR. We demonstrated that overexpression of ATF4 promotes the MDR phenotype in ESCC cells, while depletion of ATF4 in the MDR ESCC cell line induces drug re-sensitization. We also demonstrated that ATF4 transactivates STAT3 expression by directly binding to the signal transducers and activators of transcription 3 (STAT3) promoter, resulting in MDR in ESCC cells. Significantly, inhibition of STAT3 by small interfering RNA (siRNA) or a selective inhibitor (JSI-124) reintroduces therapeutic sensitivity. In addition, increased Bcl-2, survivin, and MRP1 expression levels were observed in ATF4-overexpressing cells. In conclusion, ATF4 may promote MDR in ESCC cells through the up-regulation of STAT3 expression, and thus is an attractive therapeutic target to combat therapeutic resistance in ESCC.

Benabbou N, Mirshahi P, Bordu C, et al.
A subset of bone marrow stromal cells regulate ATP-binding cassette gene expression via insulin-like growth factor-I in a leukemia cell line.
Int J Oncol. 2014; 45(4):1372-80 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
The importance of the insulin-like growth factor, IGF, as a signaling axis in cancer development, progression and metastasis is highlighted by its effects on cancer cells, notably proliferation and acquired resistance. The role of the microenvironment within which cancer cells evolve and which mediates this effect is far from clear. Here, the involvement of IGF-I in inducing multidrug resistance in a myeloid leukemia cell line, grown in the presence of bone marrow-derived stromal cells called 'Hospicells' (BMH), is demonstrated. We found that i) drug sensitive as well as resistant leukemia cells express IGF-I and its receptor IGF-IR. However, the resistant cells were found to secrete high levels of IGF-I. ii) Presence of exogenous IGF-I promoted cell proliferation, which decreased when an inhibitor of IGF-IR (picropodophyllin, PPP) was added. iii) BMH and IGF-I are both involved in the regulation of genes of the ATP binding cassette (ABC) related to resistance development (MDR1, MRP1, MRP2, MRP3 and BCRP). iv) The levels of ABC gene expression by leukemia cells were found to increase in the presence of increasing numbers of BMH. However, these levels decreased when IGF-IR was inhibited by addition of PPP. v) Co-culture of the drug-sensitive leukemia cells with BMH induced protection against the action of daunorubicin. This chemoresistance was amplified by the presence of IGF-I whereas it decreased when IGF-IR was inhibited. Our results underline the role of microenvironment in concert with the IGF-1 pathway in conferring drug resistance to leukemia cells.

Au A, Baba AA, Azlan H, et al.
Clinical impact of ABCC1 and ABCC2 genotypes and haplotypes in mediating imatinib resistance among chronic myeloid leukaemia patients.
J Clin Pharm Ther. 2014; 39(6):685-90 [PubMed] Related Publications
WHAT IS KNOWN AND OBJECTIVE: The introduction and success of imatinib mesylate (IM) has brought about a paradigm shift in chronic myeloid leukaemia (CML) treatment. However, despite the high efficacy of IM, clinical resistance develops due to a heterogeneous array of mechanisms. Pharmacogenetic variability as a result of genetic polymorphisms could be one of the most important factors influencing resistance to IM. The aim of this study was to investigate the association between genetic variations in drug efflux transporter ABCC1 (MRP1) and ABCC2 (MRP2) genes and response to IM in patients with CML.
METHODS: We genotyped 215 Malaysian patients with CML (comprising of two groups with 108 IM resistant and 107 IM responsive) for polymorphisms of ABCC1 (2012G>T and 2168G>A) and ABCC2 (-24C>T, 1249G>A and 3972C>T) genes. Genotype, allele and haplotype frequencies were compared between two groups of patients. Patients with CML were further stratified according to their clinical response to IM into those having cytogenetics and molecular responses, and the associations with genotypes were evaluated.
RESULTS AND DISCUSSION: We observed no significant differences in the distribution of any of the tested genotypes between the investigated groups. However, on evaluating the risk association, ABCC2 T₋₂₄ G₁₂₄₉ T₃₉₇₂ haplotype was found to be associated with IM resistance (P = 0·046). These results suggest that haplotype variants -24T and 3972T might be associated with lower expression of ABCC2 protein and reduced transport activity and hence might be contributing to development of IM resistance.
WHAT IS NEW AND CONCLUSION: Our results suggest the ABCC2 T₋₂₄ G₁₂₄₉ T₃₉₇₂ haplotype was associated with imatinib resistance. However, the evidence is as yet insufficient to establish this haplotype as a predictive biomarker for response to the drug.

Salvi S, Calistri D, Gurioli G, et al.
Copy number analysis of 24 oncogenes: MDM4 identified as a putative marker for low recurrence risk in non muscle invasive bladder cancer.
Int J Mol Sci. 2014; 15(7):12458-68 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
Patients with non-muscle invasive bladder cancer (NMIBC) generally have a high risk of relapsing locally after primary tumor resection. The search for new predictive markers of local recurrence thus represents an important goal for the management of this disease. We studied the copy number variations (CNVs) of 24 oncogenes (MDM4, MYCN, ALK, PDGFRA, KIT, KDR, DHFR, EGFR, MET, SMO, FGFR1, MYC, ABL1, RET, CCND1, CCND2, CDK4, MDM2, AURKB, ERBB2, TOP2A, AURKA, AR and BRAF) using multiplex ligation probe amplification technique to verify their role as predictive markers of recurrence. Formalin-fixed paraffin-embedded tissue samples from 43 patients who underwent transurethral resection of the bladder (TURB) were used; 23 patients had relapsed and 20 were disease-free after 5 years. Amplification frequencies were analyzed for all genes and MDM4 was the only gene that showed significantly higher amplification in non recurrent patients than in recurrent ones (0.65 vs. 0.3; Fisher's test p=0.023). Recurrence-free survival analysis confirmed the predictive role of MDM4 (log-rank test p=0.041). Our preliminary results indicate a putative role for the MDM4 gene in predicting local recurrence of bladder cancer. Confirmation of this hypothesis is needed in a larger cohort of NMIBC patients.

Xu H, Zhou P, Ti Y, Jia F
Quantitative assessment of the association between HDMX polymorphism and sarcoma.
Cell Biochem Biophys. 2014; 70(3):1671-6 [PubMed] Related Publications
To investigate the effects of the HDMX polymorphism on sarcoma risk. Relevant studies were identified by searching the PubMed, Embase, and Web of Science databases. Data were extracted by two independent investigators. Odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated using a fixed-effects model to assess the association between the HDMX polymorphism and sarcoma risk. We also conducted heterogeneity test, sensitivity analysis, and publication bias test. A meta-analysis of four published case-control studies involving 1,115 subjects (379 cases and 736 controls) showed no statistical association between the HDMX polymorphism and sarcoma risk (ORTT vs. GG 0.88, 95 % CI 0.68-1.14, P heterogeneity 0.819; ORTT + TG vs. GG 0.95, 95 % CI 0.79-1.15, P heterogeneity 0.937; ORTT vs. TG + GG 0.82, 95 % CI 0.65-1.04, P heterogeneity 0.589; ORT allele vs. G allele 0.91, 95 % CI 0.79-1.05, P heterogeneity 0.727; ORTG vs. GG 0.95, 95 % CI 0.74-1.22, P heterogeneity = 0.869). This null result did not alter when data were stratified according to ethnicity. Our meta-analysis indicates that the HDMX polymorphism is unlikely to contribute to individual susceptibility to sarcoma.

Ma H, Zhou H, Li P, et al.
Effect of ST3GAL 4 and FUT 7 on sialyl Lewis X synthesis and multidrug resistance in human acute myeloid leukemia.
Biochim Biophys Acta. 2014; 1842(9):1681-92 [PubMed] Related Publications
Sialyl Lewis X (sLe X, CD15s) is a key antigen produced on tumor cell surfaces during multidrug resistance (MDR) development. The present study investigated the effect of α1, 3 fucosyltransferase VII (FucT VII) and α2, 3 sialyltransferase IV (ST3Gal IV) on sLe X oligosaccharides synthesis as well as their impact on MDR development in acute myeloid leukemia cells (AML). FUT7 and ST3GAL4 were overexpressed in three AML MDR cells and bone marrow mononuclear cells (BMMC) of AML patients with MDR by real-time polymerase chain reaction (PCR). A close association was found between the expression levels of FUT7 and ST3GAL4 and the amount of sLe X oligosaccharides, as well as the phenotypic variation of MDR of HL60 and HL60/ADR cells both in vitro and in vivo. Manipulation of these two genes' expression modulated the activity of phosphoinositide-3 kinase (PI3K)/Akt signaling pathway, thereby regulating the proportionally mutative expression of P-glycoprotein (P-gp) and multidrug resistance related protein 1 (MRP1), both of which are known to be involved in MDR. Blocking the PI3K/Akt pathway by its specific inhibitor LY294002 or Akt short hairpin RNA (shRNA) resulted in the reduced MDR of HL60/ADR cells. This study indicated that sLe X involved in the development of MDR of AML cells probably through FUT7 and ST3GAL4 regulating the activity of PI3K/Akt signaling pathway and the expression of P-gp and MRP1.

Xing Y, Wang ZH, Ma DH, Han Y
FTY720 enhances chemosensitivity of colon cancer cells to doxorubicin and etoposide via the modulation of P-glycoprotein and multidrug resistance protein 1.
J Dig Dis. 2014; 15(5):246-59 [PubMed] Related Publications
OBJECTIVE: This study aimed to investigate the effects of FTY720 on inducing cell growth inhibition and enhancing the cytotoxicity of anti-cancer drugs in the human colon cancer cell line HCT-8 and its multidrug-resistant cell line HCT-8/5-fluorouracil (HCT-8/5-Fu).
METHODS: Cell viability and apoptosis after being treated with FTY720 alone or in combination with doxorubicin (DOX) and etoposide (VP16) were tested in HCT-8 and HCT-8/5-Fu cells. The changes in P-glycoprotein (P-gp) and multidrug resistance protein 1 (MRP1) were determined at the mRNA and functional levels.
RESULTS: FTY720 showed anti-proliferative activity against cancer cells in a dose-dependent and time-dependent manner and could enhance the cytotoxicity of DOX and VP16 in both HCT-8 and HCT-8/5-Fu cell lines. In addition, treatment with FTY720 resulted in the promotion of VP16-induced cell apoptosis and an increased accumulation of intracellular DOX and two specific fluorescent substrates of P-gp and MRP1 through the inhibition of efflux and the suppression of gene expression.
CONCLUSION: FTY720 exerts its chemosensitization effect in HCT-8 and HCT-8/5-Fu cell lines by promoting cell apoptosis and inhibiting P-gp and MRP1, which could be applied as a potential co-adjuvant therapeutic modality.

Lu M, Miller P, Lu X
Restoring the tumour suppressive function of p53 as a parallel strategy in melanoma therapy.
FEBS Lett. 2014; 588(16):2616-21 [PubMed] Related Publications
The tumour suppressor p53 is a master sensor of stress and it controls the expression of hundreds to thousands of genes with diverse biological functions including cell cycle arrest, apoptosis, and senescence. Consequently p53 is the most mutated gene found in human cancer and p53 mutation rate varies from 5% to 95%. Importantly p53 activity is often inactivated in tumours expressing structurally wild type p53. Thus one of the major challenges in cancer research is to restore the tumour suppressive function of p53. Intensive studies in the past decade have demonstrated that in addition to mutation, p53 activities are largely regulated by cellular factors that control the expression level and/or transcriptional activities of p53. MDM2, MDM4, p14(ARF) and the ASPP family of proteins are among the most studied regulators of p53. With increased understanding of the complexity of p53 regulation, various p53 reactivating approaches are being developed. This review will focus on the recent understanding of p53 inactivation in melanoma and the approaches to reactivate p53 in preclinical studies. Recent success in the therapeutic targeting of the BRAFV600E oncogenic protein was accompanied with subsequent relapse caused by acquired drug resistance. Restoration of the tumour suppressive function of p53 presents a parallel cancer therapeutic opportunity alongside BRAFV600E inhibition. Thus targeted therapy and concurrent reactivation of p53 may be a fertile ground to achieve synergistic killing of the 50% of cancer cells that express structurally wild type p53.

Tan WJ, Lai JC, Thike AA, et al.
Novel genetic aberrations in breast phyllodes tumours: comparison between prognostically distinct groups.
Breast Cancer Res Treat. 2014; 145(3):635-45 [PubMed] Related Publications
Phyllodes tumours of the breast are uncommon fibroepithelial neoplasms which pose management challenges due to difficulties in accurate prediction of clinical behaviour, as histological assessment has its limitations. Molecular studies have improved the understanding of these rare tumours but such findings are scant. We aimed to investigate genetic aberrations in phyllodes tumours stratified according to clinical behaviour, to identify potential genes contributing to disease progression. Twenty phyllodes tumours were separated into prognostically distinct categories depending on whether they had recurred/metastasized within the follow-up period. DNA extracted from FFPE materials was subjected to Affymetrix OncoScan™ FFPE Express molecular inversion probe microarray platform for analysis of copy number changes and mutational status. Results were cross validated with Sanger sequencing, FISH and immunohistochemistry. A higher number of chromosomal aberrations were observed in cases which recurred/metastasized, with median events of 19 compared to 3.5 in cases which did not recur/metastasize. High-level amplification and homozygous deletions were detected exclusively in the former group. Regions of high-level amplification included MDM4 (1q32.1), RAF1 (3p25), EGFR (7p12) and PDZD2 (5p13.3). EGFR amplification was confirmed on FISH and accompanied by intense EGFR immunostaining. Regions of homozygous deletion included CDKN2A (9p21) and MACROD2 (20p12.1). Homozygous deletion of 9p21 which involved CDKN2A was accompanied by loss of protein expression. No mutations were identified in all samples. These findings provide insights into identifying target genes and pathways exploited by phyllodes tumours, which would aid future development of individualised therapy.

Zhang F, Yang B, Shi S, Jiang X
RNA interference (RNAi) mediated stable knockdown of protein casein kinase 2-alpha (CK2α) inhibits migration and invasion and enhances cisplatin-induced apoptosis in HEp-2 laryngeal carcinoma cells.
Acta Histochem. 2014; 116(6):1000-6 [PubMed] Related Publications
Laryngeal carcinoma is a common malignant neoplasm occurring in the head and neck, threatening human health. Protein casein kinase 2-alpha (CK2α) has been indicated to participate in the pathogenesis of this cancer; however, the underlying mechanisms still need to be elucidated. In this study, short hairpin RNA (shRNA)-mediated RNA interference (RNAi) technology was utilized to inhibit the CK2α expression in HEp-2 laryngeal carcinoma cells. Results showed that both mRNA and protein expression levels of endogenous CK2α were markedly decreased in HEp-2 cells transfected with CK2α specific shRNA. Transwell assays revealed that stable knockdown of CK2α significantly inhibited the migration and invasion of HEp-2 cells. As compared with cells treated with negative control shRNA, epithelial cadherin (E-cadherin) expression was increased, but snail, slug and vimentin were decreased in cells transfected with CK2α shRNA, indicating that inhibition of CK2α expression may suppress the epithelial-mesenchymal transition (EMT) process of laryngeal carcinoma in vitro. Moreover, suppression of CK2α was found to enhance the apoptosis induced by cisplatin in laryngeal carcinoma cells, probably through inhibition of permeability glycoprotein (P-glycoprotein) and multidrug-resistance protein (MRP1). In conclusion, our study may provide a promising therapeutic strategy for human laryngeal carcinoma by targeting CK2α.

Gonzalez-Sanchez E, Marin JJ, Perez MJ
The expression of genes involved in hepatocellular carcinoma chemoresistance is affected by mitochondrial genome depletion.
Mol Pharm. 2014; 11(6):1856-68 [PubMed] Related Publications
Deletions and mutations in mitochondrial DNA (mtDNA), which are frequent in human tumors, such as hepatocellular carcinoma (HCC), may contribute to enhancing their malignant phenotype. Here we have investigated the effect of mtDNA depletion in the expression of genes accounting for mechanisms of chemoresistance (MOC) in HCC. Using human HCC SK-Hep-1 cells depleted of mtDNA (Rho), changes in gene expression in response to antitumor drugs previously assayed in HCC treatment were analyzed. In Rho cells, a decreased sensitivity to doxorubicin-, SN-38-, cisplatin (CDDP)-, and sorafenib-induced cell death was found. Both constitutive and drug-induced reactive oxygen species generation were decreased. Owing to activation of the NRF2-mediated pathway, MDR1, MRP1, and MRP2 expression was higher in Rho than in wild-type cells. This difference was maintained after further upregulation induced by treatment with doxorubicin, SN-38, or CDDP. Topoisomerase-IIa expression was also enhanced in Rho cells before and after treatment with these drugs. Moreover, the ability of doxorubicin, SN-38 and CDDP to induce proapoptotic signals was weaker in Rho cells, as evidenced by survivin upregulation and reductions in Bax/Bcl-2 expression ratios. Changes in these genes seem to play a minor role in the enhanced resistance of Rho cells to sorafenib, which may be related to an enhanced intracellular ATP content together with the loss of expression of the specific target of sorafenib, tyrosine kinase receptor Kit. In conclusion, these results suggest that mtDNA depletion may activate MOC able to hinder the efficacy of chemotherapy against HCC.

Zhu Y, Liu XJ, Yang P, et al.
Alkylglyceronephosphate synthase (AGPS) alters lipid signaling pathways and supports chemotherapy resistance of glioma and hepatic carcinoma cell lines.
Asian Pac J Cancer Prev. 2014; 15(7):3219-26 [PubMed] Related Publications
Chemotherapy continues to be a mainstay of cancer treatment, although drug resistance is a major obstacle. Lipid metabolism plays a critical role in cancer pathology, with elevated ether lipid levels. Recently, alkylglyceronephosphate synthase (AGPS), an enzyme that catalyzes the critical step in ether lipid synthesis, was shown to be up-regulated in multiple types of cancer cells and primary tumors. Here, we demonstrated that silencing of AGPS in chemotherapy resistance glioma U87MG/DDP and hepatic carcinoma HepG2/ADM cell lines resulted in reduced cell proliferation, increased drug sensitivity, cell cycle arrest and cell apoptosis through reducing the intracellular concentration of lysophosphatidic acid (LPA), lysophosphatidic acid-ether (LPAe) and prostaglandin E2 (PGE2), resulting in reduction of LPA receptor and EP receptors mediated PI3K/AKT signaling pathways and the expression of several multi-drug resistance genes, like MDR1, MRP1 and ABCG2. β-catenin, caspase-3/8, Bcl-2 and survivin were also found to be involved. In summary, our studies indicate that AGPS plays a role in cancer chemotherapy resistance by mediating signaling lipid metabolism in cancer cells.

Soussi T
The TP53 gene network in a postgenomic era.
Hum Mutat. 2014; 35(6):641-2 [PubMed] Related Publications
Inactivation of TP53 pathways are the most common defects observed in human cancer. Although missense mutations remain the most frequent genetic event, it is now evident that dysfunction of several members of this network such as MDM2, MDM4 (mdmX), or miR-125b can substitute for TP53 mutations. This special issue on TP53 brings the TP53 gene into the post-genomic era. Several fundamental features of wild type and mutant proteins and their modifications are reviewed, as well as animal models and clinical aspects such as recommendations for patient care. The complex structure of this gene warrants innovative strategies to infer a more accurate status of human tumors. Recommendations and guidelines for reporting and annotating TP53 variants are also provided, to help researchers generate standardized data that are easy to understand, analyze, and exchange across various cancer variant databases.

Queiroz RM, Takiya CM, Guimarães LP, et al.
Apoptosis-inducing effects of Melissa officinalis L. essential oil in glioblastoma multiforme cells.
Cancer Invest. 2014; 32(6):226-35 [PubMed] Related Publications
Current therapies for glioblastoma multiforme (GBM) are not effective. This study investigated the activity of the M. officinalis essential oil (EO) and its major component (citral) in GBM cell lines. Both EO and citral decreased the viability and induced apoptosis of GBM cells as demonstrated by DNA fragmentation and caspase-3 activation. Antioxidant prevented citral-induced death, indicating its dependence on the production of reactive oxygen species. Citral downmodulated the activity and inhibited the expression of multidrug resistance associated protein 1 (MRP1). These results show that EO, through its major component, citral, may be of potential interest for the treatment of GBM.

Selivanova G
Wild type p53 reactivation: from lab bench to clinic.
FEBS Lett. 2014; 588(16):2628-38 [PubMed] Related Publications
The p53 tumor suppressor is the most frequently inactivated gene in cancer. Several mouse models have demonstrated that the reconstitution of the p53 function suppresses the growth of established tumors. These facts, taken together, promote the idea of p53 reactivation as a strategy to combat cancer. This review will focus on recent advances in the development of small molecules which restore the function of wild type p53 by blocking its inhibitors Mdm2 and MdmX or their upstream regulators and discuss the impact of different p53 functions for tumor prevention and tumor eradication. Finally, the recent progress in p53 research will be analyzed concerning the role of p53 cofactors and cellular environment in the biological response upon p53 reactivation and how this can be applied in clinic.

Wu WR, Zhang R, Shi XD, et al.
Notch1 is overexpressed in human intrahepatic cholangiocarcinoma and is associated with its proliferation, invasiveness and sensitivity to 5-fluorouracil in vitro.
Oncol Rep. 2014; 31(6):2515-24 [PubMed] Related Publications
The Notch signaling pathway has been reported to play crucial roles in inhibiting hepatocyte differentiation and allowing formation of intrahepatic bile ducts. However, little is known about its significance in intrahepatic cholangiocarcinoma (ICC). The aim of the present study was to investigate the effects of Notch1 expression in ICC tissues and cells. The expression of Notch1 was examined in paraffin-embedded sections of ICC (n=44) by immunohistochemistry. Notch1 was knocked down by RNA interference (RNAi) in cultured ICC cells (RBE and HCCC-9810). The proliferation, invasiveness and sensitivity to 5-fluorouracil (5-FU) were detected by Cell Counting Kit-8 (CCK-8), colony formation assays, Transwell assays and flow cytometry, respectively. The expression levels of several multidrug resistance (MDR)-related genes, MDR1-P-glycoprotein (ABCB‑1), breast cancer resistance protein (ABCG‑2) and the multidrug resistance protein isoform 1 (MRP‑1), were examined by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Notch1 was overexpressed in cell membranes and cytoplasm of ICC compared with the adjacent liver tissue (35/44, 79.5%) and this was more common in cases with tumor size≥5 cm (p=0.021) and HBs-Ag positive (p=0.018). By silencing Notch1, the proliferation and invasiveness of ICC cells were inhibited and the inhibition rate of 5-FU was markedly increased. In addition, IC50 values of 5-FU in RBE cells were decreased from 148.74±0.72 to 5.37±0.28 µg/ml and the corresponding values for HCCC-9810 cells were 326.92±0.87 to 42.60±0.35 µg/ml, respectively. Furthermore, Notch1 silencing clearly increased the percentage of apoptotic cells treated by 5-FU compared with the control. Notch1 knockdown led to diminished expression levels of ABCB‑1 and MRP‑1. Therefore, Notch may play important roles in the development of ICC. Silencing Notch1 can inhibit the proliferation and invasiveness of ICC cells and increase their sensitivity to 5-FU in vitro.

Cai J, Chen S, Zhang W, et al.
Paeonol reverses paclitaxel resistance in human breast cancer cells by regulating the expression of transgelin 2.
Phytomedicine. 2014; 21(7):984-91 [PubMed] Related Publications
Paclitaxel (PTX) is a first-line antineoplastic drug that is commonly used in clinical chemotherapy for breast cancer treatment. However, the occurrence of drug resistance in chemotherapeutic treatment has greatly restricted its use. There is thus an urgent need to find ways of reversing paclitaxel chemotherapy resistance in breast cancer. Plant-derived agents have great potential in preventing the onset of the carcinogenic process and enhancing the efficacy of mainstream antitumor drugs. Paeonol, a main compound derived from the root bark of Paeonia suffruticosa, has various biological activities, and is reported to have reversal drug resistance effects. This study established a paclitaxel-resistant human breast cancer cell line (MCF-7/PTX) and applied the dual-luciferase reporter gene assay, MTT assay, flow cytometry, transfection assay, Western blotting and the quantitative real-time polymerase chain reaction (qRT-PCR) to investigate the reversing effects of paeonol and its underlying mechanisms. It was found that transgelin 2 may mediate the resistance of MCF-7/PTX cells to paclitaxel by up-regulating the expressions of the adenosine-triphosphate binding cassette transporter proteins, including P-glycoprotein (P-gp), multidrug resistance associated protein 1 (MRP1), and breast cancer resistance protein (BCRP). Furthermore, the ability of paeonol to reverse paclitaxel resistance in breast cancer was confirmed, with a superior 8.2-fold reversal index. In addition, this study found that paeonol down-regulated the transgelin 2-mediated paclitaxel resistance by reducing the expressions of P-gp, MRP1, and BCRP in MCF-7/PTX cells. These results not only provide insight into the potential application of paeonol to the reversal of paclitaxel resistance, thus facilitating the sensitivity of breast cancer chemotherapy, but also highlight a potential role of transgelin 2 in the development of paclitaxel resistance in breast cancer.

Kunická T, Souček P
Importance of ABCC1 for cancer therapy and prognosis.
Drug Metab Rev. 2014; 46(3):325-42 [PubMed] Related Publications
Multidrug resistance presents one of the most important causes of cancer treatment failure. Numerous in vitro and in vivo data have made it clear that multidrug resistance is frequently caused by enhanced expression of ATP-binding cassette (ABC) transporters. ABC transporters are membrane-bound proteins involved in cellular defense mechanisms, namely, in outward transport of xenobiotics and physiological substrates. Their function thus prevents toxicity as carcinogenesis on one hand but may contribute to the resistance of tumor cells to a number of drugs including chemotherapeutics on the other. Within 48 members of the human ABC superfamily there are several multidrug resistance-associated transporters. Due to the well documented susceptibility of numerous drugs to efflux via ABC transporters it is highly desirable to assess the status of ABC transporters for individualization of treatment by their substrates. The multidrug resistance associated protein 1 (MRP1) encoded by ABCC1 gene is one of the most studied ABC transporters. Despite the fact that its structure and functions have already been explored in detail, there are significant gaps in knowledge which preclude clinical applications. Tissue-specific patterns of expression and broad genetic variability make ABCC1/MRP1 an optimal candidate for use as a marker or member of multi-marker panel for prediction of chemotherapy resistance. The purpose of this review was to summarize investigations about associations of gene and protein expression and genetic variability with prognosis and therapy outcome of major cancers. Major advances in the knowledge have been identified and future research directions are highlighted.

Wang F, He L, Huangyang P, et al.
JMJD6 promotes colon carcinogenesis through negative regulation of p53 by hydroxylation.
PLoS Biol. 2014; 12(3):e1001819 [PubMed] Article available free on PMC after 15/12/2015 Related Publications
Jumonji domain-containing 6 (JMJD6) is a member of the Jumonji C domain-containing family of proteins. Compared to other members of the family, the cellular activity of JMJD6 is still not clearly defined and its biological function is still largely unexplored. Here we report that JMJD6 is physically associated with the tumor suppressor p53. We demonstrated that JMJD6 acts as an α-ketoglutarate- and Fe(II)-dependent lysyl hydroxylase to catalyze p53 hydroxylation. We found that p53 indeed exists as a hydroxylated protein in vivo and that the hydroxylation occurs mainly on lysine 382 of p53. We showed that JMJD6 antagonizes p53 acetylation, promotes the association of p53 with its negative regulator MDMX, and represses transcriptional activity of p53. Depletion of JMJD6 enhances p53 transcriptional activity, arrests cells in the G1 phase, promotes cell apoptosis, and sensitizes cells to DNA damaging agent-induced cell death. Importantly, knockdown of JMJD6 represses p53-dependent colon cell proliferation and tumorigenesis in vivo, and significantly, the expression of JMJD6 is markedly up-regulated in various types of human cancer especially in colon cancer, and high nuclear JMJD6 protein is strongly correlated with aggressive clinical behaviors of colon adenocarcinomas. Our results reveal a novel posttranslational modification for p53 and support the pursuit of JMJD6 as a potential biomarker for colon cancer aggressiveness and a potential target for colon cancer intervention.

Further References

de Oliveira Reis AH, de Carvalho IN, de Sousa Damasceno PB, et al.
Influence of MDM2 and MDM4 on development and survival in hereditary retinoblastoma.
Pediatr Blood Cancer. 2012; 59(1):39-43 [PubMed] Related Publications
BACKGROUND: Retinoblastoma (RB) accounts for 3% of all childhood malignancies, with different incidences around the world. This malignancy results from loss-of-function of both RB1 alleles although other genes, like MDM2 and MDM4, have been proposed to be involved in tumor development.
PROCEDURE: We genotyped rs2279744T>G and rs937283A>G in MDM2, and rs4252668T>C and rs116197192G>A in MDM4, in 104 unrelated RB patients and 104 controls. Sixty-month survival Kaplan-Meier curves and χ(2)-tests were performed for estimating the putative effect of MDM2 and MDM4 alleles on disease progression and survival of RB patients.
RESULTS: MDM2 rs2279744G was significantly more frequent in controls, indicating an apparently protective effect on RB development. However, survival of patients who carried a constitutional RB1 mutation was significantly lower with rs2279744TG or GG than with rs2279744TT. Presence of rs2279744G and a constitutional RB1 mutation was sixfold more frequent in the 0-12 month age group than other age groups at onset of symptoms (P = 0.0401). MDM4 rs4252668C was present at a significantly higher frequency in controls while the frequency of MDM4 rs116197192G was significantly higher in RB patients, suggesting that this allele might increase the risk of developing RB.
CONCLUSION: Our results indicate that MDM2 and MDM4 polymorphisms may influence development and/or survival in RB.

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