APOE

Gene Summary

Gene:APOE; apolipoprotein E
Aliases: AD2, LPG, APO-E, ApoE4, LDLCQ5
Location:19q13.32
Summary:The protein encoded by this gene is a major apoprotein of the chylomicron. It binds to a specific liver and peripheral cell receptor, and is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. This gene maps to chromosome 19 in a cluster with the related apolipoprotein C1 and C2 genes. Mutations in this gene result in familial dysbetalipoproteinemia, or type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron and VLDL remnants. [provided by RefSeq, Jun 2016]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:apolipoprotein E
Source:NCBIAccessed: 11 March, 2017

Ontology:

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

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 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 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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

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

Latest Publications: APOE (cancer-related)

Shafi O
Inverse relationship between Alzheimer's disease and cancer, and other factors contributing to Alzheimer's disease: a systematic review.
BMC Neurol. 2016; 16(1):236 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The AD etiology is yet not properly known. Interactions among environmental factors, multiple susceptibility genes and aging, contribute to AD. This study investigates the factors that play role in causing AD and how changes in cellular pathways contribute to AD.
METHODS: PUBMED database, MEDLINE database and Google Scholar were searched with no date restrictions for published articles involving cellular pathways with roles in cancers, cell survival, growth, proliferation, development, aging, and also contributing to Alzheimer's disease. This research explores inverse relationship between AD and cancer, also investigates other factors behind AD using several already published research literature to find the etiology of AD.
RESULTS: Cancer and Alzheimer's disease have inverse relationship in many aspects such as P53, estrogen, neurotrophins and growth factors, growth and proliferation, cAMP, EGFR, Bcl-2, apoptosis pathways, IGF-1, HSV, TDP-43, APOE variants, notch signals and presenilins, NCAM, TNF alpha, PI3K/AKT/MTOR pathway, telomerase, ROS, ACE levels. AD occurs when brain neurons have weakened growth, cell survival responses, maintenance mechanisms, weakened anti-stress responses such as Vimentin, Carbonic anhydrases, HSPs, SAPK. In cancer, these responses are upregulated and maintained. Evolutionarily conserved responses and maintenance mechanisms such as FOXO are impaired in AD. Countermeasures or compensatory mechanisms by AD affected neurons such as Tau, Beta Amyloid, S100, are last attempts for survival which may be protective for certain time, or can speed up AD in Alzheimer's microenvironment via C-ABL activation, GSK3, neuro-inflammation.
CONCLUSIONS: Alzheimer's disease and Cancer have inverse relationship; many factors that are upregulated in any cancer to sustain growth and survival are downregulated in Alzheimer's disease contributing to neuro-degeneration. When aged neurons or genetically susceptible neurons have weakened growth, cell survival and anti-stress responses, age related gene expression changes, altered regulation of cell death and maintenance mechanisms, they contribute to Alzheimer's disease. Countermeasures by AD neurons such as Beta Amyloid Plaques, NFTs, S100, are last attempts for survival and this provides neuroprotection for certain time and ultimately may become pathological and speed up AD. This study may contribute in developing new potential diagnostic tests, interventions and treatments.

Shi J, Yang H, Duan X, et al.
Apolipoproteins as Differentiating and Predictive Markers for Assessing Clinical Outcomes in Patients with Small Cell Lung Cancer.
Yonsei Med J. 2016; 57(3):549-56 [PubMed] Free Access to Full Article Related Publications
PURPOSE: The present study aimed to investigate the value of apolipoproteins, including ApoA-1, ApoC-III, and ApoE, in patients with small cell lung cancer (SCLC) as potential biomarkers for diagnosis, prognosis, and cancer progression.
MATERIALS AND METHODS: Lung samples were collected from 89 patients with SCLC. Nineteen lung samples from non-small cell lung cancer (NSCLC) patients and 12 normal lung tissues were used as controls. Expression profiles of ApoA-1, ApoC-III, and ApoE in different samples were examined using immunohistochemical methods, and the expression levels were correlated with cancer types, treatment, and outcomes using chi-square and Mann-Whitney tests.
RESULTS: Expression of ApoA-1 and ApoC-III in SCLC was significantly different, compared with that in NSCLC and normal lung tissues, and was correlated with recurrence of SCLC. Patients undergoing neoadjuvant chemotherapy before surgery showed significantly reduced expression of ApoA-1 and increased expression of ApoC-III and ApoE. Nevertheless, the expression levels of ApoA-1, ApoC-III, and ApoE were not correlated with SCLC staging.
CONCLUSION: ApoA-1 and ApoC-III may be used as differentiating and predictive markers for SCLC. ApoA-1, ApoC-III, and ApoE may be used to monitor the efficacy of chemotherapy.

Yencilek F, Yilmaz SG, Yildirim A, et al.
Apolipoprotein E Genotypes in Patients with Prostate Cancer.
Anticancer Res. 2016; 36(2):707-11 [PubMed] Related Publications
BACKGROUND: Apolipoprotein E (ApoE) is a potential inhibitor of cell proliferation, immune regulation and modulation of cell growth and differentiation; it also has a substantial role in antioxidant activity. ApoE has a potential role in prostate cancer progression.
MATERIALS AND METHODS: ApoE genotyping was performed using real-time polymerase chain reaction (RT-PCR) for blood samples from a group of patients with prostate cancer (n=68) and a control group (n=78).
RESULTS: The frequency of the E3/E3 genotype was significantly higher in patients compared to controls (p=0.004). E3/E3 genotype carriers were 3.6-fold more likely to be patients than controls (odds ratio=3.67, 95% confidence interval=1.451-9.155; p=0.004). Additionally, the patients with E3/E3 genotype had significantly higher Gleason score (p=0.017), and more patients with this genotype had a Gleason score higher than 7 (p=0.007). Individuals carrying the E4 allele were significantly more common in the control group (p=0.006). The frequency of the E3/E4 genotype was found to be significantly higher in controls compared to patients (p=0.007), and patients were significantly less likely to have this genotype than controls (odds ratio=0.89, 95% confidence interval=0.833-0.967, p=0.007). Individuals carrying the E2/E3 genotype had a significantly lower Gleason score (p=0.049)-all of the patients with this genotype had a Gleason score lower than 7 (p=0.024).
CONCLUSION: E3/E3 genotype may be a potential risk factor for prostate cancer and high Gleason scoring. The E4 allele maybe a risk-reducing factor for prostate cancer.

Kang R, Li P, Wang T, et al.
Apolipoprotein E epsilon 2 allele and low serum cholesterol as risk factors for gastric cancer in a Chinese Han population.
Sci Rep. 2016; 6:19930 [PubMed] Free Access to Full Article Related Publications
Apolipoprotein E (apoE) mediates lipid metabolism both in peripheral and in the brain. The human APOE gene has three polymorphic alleles that influence the risk for various types of cancer and neurodegenerative diseases. A potential association between APOE allele and the risk for gastric cancer has been implicated, but the specific allele involved and potential associations with the subtype and the grade of cancer malignancy need further clarification. We screened the APOE genotype in 550 gastric cancer patients and 550 non-cancer control individuals and found that the presence of the APOE ε2 and lower serum total cholesterol are associated with an increased risk for gastric cancer (all P ≤ 0.0005). Interestingly, APOE ε2 is also correlated with increased risk for both intestinal and diffuse histotypes but not with TN classification or stage in gastric cancer patients, suggesting that APOE polymorphic alleles are associated with the risk of development but unlikely the progression of gastric cancer. Since ε2 carriers have lower levels of serum total cholesterol than non-ε2 carriers, our findings suggest that the increased risk for gastric cancer by APOE ε2 allele might be mediated through lowered serum total cholesterol levels.

Roberts JL, He B, Erickson A, Moreau R
Improvement of mTORC1-driven overproduction of apoB-containing triacylglyceride-rich lipoproteins by short-chain fatty acids, 4-phenylbutyric acid and (R)-α-lipoic acid, in human hepatocellular carcinoma cells.
Biochim Biophys Acta. 2016; 1861(3):166-76 [PubMed] Related Publications
The activation of hepatic kinase mechanistic target of rapamycin complex 1 (mTORC1) is implicated in the development of obesity-related metabolic disorders. This study investigated the metabolic sequelae of mTORC1 hyperactivation in human hepatoma cells and the lipid-regulating mechanisms of two short-chain fatty acids: 4-phenylbutyric acid (PBA) and (R)-α-lipoic acid (LA). We created three stable cell lines that exhibit low, normal, or high mTORC1 activity. mTORC1 hyperactivation induced the expression of lipogenic (DGAT1 and DGAT2) and lipoprotein assembly (MTP and APOB) genes, thereby raising cellular triacylglyceride (TG) and exacerbating secretion of apoB-containing TG-rich lipoproteins. LYS6K2, a specific inhibitor of the p70 S6 kinase branch of mTORC1 signaling, reversed these effects. PBA and LA decreased secreted TG through distinct mechanisms. PBA repressed apoB expression (both mRNA and protein) and lowered secreted TG without mitigation of mTORC1 hyperactivity or activation of AMPK. LA decreased cellular and secreted TG by attenuating mTORC1 signaling in an AMPK-independent manner. LA did not regulate apoB expression but led to the secretion of apoB-containing TG-poor lipoproteins by repressing the expression of lipogenic genes, FASN, DGAT1, and DGAT2. Our studies provide new mechanistic insight into the hypolipidemic activity of PBA and LA in the context of mTORC1 hyperactivation and suggest that the short-chain fatty acids may aid in the prevention and treatment of hypertriglyceridemia.

Djiokeng Paka G, Doggui S, Zaghmi A, et al.
Neuronal Uptake and Neuroprotective Properties of Curcumin-Loaded Nanoparticles on SK-N-SH Cell Line: Role of Poly(lactide-co-glycolide) Polymeric Matrix Composition.
Mol Pharm. 2016; 13(2):391-403 [PubMed] Related Publications
Curcumin, a neuroprotective agent with promising therapeutic approach has poor brain bioavailability. Herein, we demonstrate that curcumin-encapsulated poly(lactide-co-glycolide) (PLGA) 50:50 nanoparticles (NPs-Cur 50:50) are able to prevent the phosphorylation of Akt and Tau proteins in SK-N-SH cells induced by H2O2 and display higher anti-inflammatory and antioxidant activities than free curcumin. PLGA can display various physicochemical and degradation characteristics for controlled drug release applications according to the matrix used. We demonstrate that the release of curcumin entrapped into a PLGA 50:50 matrix (NPs-Cur 50:50) is faster than into PLGA 65:35. We have studied the effects of the PLGA matrix on the expression of some key antioxidant- and neuroprotective-related genes such as APOE, APOJ, TRX, GLRX, and REST. NPs-Cur induced the elevation of GLRX and TRX while decreasing APOJ mRNA levels and had no effect on APOE and REST expressions. In the presence of H2O2, both NPs-Cur matrices are more efficient than free curcumin to prevent the induction of these genes. Higher uptake was found with NPs-Cur 50:50 than NPs-Cur 65:35 or free curcumin. By using PLGA nanoparticles loaded with the fluorescent dye Lumogen Red, we demonstrated that PLGA nanoparticles are indeed taken up by neuronal cells. These data highlight the importance of polymer composition in the therapeutic properties of the nanodrug delivery systems. Our study demonstrated that NPs-Cur enhance the action of curcumin on several pathways implicated in the pathophysiology of Alzheimer's disease (AD). Overall, these results suggest that PLGA nanoparticles are a promising strategy for the brain delivery of drugs for the treatment of AD.

Uthaya Kumar DB, Chen CL, Liu JC, et al.
TLR4 Signaling via NANOG Cooperates With STAT3 to Activate Twist1 and Promote Formation of Tumor-Initiating Stem-Like Cells in Livers of Mice.
Gastroenterology. 2016; 150(3):707-19 [PubMed] Free Access to Full Article Related Publications
BACKGROUND & AIMS: Obesity and alcohol consumption contribute to steatohepatitis, which increases the risk for hepatitis C virus (HCV)-associated hepatocellular carcinomas (HCCs). Mouse hepatocytes that express HCV-NS5A in liver up-regulate the expression of Toll-like receptor 4 (TLR4), and develop liver tumors containing tumor-initiating stem-like cells (TICs) that express NANOG. We investigated whether the TLR4 signals to NANOG to promote the development of TICs and tumorigenesis in mice placed on a Western diet high in cholesterol and saturated fat (HCFD).
METHODS: We expressed HCV-NS5A from a transgene (NS5A Tg) in Tlr4-/- (C57Bl6/10ScN), and wild-type control mice. Mice were fed a HCFD for 12 months. TICs were identified and isolated based on being CD133+, CD49f+, and CD45-. We obtained 142 paraffin-embedded sections of different stage HCCs and adjacent nontumor areas from the same patients, and performed gene expression, immunofluorescence, and immunohistochemical analyses.
RESULTS: A higher proportion of NS5A Tg mice developed liver tumors (39%) than mice that did not express HCV NS5A after the HCFD (6%); only 9% of Tlr4-/- NS5A Tg mice fed HCFD developed liver tumors. Livers from NS5A Tg mice fed the HCFD had increased levels of TLR4, NANOG, phosphorylated signal transducer and activator of transcription (pSTAT3), and TWIST1 proteins, and increases in Tlr4, Nanog, Stat3, and Twist1 messenger RNAs. In TICs from NS5A Tg mice, NANOG and pSTAT3 directly interact to activate expression of Twist1. Levels of TLR4, NANOG, pSTAT3, and TWIST were increased in HCC compared with nontumor tissues from patients.
CONCLUSIONS: HCFD and HCV-NS5A together stimulated TLR4-NANOG and the leptin receptor (OB-R)-pSTAT3 signaling pathways, resulting in liver tumorigenesis through an exaggerated mesenchymal phenotype with prominent Twist1-expressing TICs.

Wang Q, Jia J, Qin W, et al.
A Novel AβPP M722K Mutation Affects Amyloid-β Secretion and Tau Phosphorylation and May Cause Early-Onset Familial Alzheimer's Disease in Chinese Individuals.
J Alzheimers Dis. 2015; 47(1):157-65 [PubMed] Related Publications
BACKGROUND: Mutations within exons 16 and 17 of the amyloid-β protein precursor (AβPP) gene were the first known causes of early-onset familial Alzheimer's disease (EOFAD). Since the first AβPP mutation was reported, 39 different AβPP variations have been discovered in EOFAD.
OBJECTIVE: We described a novel AβPP M722K mutation found in a Chinese familial Alzheimer's disease pedigree and confirmed its effects on amyloid-β (Aβ) secretion and tau phosphorylation.
METHODS: We performed direct sequencing of exons 16 and 17 of the AβPP gene and coding exons 3-12 of the PSEN1 and PSEN2 genes for genetic analysis. N2a cells were transfected with wild-type AβPP, AβPP constructs harboring the M722K mutation, or AβPP constructs harboring the Swedish mutation to demonstrate the effects of the AβPP M722K mutation on Aβ secretion and tau phosphorylation.
RESULTS: Different phenotypes of patients carrying the AβPP M722K mutation maybe were related to different apolipoprotein E genotypes. The expression of AβPP M722K in mouse neuroblastoma N2a cells induced a 1.7-fold increased ratio of Aβ 42 to Aβ 40 without changes in sAβPPα and sAβPPβ. Tau phosphorylation at the AT8 sites was also increased.
CONCLUSION: Maybe the AβPP M722K mutation contributed to the cause of EOFAD in this Chinese pedigree mediated by increased Aβ 42/Aβ 40. Further studies should be conducted to validate the pathogenicity of AβPP M722K and the interactions among γ-secretase, APOE, and AβPP.

Lv C, Bai Z, Liu Z, et al.
Renal cell carcinoma risk is associated with the interactions of APOE, VHL and MTHFR gene polymorphisms.
Int J Clin Exp Pathol. 2015; 8(5):5781-6 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: The study was designed to explore the association of renal cell carcinoma (RCC) with VHL (rs779805), MTHFR (rs1801133) and APOE (rs8106822 and rs405509) polymorphisms, investigate the interactions among the single nucleotide polymorphisms (SNPs), and explore roles of the interactions in the pathogenesis of RCC in Chinese Han population.
METHODS: 81 RCC patients and 80 healthy controls were included in the study. Polymerase chain reaction (PCR) and direct sequencing methods were used in the analysis on the genotypes of APOE, VHL and MTHFR gene polymorphisms. Multifactor dimensionality reduction (MDR) method was adopted to conduct gene-gene interaction analysis. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were utilized to evaluate the correlation between gene-gene interactions and RCC risk.
RESULTS: Significant correlations were found between RCC risk and 3 SNPs (rs8106822, rs779805 and rs1801133). Genotype AA and allele A of APOE rs8106822 were significantly associated with RCC susceptibility (OR=2.65, 95% CI=1.05-6.69). Meanwhile, we found that the frequencies of genotype GG and allele G were much higher in case group, compared with controls (P<0.05 for both) and they appeared to be risk factors for RCC (OR=2.90, 95% CI=1.22-6.87; OR=1.78, 95% CI=1.14-2.27). While, allele T of MTHFR rs1801133 could decrease the risk of RCC (OR=0.62, 95% CI=0.40-0.97). MDR analysis showed that gene-gene interactions among APOE, VHL and MTHFR SNPs were closely related with RCC susceptibility.
CONCLUSION: APOE, VHL and MTHFR gene polymorphisms were related to the risk of RCC. The interactions among APOE, VHL and MTHFR genes could increase the risk of RCC.

Uen YH, Liao CC, Lin JC, et al.
Analysis of differentially expressed novel post-translational modifications of plasma apolipoprotein E in Taiwanese females with breast cancer.
J Proteomics. 2015; 126:252-62 [PubMed] Related Publications
APOE ε2 or ε4 alleles being used as indicators of breast cancer risk are controversial in Taiwanese females. We provide a concept for relative comparisons of post-translational modifications (PTMs) of plasma apolipoprotein E (ApoE) between normal controls and breast cancer patients to investigate the association of ApoE with breast cancer risk. APOE polymorphisms (ApoE isoforms) were not assessed in this study. The relative modification ratio (%) of 15 targeted and 21 modified peptides were evaluated by 1D SDS-PAGE, in-gel digestion, and label-free nano-LC/MS to compare normal controls with breast cancer patients. Plasma levels of the ApoE protein did not significantly differ between normal controls and breast cancer patients. Eleven sites with novel PTMs were identified from 7 pairs of differentially expressed targeted and modified peptides according to the relative modification ratio including methylation at the E3 (↑1.45-fold), E7 (↑1.45-fold), E11 (↑1.19-fold), E77 (↑2.02-fold), E87 (↑2.02-fold), and Q98 (↑1.62-fold) residues; dimethylation at the Q187 (↑1.44-fold) residue; dihydroxylation at the R92 (↑1.25-fold), K95 (↑1.25-fold), and R103 (↑1.25-fold) residues; and glycosylation at the S129 (↑1.14-fold) residue. The clustered methylation and dihydroxylation of plasma ApoE proteins may play a role in breast cancer.

Yang J, Yu L, Gaiteri C, et al.
Association of DNA methylation in the brain with age in older persons is confounded by common neuropathologies.
Int J Biochem Cell Biol. 2015; 67:58-64 [PubMed] Free Access to Full Article Related Publications
DNA methylation plays a crucial role in the regulation of gene expression, cell differentiation and development. Previous studies have reported age-related alterations of methylation levels in the human brain across the lifespan, but little is known about whether the observed association with age is confounded by common neuropathologies among older persons. Using genome-wide DNA methylation data from 740 postmortem brains, we interrogated 420,132 CpG sites across the genome in a cohort of individuals with ages from 66 to 108 years old, a range of ages at which many neuropathologic indices become quite common. We compared the association of DNA methylation prior to and following adjustment for common neuropathologies using a series of linear regression models. In the simplest model adjusting for technical factors including batch effect and bisulfite conversion rate, we found 8156 CpGs associated with age. The number of CpGs associated with age dropped by more than 10% following adjustment for sex. Notably, after adjusting for common neuropathologies, the total number of CpGs associated with age was reduced by approximately 40%, compared to the sex-adjusted model. These data illustrate that the association of methylation changes in the brain with age is inflated if one does not account for age-related brain pathologies. This article is part of a Directed Issue entitled: Epigenetics dynamics in development and disease.

Sen A, Nelson TJ, Alkon DL
ApoE4 and Aβ Oligomers Reduce BDNF Expression via HDAC Nuclear Translocation.
J Neurosci. 2015; 35(19):7538-51 [PubMed] Related Publications
Apolipoprotein E4 (ApoE4) is a major genetic risk factor for several neurodegenerative disorders, including Alzheimer's disease (AD). Epigenetic dysregulation, including aberrations in histone acetylation, is also associated with AD. We show here for the first time that ApoE4 increases nuclear translocation of histone deacetylases (HDACs) in human neurons, thereby reducing BDNF expression, whereas ApoE3 increases histone 3 acetylation and upregulates BDNF expression. Amyloid-β (Aβ) oligomers, which have been implicated in AD, caused effects similar to ApoE4. Blocking low-density lipoprotein receptor-related protein 1 (LRP-1) receptor with receptor-associated protein (RAP) or LRP-1 siRNA abolished the ApoE effects. ApoE3 also induced expression of protein kinase C ε (PKCε) and PKCε retained HDACs in the cytosol. PKCε activation and ApoE3 supplementation prevented ApoE4-mediated BDNF downregulation. PKCε activation also reversed Aβ oligomer- and ApoE4-induced nuclear import of HDACs, preventing the loss in BDNF. ApoE4 induced HDAC6-BDNF promoter IV binding, which reduced BDNF exon IV expression. Nuclear HDAC4 and HDAC6 were more abundant in the hippocampus of ApoE4 transgenic mice than in ApoE3 transgenic mice or wild-type controls. Nuclear translocation of HDA6 was also elevated in the hippocampus of AD patients compared with age-matched controls. These results provide new insight into the cause of synaptic loss that is the most important pathologic correlate of cognitive deficits in AD.

Lengacher CA, Reich RR, Kip KE, et al.
Moderating Effects of Genetic Polymorphisms on Improvements in Cognitive Impairment in Breast Cancer Survivors Participating in a 6-Week Mindfulness-Based Stress Reduction Program.
Biol Res Nurs. 2015; 17(4):393-404 [PubMed] Related Publications
Breast cancer (BC) survivors often report cognitive impairment, which may be influenced by single-nucleotide polymorphisms (SNPs). The purpose of this study was to test whether particular SNPs were associated with changes in cognitive function in BC survivors and whether these polymorphisms moderated cognitive improvement resulting from the Mindfulness-Based Stress Reduction for Breast Cancer (MBSR[BC]) program. BC survivors recruited from Moffitt Cancer Center and the University of South Florida's Breast Health Program, who had completed adjuvant radiation and/or chemotherapy treatment, were randomized to either the 6-week MBSR(BC) program (n = 37) or usual care (UC; n = 35) group. Measures of cognitive function and demographic and clinical history data were attained at baseline and at 6 and 12 weeks. A total of 10 SNPs from eight genes known to be related to cognitive function were analyzed using blood samples. Results showed that SNPs in four genes (ankyrin repeat and kinase domain containing 1 [ANKK1], apolipoprotein E [APOE], methylenetetrahydrofolate reductase [MTHFR], and solute carrier family 6 member 4 [SLC6A4]) were associated with cognitive impairment. Further, rs1800497 in ANKK1 was significantly associated with improvements in cognitive impairment in response to MBSR(BC). These results may help to identify individuals who would be better served by MBSR(BC) or other interventions.

Yang C, Tian G, Mi J, et al.
Causal relevance of circulating high-density lipoprotein cholesterol with cancer: a Mendelian randomization meta-analysis.
Sci Rep. 2015; 5:9495 [PubMed] Free Access to Full Article Related Publications
We summarized published data on the associations of apolipoprotein E (APOE) gene ε2/ε3/ε4 polymorphism with both cancer risk and circulating lipid profiles, aiming to examine the causal relevance between lipids and cancer risk. Article identification and data abstraction were conducted in duplicate and independently by two authors. Data were analyzed by STATA software. Twenty-five articles that examined the associations of APOE gene ε2/ε3/ε4 polymorphism with either cancer risk (n = 22) or circulating lipid changes (n = 4) were eligible. The presence of ε2 and ε4 alleles showed no overall associations with overall cancer risk when compared with ε3 allele. The ε4 allele was significantly associated with 1.40-fold (odds ratio or OR = 1.40; 95% confidence interval or CI: 1.00-1.94; P = 0.047) increased risk of developing cancer in Asian populations, and the presence of heterogeneity was low (I(2) = 37.6%). Carriers of ε3/ε4 genotype had a significant reduction in circulating HDL-C (WMD = -2.62; 95% CI: -4.19 to -1.04; P = 0.001) without heterogeneity (I(2) = 16.6%). The predicted odds of having cancer for 1 mg/dL reduction in circulating HDL-C was 1.14 (95% CI: 1.00 to 1.89). The findings of this Mendelian randomization meta-analysis demonstrate that reduced circulating HDL-C might be a potentially causal risk factor for the development of overall cancer in Asians.

Ivanova TI, Krikunova LI, Ryabchenko NI, et al.
Association of the apolipoprotein E 2 allele with concurrent occurrence of endometrial hyperplasia and endometrial carcinoma.
Oxid Med Cell Longev. 2015; 2015:593658 [PubMed] Free Access to Full Article Related Publications
Genes encoding proteins with antioxidant properties may influence susceptibility to endometrial hyperplasia (EH) and endometrial carcinoma (ECa). Patients with EH (n = 89), EH concurrent with ECa (n = 76), ECa (n = 186), and healthy controls (n = 1110) were genotyped for five polymorphic variants in the genes involved in metabolism of lipoproteins (APOE Cys112Arg and Arg158Cys), iron (HFE Cys282Tyr and His63Asp), and catecholamines (COMT Val158Met). Patients and controls were matched by ethnicity (all Caucasians), age, body mass index (BMI), and incidence of hypertension and diabetes. The frequency of the APOE E 2 allele (158Cys) was higher in patients with EH + ECa than in controls (P = 0.0012, P(Bonferroni) = 0.018, OR = 2.58, 95% CI 1.49-4.45). The APOE E 4 allele (112Arg) was more frequently found in patients with EH than in controls and HFE minor allele G (63Asp) had a protective effect in the ECa group, though these results appeared to be nonsignificant after correction for multiple comparisons. The results of the study indicate that E 2 allele might be associated with concurrent occurrence of EH and ECa.

Fukuhara T, Wada M, Nakamura S, et al.
Amphipathic α-helices in apolipoproteins are crucial to the formation of infectious hepatitis C virus particles.
PLoS Pathog. 2014; 10(12):e1004534 [PubMed] Free Access to Full Article Related Publications
Apolipoprotein B (ApoB) and ApoE have been shown to participate in the particle formation and the tissue tropism of hepatitis C virus (HCV), but their precise roles remain uncertain. Here we show that amphipathic α-helices in the apolipoproteins participate in the HCV particle formation by using zinc finger nucleases-mediated apolipoprotein B (ApoB) and/or ApoE gene knockout Huh7 cells. Although Huh7 cells deficient in either ApoB or ApoE gene exhibited slight reduction of particles formation, knockout of both ApoB and ApoE genes in Huh7 (DKO) cells severely impaired the formation of infectious HCV particles, suggesting that ApoB and ApoE have redundant roles in the formation of infectious HCV particles. cDNA microarray analyses revealed that ApoB and ApoE are dominantly expressed in Huh7 cells, in contrast to the high level expression of all of the exchangeable apolipoproteins, including ApoA1, ApoA2, ApoC1, ApoC2 and ApoC3 in human liver tissues. The exogenous expression of not only ApoE, but also other exchangeable apolipoproteins rescued the infectious particle formation of HCV in DKO cells. In addition, expression of these apolipoproteins facilitated the formation of infectious particles of genotype 1b and 3a chimeric viruses. Furthermore, expression of amphipathic α-helices in the exchangeable apolipoproteins facilitated the particle formation in DKO cells through an interaction with viral particles. These results suggest that amphipathic α-helices in the exchangeable apolipoproteins play crucial roles in the infectious particle formation of HCV and provide clues to the understanding of life cycle of HCV and the development of novel anti-HCV therapeutics targeting for viral assembly.

Kulminski AM, Arbeev KG, Culminskaya I, et al.
Trade-offs in the effects of the apolipoprotein E polymorphism on risks of diseases of the heart, cancer, and neurodegenerative disorders: insights on mechanisms from the Long Life Family Study.
Rejuvenation Res. 2015; 18(2):128-35 [PubMed] Free Access to Full Article Related Publications
The lack of evolutionary established mechanisms linking genes to age-related traits makes the problem of genetic susceptibility to health span inherently complex. One complicating factor is genetic trade-off. Here we focused on long-living participants of the Long Life Family Study (LLFS), their offspring, and spouses to: (1) Elucidate whether trade-offs in the effect of the apolipoprotein E e4 allele documented in the Framingham Heart Study (FHS) are a more general phenomenon, and (2) explore potential mechanisms generating age- and gender-specific trade-offs in the effect of the e4 allele on cancer, diseases of the heart, and neurodegenerative disorders assessed retrospectively in the LLFS populations. The e4 allele can diminish risks of cancer and diseases of the heart and confer risks of diseases of the heart in a sex-, age-, and LLFS-population-specific manner. A protective effect against cancer is seen in older long-living men and, potentially, their sons (>75 years, relative risk [RR]>75=0.48, p=0.086), which resembles our findings in the FHS. The protective effect against diseases of the heart is limited to long-living older men (RR>76=0.50, p=0.016), as well. A detrimental effect against diseases of the heart is characteristic for a normal LLFS population of male spouses and is specific for myocardial infarction (RR=3.07, p=2.1×10(-3)). These trade-offs are likely associated with two inherently different mechanisms, including disease-specific (detrimental; characteristic for a normal male population) and systemic, aging-related (protective; characteristic for older long-living men) mechanisms. The e4 allele confers risks of neurological disorders in men and women (RR=1.98, p=0.046). The results highlight the complex role of the e4 allele in genetic susceptibility to health span.

Ng T, Chan M, Khor CC, et al.
The genetic variants underlying breast cancer treatment-induced chronic and late toxicities: a systematic review.
Cancer Treat Rev. 2014; 40(10):1199-214 [PubMed] Related Publications
A systematic review was performed to describe the findings from 19 genetic association studies that have examined the genetic variants underlying four common treatment-induced chronic and late toxicities in breast cancer patients, and to evaluate the quality of reporting. Three out of 5 studies found an association between HER2 lle655Val polymorphisms and trastuzumab-induced cardiotoxicity. Two studies found a positive association between cognitive impairment and the Val allele of the COMT gene and the ε4 allele of the apolipoprotein E gene. Genetic associations were established between fatigue and the G/G genotype of IL6-174 and TNF-308, and the Met allele of the COMT gene in 4 studies. Among studies (N=8) that evaluated the genetic associations underlying peripheral neuropathy, CYP2C8∗3 variant is commonly reported as the associated gene. Most studies failed to conform to the major criteria listed in the STREGA guidelines, with a lack of transparent reporting of methods and results.

Martin P, Noonan S, Mullen MP, et al.
Predicting response to vascular endothelial growth factor inhibitor and chemotherapy in metastatic colorectal cancer.
BMC Cancer. 2014; 14:887 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Bevacizumab improves progression free survival (PFS) and overall survival (OS) in metastatic colorectal cancer patients however currently there are no biomarkers that predict response to this treatment. The aim of this study was to assess if differential protein expression can differentiate patients who respond to chemotherapy and bevacizumab, and to assess if select proteins correlate with patient survival.
METHODS: Pre-treatment serum from patients with metastatic colorectal cancer (mCRC) treated with chemotherapy and bevacizumab were divided into responders and nonresponders based on their progression free survival (PFS). Serum samples underwent immunoaffinity depletion and protein expression was analysed using two-dimensional difference gel electrophoresis (2D-DIGE), followed by LC-MS/MS for protein identification. Validation on selected proteins was performed on serum and tissue samples from a larger cohort of patients using ELISA and immunohistochemistry, respectively (n = 68 and n = 95, respectively).
RESULTS: 68 proteins were identified following LC-MS/MS analysis to be differentially expressed between the groups. Three proteins (apolipoprotein E (APOE), angiotensinogen (AGT) and vitamin D binding protein (DBP)) were selected for validation studies. Increasing APOE expression in the stroma was associated with shorter progression free survival (PFS) (p = 0.0001) and overall survival (OS) (p = 0.01), DBP expression (stroma) was associated with shorter OS (p = 0.037). Increasing APOE expression in the epithelium was associated with a longer PFS and OS, and AGT epithelial expression was associated with a longer PFS (all p < .05). Increasing serum AGT concentration was associated with shorter OS (p = 0.009).
CONCLUSIONS: APOE, DBP and AGT identified were associated with survival outcomes in mCRC patients treated with chemotherapy and bevacizumab.

Koleck TA, Bender CM, Sereika SM, et al.
Apolipoprotein E genotype and cognitive function in postmenopausal women with early-stage breast cancer.
Oncol Nurs Forum. 2014; 41(6):E313-25 [PubMed] Free Access to Full Article Related Publications
PURPOSE/OBJECTIVES: To examine the role of apolipoprotein E (APOE) genotype in the cognitive function of postmenopausal women with early-stage breast cancer prior to initiation of adjuvant therapy and over time with treatment.
DESIGN: Longitudinal, genetic association study.
SETTING: Urban university cancer center.
SAMPLE: Three cohorts of postmenopausal women: 37 women with breast cancer receiving chemotherapy and anastrozole, 41 women with breast cancer receiving anastrozole alone, and 50 healthy women.
METHODS: Cognitive function was evaluated three times during a 12-month period using a comprehensive neuropsychological test battery. Participants were genotyped and classified based on the presence or absence of at least one APOE e4 allele. Multiple linear regression was used to determine if APOE genotype accounted for observed variability in cognitive function data.
MAIN RESEARCH VARIABLES: APOE genotype, breast cancer treatment, and cognitive function.
FINDINGS: Performance or changes in performance on tasks of executive function, attention, verbal learning and memory, and visual learning and memory were found to be influenced by APOE genotype and/or interactions between APOE genotype and study cohort.
CONCLUSIONS: The results indicate that cognitive function in postmenopausal women with breast cancer is modified by APOE genotype and the combination of APOE genotype and treatment.
IMPLICATIONS FOR NURSING: APOE genotype, along with other biomarkers, may be used in the future to assist nurses in identifying women with breast cancer most at risk for cognitive decline.

Bao Q, Pan J, Qi H, et al.
Aging and age-related diseases--from endocrine therapy to target therapy.
Mol Cell Endocrinol. 2014; 394(1-2):115-8 [PubMed] Related Publications
Aging represents an important health issue not only for the individual, but also for society in general. Burdens associated with aging are expanding as longevity increases. This has led to an enhanced focus on issues related to aging and age-related diseases. Until recently, anti-aging endocrine-therapy has been largely limited to hormone-replacement therapy (HRT) that is associated with multiple side effects, including an increased risk of cancer. This has greatly limited the application of HRT in anti-aging therapy. Recently, the focus of anti-aging research has expanded from endocrine signaling pathways to effects on regulatory gene networks. In this regard, the GHRH-GH-IGF-1/Insulin, TOR-S6K1,NAD(+)-Sirtuin, P53, Klotho and APOE pathways have been linked to processes associated with age-related diseases, including cancer, cardiovascular disease, diabetes, osteoporosis, and neurodegenerative diseases, all of which directly influence health in aging, and represent key targets in anti-aging therapy.

Tian Y, Wang J, Ye Y, et al.
Apolipoprotein E polymorphism and colorectal neoplasm: results from a meta-analysis.
PLoS One. 2014; 9(7):e102477 [PubMed] Free Access to Full Article Related Publications
To investigate the relationship of Apolipoprotein E (APOE) gene polymorphism to colorectal neoplasia (CRN), we performed a systematic review and meta-analysis. Eligible studies were identified through a systematic literature review from PubMed, EMBASE, and the Science Citation Index up to February 2014. A combined analysis was performed, followed by a subgroup analyses stratified by the study design. We used data collected from 8 prospective studies involving respectively a total of 9243 participants and 4310 CRN cases which including 438 patients with colorectal adenoma (CRA), and 3873 patients with colorectal carcinoma (CRC). The pooled data from this meta-analysis indicated there was no significant association between APOE polymorphism and CRN (ε2: P = 0.51, OR 1.04 95% CI 0.93 to 1.16; ε4: P = 0.72, OR 0.98 95% CI 0.90 to 1.07). Interestingly, subgroup analysis demonstrated there was a significant decreased risk for proximal CRN in patients with APOE ε4 (P = 0.0007, OR 0.52 95% CI 0.35 to 0.76). Data showed no significant association between APOE genotype and overall CRN. However, compared with those carry APOE ε3 alleles, persons with APOE ε4 genotype have significant decreased risk suffering from proximal CRN but not from distal CRN.

Correa DD, Satagopan J, Baser RE, et al.
APOE polymorphisms and cognitive functions in patients with brain tumors.
Neurology. 2014; 83(4):320-7 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: The goal of this study was to assess whether the APOE ε4 allele and other APOE single nucleotide polymorphisms (SNPs) influence neuropsychological and neuroimaging outcomes in patients with brain tumors.
METHODS: Two hundred eleven patients with brain tumors participated in the study. All patients completed standardized neuropsychological tests and provided a blood sample for APOE genotyping. Ratings of white matter abnormalities were performed on MRI scans. Patients were classified into 2 groups based on the presence (n = 50) or absence (n = 161) of at least one APOE ε4 allele. Additional APOE SNPs were genotyped in a subset of 150 patients.
RESULTS: Patients with at least one APOE ε4 allele had significantly lower scores in verbal learning and delayed recall, and marginally significant lower scores in executive function, in comparison to noncarriers of an ε4 allele. Patients with at least one ε4 allele and history of cigarette smoking had significantly higher scores in working memory and verbal learning than ε4 carriers who never smoked. Nine additional APOE SNPs were significantly associated with attention and executive and memory abilities. There were no significant differences between ε4 carriers and noncarriers on the extent of white matter abnormalities on MRI.
CONCLUSIONS: The findings suggest that patients with brain tumors who are carriers of the APOE ε4 allele may have increased vulnerability to developing memory and executive dysfunction, and that additional SNPs in the APOE gene may be associated with cognitive outcome.


LXR agonism inhibits metastatic melanoma through activation of ApoE.
Cancer Discov. 2014; 4(5):OF16 [PubMed] Related Publications
Nuclear hormone receptor targeting suppresses melanoma progression in diverse preclinical models.

Liu Y, Wang X, Li S, et al.
The role of von Willebrand factor as a biomarker of tumor development in hepatitis B virus-associated human hepatocellular carcinoma: a quantitative proteomic based study.
J Proteomics. 2014; 106:99-112 [PubMed] Related Publications
UNLABELLED: Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC), the sixth most common cancer worldwide. To explore potential biomarkers for HCC, iTRAQ coupled with mass spectrometry was used to analyze proteins in plasma from individuals with HBV-associated HCC, nonmalignant cirrhosis, chronic hepatitis B, and healthy individuals. Twenty-one aberrantly expressed proteins were identified from HCC patients as compared with nontumor controls. Overexpression of von Willebrand factor (vWF) was confirmed by Western blotting, and immunohistochemical analysis from liver biopsies and ELISA from plasma samples revealed a correlation between vWF expression and HCC clinicopathologic staging. Furthermore, siRNA-induced vWF silencing reduced HBV replication by over two-fold via the interferon-signaling pathway and impaired the invasion and migration of HCC cells in vitro. These results indicate that vWF can serve as a biomarker, and perhaps an alternative target for therapeutic intervention of HCC progression and HBV viral infection.
BIOLOGICAL SIGNIFICANCE: We report comparative plasma proteome profiles of HBV-associated HCC and nonmalignant chronic liver diseases, including chronic hepatitis B and cirrhosis. The quantification of these datasets showed altered abundance of 21 proteins in HBV-related HCC and provides a reference point for future applied and basic research. In addition, we have demonstrated that the candidate protein vWF is involved in the pathogenesis of HBV infection and replication, and also associated with clinicopathologic staging of HCC patients with HBV infection. Overall these findings provide information on the mechanism of HCC development, which may assist in the development of novel cancer and HBV therapeutic drugs.

Papi A, De Carolis S, Bertoni S, et al.
PPARγ and RXR ligands disrupt the inflammatory cross-talk in the hypoxic breast cancer stem cells niche.
J Cell Physiol. 2014; 229(11):1595-606 [PubMed] Related Publications
Cancer stem cells (CSCs) are affected by the local micro-environment, the niche, in which inflammatory stimuli and hypoxia act as steering factors. Here, two nuclear receptors (NRs) agonists, i.e. pioglitazone (PGZ), a ligand of peroxisome proliferator activated receptor-γ, and 6-OH-11-O-hydroxyphenanthrene (IIF), a ligand of retinoid X receptors, were investigated for their capability to interference with the cross-talk between breast CSCs and the niche compartment. We found that IIF potentiates the ability of PGZ to hamper the mammospheres-forming capability of human breast tumours and MCF7 cancer cells, reducing the expression of CSCs regulatory genes (Notch3, Jagged1, SLUG, Interleukin-6, Apolipoprotein E, Hypoxia inducible factor-1α and Carbonic anhydrase IX). Notably, these effects are not observed in normal-MS obtained from human breast tissue. Importantly, NRs agonists abolish the capability of hypoxic MCF7 derived exosomes to induce a pro-inflammatory phenotype in mammary glands fibroblasts. Moreover, NRs agonist also directly acts on breast tumour associated fibroblasts to downregulate nuclear factor-κB pathway and metalloproteinases (MMP2 and MMP9) expression and activity. In conclusion, NRs agonists disrupt the inflammatory cross-talk of the hypoxic breast CSCs niche.

Pencheva N, Buss CG, Posada J, et al.
Broad-spectrum therapeutic suppression of metastatic melanoma through nuclear hormone receptor activation.
Cell. 2014; 156(5):986-1001 [PubMed] Related Publications
Melanoma metastasis is a devastating outcome lacking an effective preventative therapeutic. We provide pharmacologic, molecular, and genetic evidence establishing the liver-X nuclear hormone receptor (LXR) as a therapeutic target in melanoma. Oral administration of multiple LXR agonists suppressed melanoma invasion, angiogenesis, tumor progression, and metastasis. Molecular and genetic experiments revealed these effects to be mediated by LXRβ, which elicits these outcomes through transcriptional induction of tumoral and stromal apolipoprotein-E (ApoE). LXRβ agonism robustly suppressed tumor growth and metastasis across a diverse mutational spectrum of melanoma lines. LXRβ targeting significantly prolonged animal survival, suppressed the progression of established metastases, and inhibited brain metastatic colonization. Importantly, LXRβ activation displayed melanoma-suppressive cooperativity with the frontline regimens dacarbazine, B-Raf inhibition, and the anti-CTLA-4 antibody and robustly inhibited melanomas that had acquired resistance to B-Raf inhibition or dacarbazine. We present a promising therapeutic approach that uniquely acts by transcriptionally activating a metastasis suppressor gene.

Kulminski AM, Arbeev KG, Culminskaya I, et al.
Age, gender, and cancer but not neurodegenerative and cardiovascular diseases strongly modulate systemic effect of the Apolipoprotein E4 allele on lifespan.
PLoS Genet. 2014; 10(1):e1004141 [PubMed] Free Access to Full Article Related Publications
Enduring interest in the Apolipoprotein E (ApoE) polymorphism is ensured by its evolutionary-driven uniqueness in humans and its prominent role in geriatrics and gerontology. We use large samples of longitudinally followed populations from the Framingham Heart Study (FHS) original and offspring cohorts and the Long Life Family Study (LLFS) to investigate gender-specific effects of the ApoE4 allele on human survival in a wide range of ages from midlife to extreme old ages, and the sensitivity of these effects to cardiovascular disease (CVD), cancer, and neurodegenerative disorders (ND). The analyses show that women's lifespan is more sensitive to the e4 allele than men's in all these populations. A highly significant adverse effect of the e4 allele is limited to women with moderate lifespan of about 70 to 95 years in two FHS cohorts and the LLFS with relative risk of death RR = 1.48 (p = 3.6 × 10(-6)) in the FHS cohorts. Major human diseases including CVD, ND, and cancer, whose risks can be sensitive to the e4 allele, do not mediate the association of this allele with lifespan in large FHS samples. Non-skin cancer non-additively increases mortality of the FHS women with moderate lifespans increasing the risks of death of the e4 carriers with cancer two-fold compared to the non-e4 carriers, i.e., RR = 2.07 (p = 5.0 × 10(-7)). The results suggest a pivotal role of non-sex-specific cancer as a nonlinear modulator of survival in this sample that increases the risk of death of the ApoE4 carriers by 150% (p = 5.3 × 10(-8)) compared to the non-carriers. This risk explains the 4.2 year shorter life expectancy of the e4 carriers compared to the non-carriers in this sample. The analyses suggest the existence of age- and gender-sensitive systemic mechanisms linking the e4 allele to lifespan which can non-additively interfere with cancer-related mechanisms.

Ozen F, Polat F, Arslan S, Ozdemir O
Combined germline variations of thrombophilic genes promote genesis of lung cancer.
Asian Pac J Cancer Prev. 2013; 14(9):5449-54 [PubMed] Related Publications
BACKGROUND: A large variety of familiar and non-familiar lung carcinomas (LC) are caused by long term exposure to chemical carcinogens that are present in tobacco smoke. We aimed to investigate the prevalence of 5 thrombophilic germ-line mutations in patients with lung carcinomas.
MATERIALS AND METHODS: A total of 52 LC patients and 212 healthy controls from same population were analyzed for FV Leiden, factor V H1299R (R2), PAI-1, MTHFR C677T, MTHFR A1298C, ACE I/D, and Apo E genes and compared.
RESULTS: Overall, heterozygous and/or homozygous point mutations in FV Leiden Apo E2, PAI-1 and MTHFR C677T genes were associated with LC in the current cohort. There was no meaningful association between LC and ACE I/D gene markers.
CONCLUSIONS: The current results showed that LC is related to combined thrombophilic gene mutations and individuals with homozygosity of 4G in PAI-1 and MTHFR C677T genes and heterozygosity of FV Leiden, Apo E4 genes have a germ-line risk for LC tumorigenesis.

Kim HJ, Moon JH, Kim HM, et al.
The hypolipidemic effect of cilostazol can be mediated by regulation of hepatic low-density lipoprotein receptor-related protein 1 (LRP1) expression.
Metabolism. 2014; 63(1):112-9 [PubMed] Related Publications
OBJECTIVES: Cilostazol, a selective phosphodiesterase 3 (PDE3) inhibitor, is a vasodilator and an anti-thrombotic agent. The mechanism whereby cilostazol reduces plasma triglyceride is not completely understood. Here we investigated the effect of cilostazol on a remnant lipoprotein receptor, low-density lipoprotein receptor-related protein 1 (LRP1), which has been reported to play an essential role in clearance of circulating triglyceride in the liver.
MATERIALS/METHODS: Total cellular expression, and functional and transcriptional regulation of LRP1 were analyzed in human hepatocarcinoma cell lines incubated with cilostazol. Also, C57BL/6 mice were subjected to high-fat diet (60% kcal) and cilostazol (30 mg/kg) treatment for 10 weeks.
RESULTS: Cilostazol increased both mRNA and protein expression of LRP1 in HepG2 and Hep3B cells. In addition, enhanced transcriptional activity of the LRP1 promoter containing a peroxisome proliferator response element (PPRE) was observed after cilostazol exposure. Cilostazol treatment enhanced the uptake of lipidated apoE3, and this effect was abolished when LRP1 was silenced by siRNA knockdown. High-fat diet induced hyperglycemia with high level of plasma triglycerides, and reduced hepatic LRP1 expression in mice. Treatment with cilostazol for the same period of time, however, successfully prevented this down-regulation of LRP1 expression and reduced plasma triglycerides.
CONCLUSION: Taken together, our results demonstrated that cilostazol enhances LRP1 expression in liver by activating PPARγ through the PPRE in the LRP1 promoter. Increased hepatic LRP1 may be essential for the reduction of circulating triglycerides brought about by cilostazol.

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