The Functions of the Demethylase JMJD3 in Cancer.

Cancer is a major cause of death worldwide. Epigenetic changes in response to external (diet, sports activities, etc.) and internal events are increasingly implicated in tumor initiation and progression. In this review, we focused on post-translational changes in histones and, more particularly, the tri methylation of lysine from histone 3 (H3K27me3) mark, a repressive epigenetic mark often under- or overexpressed in a wide range of cancers. Two actors regulate H3K27 methylation: Jumonji Domain-Containing Protein 3 demethylase (JMJD3) and Enhancer of zeste homolog 2 (EZH2) methyltransferase. A number of studies have highlighted the deregulation of these actors, which is why this scientific review will focus on the role of JMJD3 and, consequently, H3K27me3 in cancer development. Data on JMJD3's involvement in cancer are classified by cancer type: nervous system, prostate, blood, colorectal, breast, lung, liver, ovarian, and gastric cancers.

Global analysis of H3K27me3 as an epigenetic marker in prostate cancer progression.

BACKGROUND: H3K27me3 histone marks shape the inhibition of gene transcription. In prostate cancer, the deregulation of H3K27me3 marks might play a role in prostate tumor progression. METHODS: We investigated genome-wide H3K27me3 histone methylation profile using chromatin immunoprecipitation (ChIP) and 2X400K promoter microarrays to identify differentially-enriched regions in biopsy samples from prostate cancer patients. H3K27me3 marks were assessed in 34 prostate tumors: 11 with Gleason score > 7 (GS > 7), 10 with Gleason score ≤ 7 (GS ≤ 7), and 13 morphologically normal prostate samples. RESULTS: Here, H3K27me3 profiling identified an average of 386 enriched-genes on promoter regions in healthy control group versus 545 genes in GS ≤ 7 and 748 genes in GS > 7 group. We then ran a factorial discriminant analysis (FDA) and compared the enriched genes in prostate-tumor biopsies and normal biopsies using ANOVA to identify significantly differentially-enriched genes. The analysis identified ALG5, EXOSC8, CBX1, GRID2, GRIN3B, ING3, MYO1D, NPHP3-AS1, MSH6, FBXO11, SND1, SPATS2, TENM4 and TRA2A genes. These genes are possibly associated with prostate cancer. Notably, the H3K27me3 histone mark emerged as a novel regulatory mechanism in poor-prognosis prostate cancer. CONCLUSIONS: Our findings point to epigenetic mark H3K27me3 as an important event in prostate carcinogenesis and progression. The results reported here provide new molecular insights into the pathogenesis of prostate cancer.

The association between histone 3 lysine 27 trimethylation (H3K27me3) and prostate cancer: relationship with clinicopathological parameters.

BACKGROUND: It is well established that genetic and epigenetic alterations are common events in prostate cancer, which may lead to aberrant expression of critical genes. The importance of epigenetic mechanisms in prostate cancer carcinogenesis is increasingly evident. In this study, the focus will be on histone modifications and the primary objectives are to map H3K27me3 marks and quantify RAR beta 2, ER alpha, SRC3, RGMA, PGR, and EZH2 gene expressions in prostate cancer tissues compared to normal tissues. In addition, a data analysis was made in connection with the clinicopathological parameters. METHODS: 71 normal specimens and 66 cancer prostate tissues were randomly selected in order to assess the proportion of the repressive H3K27me3 mark and gene expression. H3K27me3 level was evaluated by ChIP-qPCR and mRNA expression using RT-qPCR between prostate cancer and normal tissues. Subsequently, western-blotting was performed for protein detection. The analysis of variance (ANOVA) was performed, and Tukey's test was used to correct for multiple comparisons (p-value threshold of 0.05). The principal component analysis (PCA) and discriminant factorial analysis (DFA) were used to explore the association between H3K27me3 level and clinicopathological parameters. RESULTS: The study demonstrated that H3K27me3 level was significantly enriched at the RAR beta 2, ER alpha, PGR, and RGMA promoter regions in prostate cancer tissues compared to normal tissues. After stratification by clinicopathological parameters, the H3K27me3 level was positively correlated with Gleason score, PSA levels and clinical stages for RAR beta 2, ER alpha, PGR, and RGMA. High H3K27me3 mark was significantly associated with decreased RAR beta 2, ER alpha, PGR and RGMA gene expressions in prostate cancer sample compared to the normal one. Moreover, the results showed that mRNA level of EZH2, AR and SRC3 are upregulated in prostate cancer compared to normal prostate tissues and this correlates positively with Gleason score, PSA levels and clinical stages. Obviously, these observations were confirmed by protein level using western-blot. CONCLUSIONS: This data clearly demonstrated that H3K27me3 level correlated with aggressive tumor features. Also this study revealed that reverse correlation of RAR beta 2, ER alpha, PGR, and RGMA expressions with EZH2, SRC3, and AR expressions in prostate cancer tissues suggests that these genes are the target of EZH2. Therefore, all therapeutic strategies leading to histone demethylation with epigenetic drugs such as histone methyltransferase inhibitor may be relevant treatments against prostate cancer.

Leptin induces a proliferative response in breast cancer cells but not in normal breast cells.

Obesity is a risk factor for breast cancer in postmenopausal women. Leptin, a hormone excessively produced during obesity, is suggested to be involved in breast cancer. The aim of the study was to investigate procarcinogenic potential of leptin by evaluating influence of leptin on cell proliferation, cell cycle, apoptosis, and signaling on numerous breast cells lines, including 184B5 normal cells, MCF10A fibrocystic cells and MCF-7, MDA-MB-231, and T47D cancer cells. Expressions of leptin and Ob-R were analyzed using qRT-PCR and immunohistochemistry, proliferation using fluorimetric resazurin reduction test and xCELLigence system, apoptosis and cell cycle by flow cytometry, and effect of leptin on different signalling pathways using qRT-PCR and Western blot. Cells were exposed to increasing concentrations of leptin. All cell lines expressed mRNA and protein of leptin and Ob-R. Leptin stimulated proliferation of all cell lines except for 184B5 and MDA-MB-231 cells. Leptin inhibited apoptosis but didn't alter proportion of cells within cell cycle in MCF7 cells. Leptin induced overexpression of leptin, Ob-R, estrogen receptor, and aromatase mRNA in MCF-7 and T47D cells. Autoregulation induced by leptin, relationship with estrogen pathway, and proliferative and antiapoptic activity in breast cancer cells may explain that obesity-associated hyperleptinemia may be a breast cancer risk factor.

Comparative effects of soy phytoestrogens and 17ß-estradiol on DNA methylation of a panel of 24 genes in prostate cancer cell lines.

Major phytoestrogens genistein and daidzein have been reported to have the ability to reverse DNA methylation in cancer cell lines. The mechanism by which genistein and daidzein have an inhibiting action on DNA methylation is not well understood. The aim of this study was to investigate the effects of soy phytoestrogens and the natural estrogen 17ß-estradiol (E2) to determine whether one of the estrogen receptors is mobilized for the action of these compounds on DNA methylation. We also made a comparative study with a DNA methylation inhibitor (5-azacytidine) and a DNA methylation activator (budesonide). Three prostate cell lines, PC-3, DU-145, and LNCaP, were treated with 40 µM genistein, 110 µM daidzein, 2 µM budesonide, 2 µM 5-azacytidine, and 10 µM E2. In these 3 human prostate cancer cell lines, we performed methylation quantification using methyl-profiler-DNA-methylation analysis. Soy phytoestrogens and E2 induced a demethylation of all the promoter regions studied except for those that were unmethylated in control cells. Our results showed that E2 induces, like soy phytoestrogen, a decrease in DNA methylation in prostate cancer cell lines. This action may be mediated through ERß.

Epigenetic modulation of BRCA1 and BRCA2 gene expression by equol in breast cancer cell lines.

S-Equol is a metabolite resulting from the conversion of daidzein, a soya phyto-oestrogen, by the gut microflora. The potential protective effects of equol in breast cancer are still under debate. Consequently, we investigated the effects of equol on DNA methylation of breast cancer susceptibility genes (BRCA1 and BRCA2) and oncosuppressors in breast cancer cell lines (MDA-MB-231 and MCF-7) and in a dystrophic breast cell line (MCF-10a) following exposure to S-equol (2 µm) for 3 weeks. We demonstrated by quantitative analysis of methylated alleles a significant decrease in the methylation of the cytosine phosphate guanine (CpG) islands in the promoters of BRCA1 and BRCA2 after the S-equol treatment in MCF-7 and MDA-MB-231 cells and a trend in MCF-10a cells. We also showed that S-equol increases BRCA1 and BRCA2 protein expression in the nuclei and the cytoplasm in MCF-7, MDA-MB-231 and MCF-10a cell lines by immunohistochemistry. The increase in BRCA1 and BRCA2 proteins was also found after Western blotting in the studied cell lines. In summary, we demonstrated the demethylating effect of S-equol on the CpG islands inside the promoters of BRCA1 and BRCA2 genes, resulting in an increase in the level of expressed oncosuppressors in breast cancer cell lines.

Effects of GSK-J4 on JMJD3 Histone Demethylase in Mouse Prostate Cancer Xenografts.

BACKGROUND/AIM: Histone methylation status is required to control gene expression. H3K27me3 is an epigenetic tri-methylation modification to histone H3 controlled by the demethylase JMJD3. JMJD3 is dysregulated in a wide range of cancers and has been shown to control the expression of a specific growth-modulatory gene signature, making it an interesting candidate to better understand prostate tumor progression in vivo. This study aimed to identify the impact of JMJD3 inhibition by its inhibitor, GSK4, on prostate tumor growth in vivo. MATERIALS AND METHODS: Prostate cancer cell lines were implanted into Balb/c nude male mice. The effects of the selective JMJD3 inhibitor GSK-J4 on tumor growth were analyzed by bioluminescence assays and H3K27me3-regulated changes in gene expression were analyzed by ChIP-qPCR and RT-qPCR. RESULTS: JMJD3 inhibition contributed to an increase in tumor growth in androgen-independent (AR-) xenografts and a decrease in androgen-dependent (AR+). GSK-J4 treatment modulated H3K27me3 enrichment on the gene panel in DU-145-luc xenografts while it had little effect on PC3-luc and no effect on LNCaP-luc. Effects of JMJD3 inhibition affected the panel gene expression. CONCLUSION: JMJD3 has a differential effect in prostate tumor progression according to AR status. Our results suggest that JMJD3 is able to play a role independently of its demethylase function in androgen-independent prostate cancer. The effects of GSK-J4 on AR+ prostate xenografts led to a decrease in tumor growth.

Evaluation of breast cancer risk in a multigenic model including low penetrance genes involved in xenobiotic and estrogen metabolisms.

Breast cancer has become the most frequent cancer among women in Westernized countries. The majority of breast cancers are due to low penetrance genes, which can act with environmental factors, particularly nutrition. Polymorphisms in gene coding for xenobiotic and estrogen metabolic pathways could increase individual cancer susceptibility and lead to the indication of individuals at higher cancer risk. A population-based, case-control study consisting of 911 breast cancer cases and 1,000 healthy control cases was performed. The association between 11 single nucleotide polymorphisms (SNP) in 7 genes and breast cancer risk was investigated in a multigenic model. The CYP1B1-432 Leu-Val and Val-Val genotypes significantly increased risk [odds ratio (OR) = 1.23, 95% confidence interval (CI) = 1.08-1.39; OR = 1.51, 95% CI = 1.17-1.94, respectively] similarly as observed with CYP1B1-453 (Asn-Ser genotype: OR = 1.17, 95% CI = 1.00-1.37; Ser-Ser genotype: OR = 1.38, 95% CI = 1.00-1.89). We showed that catechol-O-methyltransferase (COMT) could modulate the risk conferred by CYP1B1, ESR, GSTP1, and NAT2 acetylation phenotype. Additionally, a higher risk conferred by the variant for COMT was noted only for individuals presenting a high waist-to-hip ratio (COMT Val-Met, OR = 1.60, 95% CI = 1.04-2.44; COMT Met-Met, OR = 1.57, 95% CI = 0.98-2.53), suggesting a relationship with abdominal adiposity. In conclusion, COMT constitutes a crucial element in estrogen metabolism by regulating carcinogen metabolites elimination and, consequently, is a major factor in breast cancer risk.

Transcriptional profiling of breast cancer cells exposed to soy phytoestrogens after BRCA1 knockdown with a whole human genome microarray approach.

The estrogen-like properties of the soy phytoestrogens could modulate the estrogen-dependent expression of BRCA1 oncosuppressor, which is highly involved in hereditary and sporadic breast cancer. In order to better understand the importance of BRCA1 function and the role of other genes involved around BRCA1 in the phytoestrogen pathways, we have exploited the BRCA1-specific knockdown by RNA interference using double stranded small interfering RNA (siRNA) in breast tumor cell lines (MCF-7, MDA-MB-231) and a fibrokystic breast cell line (MCF-10a) and treated with 18.5 microM genistein or 78.5 microM daidzein for 72 h. We used pangenomic microarrays and subsequently TLDA analysis and demonstrated that cumulated BRCA1 knockdown with soy isoflavone supplementations in breast cell lines seems to modulate apoptosis, MAPK pathway, cell communication, xenobiotic metabolism, and sterol metabolism. Also, transient BRCA1 deficiency in breast cell lines significantly diminished or reversed gene expression after phytoestrogen supplementation. We observed that the significant decrease expression of apoptosis-related genes such as BAX, and the increase expression of BCL2, under BRCA1 knockdown condition, were completely reversed after phytoestrogen treatments. These results underlined the role of BRCA1 expression in breast carcinogenesis and suggested that soy phytoestrogen supplementation could play a role in cancer.

Soy phytoestrogens modify DNA methylation of GSTP1, RASSF1A, EPH2 and BRCA1 promoter in prostate cancer cells.

BACKGROUND: The aim of this study was to determine the effects of soy phytoestrogens on the methylation of promoter genes in prostate tumors. The incidence of prostate cancer in Asia is thirty percent lower than in Western countries. Since soy phytoestrogens represent a large portion of the Asian diet, evidence suggests their protective effect against prostate cancer. MATERIALS AND METHODS: In three human prostate cancer cell lines, methylation-specific-PCR was used to determine the effect of soy isoflavones (genistein and daidzein), compared to known demethylating agent 5-azacytidine as control in the promoter regions of glutathione S-transferase P1 (GSTP1), Ras association domain family 1 (RASSF1A), ephrin B2 (EPHB2) and breast cancer 1 (BRCA1) genes. In parallel, immunohistochemistry was used to assess the effects of genistein, daidzein and 5-azacytidine treatment on the corresponding protein expression. RESULTS: All studied promoters, with the exception of that for BRCA1, were strongly methylated without treatment. After treatment by phytoestrogens, demethylation of GSTP1 and EPHB2 promoter regions was observed and an increase in their protein expression was demonstrated by immunohistochemistry. CONCLUSION: Epigenetic modifications of DNA, such as the promoter CpG island demethylation of tumor suppressor genes, might be related to the protective effect of soy on prostate cancer.

Epi-drugs as triple-negative breast cancer treatment.

Triple-negative breast cancer (TNBC) types with poor prognosis are due to the absence of estrogen receptors, progesterone receptors and HEGFR-2. The lack of suitable therapy for TNBC has led the research community to turn toward epigenetic regulation and its protagonists that can modulate certain oncogenes and tumor suppressors. This has opened an important new field of therapy using epi-drugs, in preclinical and clinical trials. The epi-drugs are natural or synthetic molecules capable of inhibiting or modulating the activity of epigenetic proteins such as DNA methyltransferases, modulating the expression of interferon microRNAs, as well as histone methyltransferases, demethylases, acetyltransferases and deacetylases. This review investigated the epi-drugs used in the treatment of TNBC.

TIP60/P400/H4K12ac Plays a Role as a Heterochromatin Back-up Skeleton in Breast Cancer.

BACKGROUND/AIM: In breast cancer, initiation of carcinogenesis leads to epigenetic dysregulation, which can lead for example to the loss of the heterochromatin skeleton SUV39H1/H3K9me3/HP1 or the supposed secondary skeleton TIP60/P400/H4K12ac/BRD (2/4), which allows the maintenance of chromatin integrity and plasticity. This study investigated the relationship between TIP60, P400 and H4K12ac and their implications in breast tumors. MATERIALS AND METHODS: Seventy-seven patients diagnosed with breast cancer were included in this study. Chromatin immunoprecipitation (ChIP) assay was used to identify chromatin modifications. Western blot and reverse transcription and quantitative real-time PCR were used to determine protein and gene expression, respectively. RESULTS: We verified the variation in H4K12ac enrichment and the co-localization of H4K12ac and TIP60 on the euchromatin and heterochromatin genes, respectively, by ChIP-qPCR and ChIP-reChIP, which showed an enrichment of H4K12ac on specific genes in tumors compared to the adjacent healthy tissue and a co-localization of H4K12ac with TIP60 in different breast tumor types. Furthermore, RNA and protein expression of TIP60 and P400 was investigated and overexpression of TIP60 and P400 mRNA was associated with tumor aggressiveness. CONCLUSION: There is a potential interaction between H4K12ac and TIP60 in heterochromatin or euchromatin in breast tumors.

Digging Deeper into Breast Cancer Epigenetics: Insights from Chemical Inhibition of Histone Acetyltransferase TIP60 In Vitro.

Breast cancer is often sporadic due to several factors. Among them, the deregulation of epigenetic proteins may be involved. TIP60 or KAT5 is an acetyltransferase that regulates gene transcription through the chromatin structure. This pleiotropic protein acts in several cellular pathways by acetylating proteins. RNA and protein expressions of TIP60 were shown to decrease in some breast cancer subtypes, particularly in triple-negative breast cancer (TNBC), where a low expression of TIP60 was exhibited compared with luminal subtypes. In this study, the inhibition of the residual activity of TIP60 in breast cancer cell lines was investigated by using two chemical inhibitors, TH1834 and NU9056, first on the acetylation of the specific target, lysine 4 of histone 3 (H3K4) by immunoblotting, and second, by chromatin immunoprecipitation (ChIP)-qPCR (-quantitative Polymerase Chain Reaction). Subsequently, significant decreases or a trend toward decrease of H3K4ac in the different chromatin compartments were observed. In addition, the expression of 48 human nuclear receptors was studied with TaqMan Low-Density Array in these breast cancer cell lines treated with TIP60 inhibitors. The statistical analysis allowed us to comprehensively characterize the androgen receptor and NR3C2 receptors in TNBC cell lines after TH1834 or NU9056 treatment. The understanding of the residual activity of TIP60 in the evolution of breast cancer might be a major asset in the fight against this disease, and could allow TIP60 to be used as a biomarker or therapeutic target for breast cancer progression in the future.

Genetic polymorphisms in CYP1A1, CYP1B1, COMT, GSTP1 and NAT2 genes and association with bladder cancer risk in a French cohort.

UNLABELLED: Tobacco smoking and environmental exposures are the main known risk factors for bladder cancer (BC) via exposure to chemical carcinogens. Genetic differences in the metabolism of chemicals have been suggested to be associated with individual susceptibility to BC. Polymorphisms in genes coding to metabolising enzymes, resulting in variation of carcinogen detoxification efficiency, may therefore change the response of individuals to chemical carcinogens and be associated with an increased BC risk. PATIENTS AND METHODS: The aim of the study was to investigate the association between functional polymorphisms in CYP1A1, CYP1B1, COMT, GSTP1 and NAT2 genes and BC risk, through a hospital-based case-control study. The genotyping of 11 Single Nucleotide Polymorphisms (SNPs) was carried out on DNA of 51 bladder cancer male patients and 45 male controls. The technique of MGB (Minor Groove Binder) probes that utilize allelic discrimination with the Taqman(R) method was used. RESULTS: Individuals with NAT2 slow acetylator genotypes had a significant increase in risk of BC compared to individuals with NAT2 rapid acetylators (OR adjusted for smoking status=2.70; 95% CI, 1.10-6.61). GSTP1 Ile(105)Val variants (deletion of one - Ile/Val- and two -Val/Val-, null genotype- copies) showed a marginal increased risk of BC with OR adjusted for smoking status of 2.27 (95% CI, 0.97-5.31) compared to individuals carrying wild-type genotype (Ile/Ile). No statistically significant effects on BC risk with CYP1A1, CYP11B1 and COMT genotypes were observed. CONCLUSION: The results are consistent with previous literature among Caucasian populations.

Methylation analysis of BRCA1, RASSF1, GSTP1 and EPHB2 promoters in prostate biopsies according to different degrees of malignancy.

Prostate cancer is the most common cancer among men and the second leading cause of cancer-related deaths in the United States. CpG island methylation causes gene silencing and could be decisive in prostate carcinogenesis and progression. Its role was investigated at multiple gene sites during prostate carcinogenesis. Methylation-specific polymerase chain reaction (MS-PCR) was used to analyze 4 interest gene promoter status in 12 patients with adenocarcinoma, 7 patients with prostate intraepithelial neoplasia, 3 patients with peritumor tissues and 15 healthy patients, so a total of 37 prostate biopsy samples constituted the cohort of the study. Despite the biopsy histology, the results have confirmed that BRCA1, RASSF1, GSTP1 and EPHB2 promoter methylation was found in each sample, except two.

Immunohistochemical staining of mucin 1 in prostate tissues.

UNLABELLED: Prostate cancer is a major public health problem in the world. Molecular studies are necessary for the development of prognostic markers in prostate cancer. There is a great interest in mucin studies in treatment development of human malignancies, including prostate cancer. Nevertheless, their expressions in prostate cancer need further investigation. MATERIALS AND METHODS: Mucin 1 (MUC1) expression was examined in 100 prostate biopsies and were compared with prostate carcinoma cell lines (DU-145, PC-3, LNCaP) by immunohistochemistry. RESULTS: Biopsies were healthy, tumor, peritumor or presented an intraepithelial neoplasia. Staining of MUC1 was exihibited in PC-3 cells, was higher in DU-145, and was not expressed by LNCaP. Tumor sections presented more positive expression of MUC1 than non-tumor sections. CONCLUSION: MUC1 expression is correlated with the histological degree of malignancy.

Expression profiling by whole-genome microarray hybridization reveals differential gene expression in breast cancer cell lines after lycopene exposure.

The correlation between diet and variation in gene-expression is an important field which could be considered to approach cancer pathways comprehension. We examined the effects of lycopene on breast cancer cell lines using pangenomic arrays. Lycopene is derived predominantly from tomatoes and tomato products and there is some epidemiologic evidence for a preventive role in breast cancer. Previously, we investigated lycopene in breast cancer using a dedicated breast cancer microarray. To confirm these results and explore pathways other than those implicated in breast cancer, for this study we used pangenomic arrays containing 25,000 oligonucleotides. This in vitro study assayed two human mammary cancer cell lines (MCF-7 and MDA-MB-231), and a fibrocystic breast cell line (MCF-10a) treated or not with 10 microM lycopene for 48 h. A competitive hybridization was performed between Cy3-labeled lycopene treated RNA and Cy5-labeled untreated RNA to define differentially expressed genes. Using t-test analysis, a subset of 391 genes was found to be differentially modulated by lycopene between estrogen-positive cells (MCF-7) and estrogen-negative cells (MDA-MB-231, MCF-10a). Hierarchical clustering revealed 726 discriminatory genes between breast cancer cell lines (MCF-7, MDA-MB-231) and the fibrocystic breast cell line (MCF-10a). Modified gene expression was observed in various molecular pathways, such as apoptosis, cell communication, MAPK and cell cycle as well as xenobiotic metabolism, fatty acid biosynthesis and gap junctional intercellular communication.

DNA repair gene ERCC2 polymorphisms and associations with breast and ovarian cancer risk.

Breast and ovarian cancers increased in the last decades. Except rare cases with a genetic predisposition and high penetrance, these pathologies are viewed as a polygenic disease. In this concept, association studies look for genetic variations such as polymorphisms in low penetrance genes, i.e. genes in interaction with environmental factors. DNA repair systems that protect the genome from deleterious endogenous and exogenous damages have been shown to have significantly reduced. In particular, enzymes of the nucleotide excision repair pathway are suspected to be implicated in cancer. In this study, 2 functional polymorphisms in a DNA repair gene ERCC2 were analyzed. The population included 911 breast cancer cases, 51 ovarian cancer cases and 1000 controls. The genotyping of 2 SNP (Single Nucleotide Polymorphism) was carried out on the population with the MGB (Minor Groove Binder) probe technique which consists of the use of the allelic discrimination with the Taqman method. This study enabled us to show an increase in risk of breast cancer with no oral contraceptive users and with women exhibiting a waist-to-hip ratio (WHR) > 0.85 for Asn homozygous for ERCC2 312.

Association between genetic polymorphisms and ovarian cancer risk.

BACKGROUND: The etiology of ovarian cancer is not fully understood. Polymorphisms in low penetrance genes involved in carcinogen and estrogen metabolism are hypothesized to play a role in the initiation of carcinogenesis. PATIENTS AND METHODS: A case-control study was conducted to investigate the role of these polymorphisms in ovarian cancer risk. The participants were genotyped for eleven polymorphisms in seven genes involved in estrogen and xenobiotic metabolism (CYP1A1, CYP1B1, COMT, GSTP1, NAT2, estrogen receptor ESR, and progesterone receptor PGR). RESULTS AND CONCLUSION: The odds ratios for ovarian cancer risk were 2.02 (95% confidence interval [CI] = 1.14-3.56) in the NAT2 intermediate acetylators and 4.07 (95% CI = 1.30-12.70) in the slow acetylators. At least three cumulative high-risk genotypes increased ovarian cancer risk, but not significantly. More studies are needed in order to define genetic ovarian risk factors.

DNA repair gene ERCC2, XPC, XRCC1, XRCC3 polymorphisms and associations with bladder cancer risk in a French cohort.

In polygenic diseases, association studies look for genetic variation such as polymorphisms in low penetrance genes, i.e. genes in interaction with environmental factors. DNA repair systems that protect the genome from deleterious endogenous and exogenous damage have been shown to significantly reduce activity. In particular, enzymes of the nucleotide excision repair pathway are suspected to be implicated in cancer. In this study bladder cancer which is viewed as a polygenic disease was investigated. The functional polymorphisms of four DNA repair genes, excision repair cross-complementing group 2 (ERCC2), Xeroderma Pigmentosum group C (XPC), and Xray repair cross-complementing groups 1 and 3 (XRCC1 and XRCC3) were analyzed. The studied population included 51 bladder cancer cases and 45 controls. The genotyping of six SNP (single nucleotide polymorphism) was carried out on these populations with the MGB (Minor Groove Binder) probe technique which uses allelic discrimination with the Taqman method. The Gln allele of the XPC 939 polymorphism was found to be associated with an increase in bladder cancer risk.