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  • 1
    Keywords: CANCER ; CELLS ; EXPRESSION ; carcinoma ; Germany ; SITE ; GENES ; PROTEIN ; PROTEINS ; TISSUE ; CARCINOGENESIS ; PHOSPHORYLATION ; antibodies ; MOUSE ; LESIONS ; PROGRESSION ; immunohistochemistry ; CERVIX ; CELL-LINE ; REGION ; REGIONS ; CARCINOMAS ; INTERCELLULAR COMMUNICATION ; STRATIFIED EPITHELIUM ; JUNCTION ; premalignant ; gap junction ; cell communication
    Abstract: Connexins are proteins that form the connexons, gap junction structures, which allow cells to communicate. Phosphorylation of connexins has been found to impair this communication. Using an antibody specifically recognizing the S279/S282-phosphorylated form of connexin43 (Cx43) for immunohistochemistry, we have analysed Cx43 phosphorylation in normal epithelium, CIN III lesions, and carcinomas of the cervix. We found that in normal epithelium the basal layer was devoid of staining and most of the protein was localized in stratum spinosum and stratum granulosum. In pre-malignant CIN-III lesions Cx43 was strongly phosphorylated, but the basal layer was still negative. In squamous carcinomas, the cells were intensely stained. In these tumours, sites of strong staining were adjacent to less stained regions, suggesting that the tumours are intrinsically heterogeneous. Immunoblotting of proteins extracted from carcinomas with the specific antibody showed the classical pattern of multiple reacting bands, with the appearance of low migrating forms of the protein. Our results suggest that increased S279/S282 phosphorylation of Cx43 is the result of altered tissue structure rather than of cell malignization. (c) 2005 Elsevier Ireland Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 15958277
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  • 2
    Keywords: CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; tumor ; carcinoma ; CELL ; Germany ; human ; INHIBITION ; GENE ; PROTEIN ; TISSUE ; CARCINOGENESIS ; DOWN-REGULATION ; E7 ; papillomavirus ; TARGET ; virus ; ELEMENT ; LESIONS ; PROMOTER ; cervical cancer ; CERVICAL-CANCER ; p53 ; GROWTH-INHIBITION ; human papillomavirus ; CANCER-CELLS ; HPV ; E6 ; ONCOGENE ; HPV16 ; HUMAN-PAPILLOMAVIRUS ; CARCINOMAS ; POSITIVE CANCER-CELLS ; TRANSLOCATION ; OVEREXPRESSION ; REPRESSION ; RETINOIC ACID ; E6 ONCOPROTEIN ; TUMOR-SUPPRESSOR ; papillomaviruses ; LEVEL ; tumor suppressor gene ; EPITHELIUM ; USA ; oncogenes ; B-CELL ; HUMAN PAPILLOMAVIRUSES ; tumor suppressor genes ; NOV ; tumor suppressor ; Luciferase reporter ; BTG2 ; cervical cancers ; viral carcinogenesis
    Abstract: Human papillomavirus (HPV)-induced carcinogenesis is critically dependent on the activities of the viral E6 and E7 oncogenes. Here, we demonstrate that expression of the putative tumor suppressor gene B-cell translocation gene-2 (BTG2) is reinduced in HPV16- and HPV18-positive cancer cells on silencing of viral oncogene expression, indicating that BTG2 is repressed by oncogenic HPVs. Inhibition of BTG2 expression was mediated by the HPV E6 oncogene and occurred in a p53-dependent manner. Luciferase reporter gene analyses revealed that BTG2 repression takes place at the transcriptional level and is dependent on the integrity of the major p53-response element within the BTG2 promoter. Ectopic expression of BTG2 acted antiproliferative in cervical cancer cells. Tissue specimens commonly exhibited reduced BTG2 protein levels in HPV-positive high-grade lesions (CIN2/3) and cervical carcinomas, when compared with normal cervical epithelium. These findings identify the antiproliferative BTG2 gene as a novel cellular target blocked by the HPV E6 oncoprotein. (C) 2009 UICC
    Type of Publication: Journal article published
    PubMed ID: 19551855
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  • 3
    Keywords: CANCER ; SURVIVAL ; RISK ; FAMILY ; ASSOCIATION ; SUSCEPTIBILITY ; BREAST-CANCER ; MUTATIONS ; MUTATION CARRIERS ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; CONSORTIUM
    Abstract: Purpose: An assay for the single-nucleotide polymorphism (SNP), rs61764370, has recently been commercially marketed as a clinical test to aid ovarian cancer risk evaluation in women with family histories of the disease. rs67164370 is in a 3'-UTR miRNA binding site of the KRAS oncogene and is a candidate for epithelial ovarian cancer (EOC) susceptibility. However, only one published article, analyzing fewer than 1,000 subjects in total, has examined this association. Experimental Design: Risk association was evaluated in 8,669 cases of invasive EOC and 10,012 controls from 19 studies participating in the Ovarian Cancer Association Consortium, and in 683 cases and 2,044 controls carrying BRCA1 mutations from studies in the Consortium of Investigators of Modifiers of BRCA1/2. Prognosis association was also examined in a subset of five studies with progression-free survival (PFS) data and 18 studies with all-cause mortality data. Results: No evidence of association was observed between genotype and risk of unselected EOC (OR = 1.02, 95% CI: 0.95-1.10), serous EOC (OR = 1.08, 95% CI: 0.98-1.18), familial EOC (OR = 1.09, 95% CI: 0.78-1.54), or among women carrying deleterious mutations in BRCA1 (OR = 1.09, 95% CI: 0.88-1.36). There was little evidence for association with survival time among unselected cases (HR = 1.10, 95% CI: 0.99-1.22), among serous cases (HR = 1.12, 95% CI = 0.99-1.28), or with PFS in 540 cases treated with carboplatin and paclitaxel (HR = 1.18, 95% CI: 0.93-1.52). Conclusions: These data exclude the possibility of an association between rs61764370 and a clinically significant risk of ovarian cancer or of familial ovarian cancer. Use of this SNP for ovarian cancer clinical risk prediction, therefore, seems unwarranted.
    Type of Publication: Journal article published
    PubMed ID: 21385923
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  • 4
    Keywords: EXPRESSION ; GENE ; BREAST-CANCER ; OVARIAN-CANCER ; PROSTATE-CANCER ; telomere length ; COMMON VARIANT ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; FUNCTIONAL VARIATION
    Abstract: Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with endometrial cancer. To evaluate the role of genetic variants at the TERT-CLPTM1L region in endometrial cancer risk, we carried out comprehensive fine-mapping analyses of genotyped and imputed SNPs using a custom Illumina iSelect array which includes dense SNP coverage of this region. We examined 396 SNPs (113 genotyped, 283 imputed) in 4,401 endometrial cancer cases and 28,758 controls. Single-SNP and forward/backward logistic regression models suggested evidence for three variants independently associated with endometrial cancer risk (P = 4.9 x 10(-6) to P = 7.7 x 10(-5)). Only one falls into a haplotype previously associated with other cancer types (rs7705526, in TERT intron 1), and this SNP has been shown to alter TERT promoter activity. One of the novel associations (rs13174814) maps to a second region in the TERT promoter and the other (rs62329728) is in the promoter region of CLPTM1L; neither are correlated with previously reported cancer-associated SNPs. Using TCGA RNASeq data, we found significantly increased expression of both TERT and CLPTM1L in endometrial cancer tissue compared with normal tissue (TERT P = 1.5 x 10(-18), CLPTM1L P = 1.5 x 10(-19)). Our study thus reports a novel endometrial cancer risk locus and expands the spectrum of cancer types associated with genetic variation at 5p15, further highlighting the importance of this region for cancer susceptibility.
    Type of Publication: Journal article published
    PubMed ID: 25487306
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  • 5
    Keywords: EXPRESSION ; carcinoma ; polymorphism ; BREAST-CANCER ; COLON-CANCER ; GENOME-WIDE ASSOCIATION ; UDP-GLUCURONOSYLTRANSFERASES ; IRON TRANSPORT ; FAMILY SLC25 ; HEPHAESTIN
    Abstract: BACKGROUND: Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk. METHODS: In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q〈0.2 was applied to adjust for multiple comparisons. RESULTS: The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p〈0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4). CONCLUSION: These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.
    Type of Publication: Journal article published
    PubMed ID: 26091520
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  • 6
    Keywords: carcinoma ; MODELS ; POPULATION ; VARIANTS ; BREAST-CANCER ; TRANSCRIPTION FACTORS ; PROFILES ; SET ; susceptibility loci ; GENOME-WIDE ASSOCIATION
    Abstract: BACKGROUND: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by co-expression may also be enriched for additional EOC risk associations. METHODS: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly co-expressed with each selected TF gene in the unified microarray data set of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this data set were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). RESULTS: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P〈0.05 and FDR〈0.05). These results were replicated (P〈0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. CONCLUSION: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. IMPACT: Network analysis integrating large, context-specific data sets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization.
    Type of Publication: Journal article published
    PubMed ID: 26209509
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  • 7
    Abstract: BACKGROUND: In vitro and observational epidemiological studies suggest that vitamin D may play a role in cancer prevention. However, the relationship between vitamin D and ovarian cancer is uncertain, with observational studies generating conflicting findings. A potential limitation of observational studies is inadequate control of confounding. To overcome this problem, we used Mendelian randomization (MR) to evaluate the association between single nucleotide polymorphisms (SNPs) associated with circulating 25-hydroxyvitamin D [25(OH)D] concentration and risk of ovarian cancer. METHODS: We employed SNPs with well-established associations with 25(OH)D concentration as instrumental variables for MR: rs7944926 (DHCR7), rs12794714 (CYP2R1) and rs2282679 (GC). We included 31 719 women of European ancestry (10 065 cases, 21 654 controls) from the Ovarian Cancer Association Consortium, who were genotyped using customized Illumina Infinium iSelect (iCOGS) arrays. A two-sample (summary data) MR approach was used and analyses were performed separately for all ovarian cancer (10 065 cases) and for high-grade serous ovarian cancer (4121 cases). RESULTS: The odds ratio for epithelial ovarian cancer risk (10 065 cases) estimated by combining the individual SNP associations using inverse variance weighting was 1.27 (95% confidence interval: 1.06 to 1.51) per 20 nmol/L decrease in 25(OH)D concentration. The estimated odds ratio for high-grade serous epithelial ovarian cancer (4121 cases) was 1.54 (1.19, 2.01). CONCLUSIONS: Genetically lowered 25-hydroxyvitamin D concentrations were associated with higher ovarian cancer susceptibility in Europeans. These findings suggest that increasing plasma vitamin D levels may reduce risk of ovarian cancer.
    Type of Publication: Journal article published
    PubMed ID: 27594614
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  • 8
    Keywords: CANCER ; CELLS ; radiotherapy ; tumor ; CELL ; COMBINATION ; Germany ; human ; IN-VIVO ; SUPPORT ; GENE ; GENES ; PROTEIN ; SURGERY ; MICE ; TIME ; PATIENT ; RESPONSES ; DNA ; IFN-GAMMA ; INDUCTION ; ANTIGEN ; ANTIGENS ; T cells ; T-CELL ; T-CELLS ; cytokines ; IMMUNE-RESPONSES ; TARGET ; virus ; HUMANS ; cervical cancer ; CERVICAL-CANCER ; chemotherapy ; DELIVERY ; HPV ; HUMAN-PAPILLOMAVIRUS ; VACCINE ; GRANZYME-B ; ANTIGEN-PRESENTING CELLS ; immune response ; IMMUNE-RESPONSE ; IMMUNOTHERAPY ; IMMUNOGENICITY ; human papilloma virus ; ADJUVANT ; PLASMID DNA ; CYTOTOXIC T-LYMPHOCYTES ; IMMUNIZATION ; CYTOKINE ; REGRESSION ; secretion ; LIFE ; ENHANCEMENT ; cancer vaccine ; QUALITY-OF-LIFE ; DNA vaccine ; quality of life ; USA ; immunology ; tumor regression ; gene shuffling ; virology ; 3 ; Genetic ; therapeutic ; TUMOR-REGRESSION ; EXPRESSION CASSETTES ; genetic adjuvants ; gynecology
    Abstract: Treatment of patients with cervical cancer by conventional methods (mainly surgery, but also radiotherapy and chemotherapy) results in a significant loss in quality of life. A therapeutic DNA vaccine directed to tumor-specific antigens of the human papilloma virus (HPV) could be an attractive treatment option. We have developed a nontransforming HIV-16 E7-based DNA vaccine containing all putative T cell epitopes (HPV-16 E7SH). DNA vaccines, however, are less immunogenic than protein- or peptide-based vaccines in larger animals and humans. In this study, we have investigated an adjuvant gene support of the HPV-16 E7SH therapeutic cervical cancer vaccine. DNA encoded cytokines (IL-2, IL-12, GM-CSF, IFN-gamma) and the chemokine M1P1-alpha were coapplied either simultaneously or at different time points pre- or post-E7SH vaccination. In addition, sequence-optimized adjuvant genes were compared to wild type genes. Three combinations investigated lead to an enhanced iFN-gamma response of the induced T cells in mice. Interestingly, IFN-1 secretion of splenocytes did not strictly correlate with tumor response in tumor regression experiments. Gene-encoded Mill-la applied 5 days prior to E7SH-immunization combined with IFN-gamma or 1L-12 (3 days) or IL-2 (5 days) post immunization lead to a significantly enhanced tumor response that was clearly associated with granzyme B secretion and target cells lysis. Our results suggest that a conditioning application and combination with adjuvant genes may be a promising strategy to enhance synergistically immune responses by DNA immunization for the treatment of cervical cancer. (C) 2009 UICC
    Type of Publication: Journal article published
    PubMed ID: 19358269
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  • 9
    Keywords: EXPRESSION ; carcinoma ; RISK ; ORAL-CONTRACEPTIVES ; GROWTH-FACTOR-BETA ; TRENDS ; MAMMARY-GLAND ; TGF-BETA ; DECORIN ; GENOME-WIDE ASSOCIATION
    Abstract: Alterations in stromal tissue components can inhibit or promote epithelial tumorigenesis. Decorin (DCN) and lumican (LUM) show reduced stromal expression in serous epithelial ovarian cancer (sEOC). We hypothesized that common variants in these genes associate with risk. Associations with sEOC among Caucasians were estimated with odds ratios (OR) among 397 cases and 920 controls in two U. S.-based studies (discovery set), 436 cases and 1,098 controls in Australia (replication set 1) and a consortium of 15 studies comprising 1,668 cases and 4,249 controls (replication set 2). The discovery set and replication set 1 (833 cases and 2,013 controls) showed statistically homogeneous (P-heterogeneity 〉= 0.48) decreased risks of sEOC at four variants: DCN rs3138165, rs13312816 and rs516115, and LUM rs17018765 (OR = 0.6 to 0.9; P-trend = 0.001 to 0.03). Results from replication set 2 were statistically homogeneous (P-heterogeneity 〉= 0.13) and associated with increased risks at DCN rs3138165 and rs13312816, and LUM rs17018765: all ORs = 1.2; P-trend 〈= 0.02. The ORs at the four variants were statistically heterogeneous across all 18 studies (P-heterogeneity 〈= 0.03), which precluded combining. In post-hoc analyses, interactions were observed between each variant and recruitment period (P-interaction 〈= 0.003), age at diagnosis (P-interaction=0.04), and year of diagnosis (P-interaction=0.05) in the five studies with available information (1,044 cases, 2,469 controls). We conclude that variants in DCN and LUM are not directly associated with sEOC, and that confirmation of possible effect modification of the variants by non-genetic factors is required
    Type of Publication: Journal article published
    PubMed ID: 21637745
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  • 10
    Keywords: TOOL ; ARRAYS ; LARGE-SCALE ASSOCIATION ; ERROR
    Abstract: Recent Genome-Wide Association Studies (GWAS) have identified four low-penetrance ovarian cancer susceptibility loci. We hypothesized that further moderate- or low-penetrance variants exist among the subset of single-nucleotide polymorphisms (SNPs) not well tagged by the genotyping arrays used in the previous studies, which would account for some of the remaining risk. We therefore conducted a time- and cost-effective stage 1 GWAS on 342 invasive serous cases and 643 controls genotyped on pooled DNA using the high-density Illumina 1M-Duo array. We followed up 20 of the most significantly associated SNPs, which are not well tagged by the lower density arrays used by the published GWAS, and genotyping them on individual DNA. Most of the top 20 SNPs were clearly validated by individually genotyping the samples used in the pools. However, none of the 20 SNPs replicated when tested for association in a much larger stage 2 set of 4,651 cases and 6,966 controls from the Ovarian Cancer Association Consortium. Given that most of the top 20 SNPs from pooling were validated in the same samples by individual genotyping, the lack of replication is likely to be due to the relatively small sample size in our stage 1 GWAS rather than due to problems with the pooling approach. We conclude that there are unlikely to be any moderate or large effects on ovarian cancer risk untagged by less dense arrays. However, our study lacked power to make clear statements on the existence of hitherto untagged small-effect variants.
    Type of Publication: Journal article published
    PubMed ID: 22794196
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