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    Keywords: CANCER ; tumor ; carcinoma ; neoplasms ; POPULATION ; RISK ; GENE ; TUMORS ; ASSOCIATION ; LINKAGE ; polymorphism ; SUSCEPTIBILITY ; ovarian cancer ; OVARIAN-CANCER ; SNP ; mass spectrometry ; MELANOMA ; MASS-SPECTROMETRY ; LINKAGE DISEQUILIBRIUM ; MUTATIONS ; Jun ; MALIGNANT-MELANOMA ; HEALTHY ; BRAF ; MASSES ; RE ; CANCER SUSCEPTIBILITY ; TESTS ; KRAS ; LINKAGE PHASE ; LMP ; low malignant potential
    Abstract: Objective. The object of this study was to test the hypothesis that BRAF is a low-risk susceptibility gene for low malignant potential (LMP) ovarian cancer. A recent study of the relationship between BRAF polymorphisms and malignant melanoma identified strong linkage disequilibrium across the BRAF gene with one of the three most common haplotypes (haplotype C) having a population attributable risk of approximately 1.6%. We therefore hypothesized that the same BRAF haplotype may confer an increased risk of serous ovarian tumors of low malignant potential. Methods. We genotyped 383 cases of LMP ovarian cancer, including 234 of serous histology, and 987 controls for seven SNPs, representative of the most common BRAF gene haplotypes, using MALDI-TOF mass spectrometry. Results. Haplotype information was obtained for 369 LMP ovarian cancer cases and 983 healthy controls. None of the haplotypes were found to be associated with risk of LMP ovarian cancer (OR for haplotype C 0.81, 95% Cl 0.54-1.22), or with the risk of serous LMP ovarian cancer (OR for haplotype C 0.90, 95% CI = 0.56- 1.45). Conclusion. We found no evidence to suggest that BRAF is a low-risk LMP ovarian cancer susceptibility gene. (c) 2005 Published by Elsevier Inc
    Type of Publication: Journal article published
    PubMed ID: 15904951
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    Keywords: FOLLOW-UP ; BREAST-CANCER ; SWEDEN ; aspirin ; MALIGNANCY ; RHEUMATOID-ARTHRITIS PATIENTS ; METAANALYSIS ; FAMILIAL RISKS ; HOSPITALIZATIONS ; HYPOTHYROIDISM
    Abstract: OBJECTIVES: Patients with autoimmune (AI) diseases are diagnosed with increased frequencies of some cancers, which may depend on the underlying dysregulation of the immune system or treatment. Data on female cancers are limited. METHODS: We analyzed systematically risk and survival of female cancers of the breast, uterus, ovary and other genital organs in close to 200,000 patients diagnosed with any of 33 different AI diseases. Standardized incidence ratios (SIRs) for risk and hazard ratios (HRs) for survival were calculated for subsequent incident cancers or cancer deaths up to year 2008. RESULTS: For all breast cancer after any AI diseases, the SIR was 0.94; SIRs were modestly increased after two AI diseases and decreased after nine AI diseases, including Sjogren syndrome (0.46). For cervical cancer, the risk was increased after discoid lupus erythematosus (3.34) and systemic sclerosis (2.43). The HR was 2.12 in chronic rheumatic heart disease patients. The overall SIR for endometrial cancer was 0.85, with low SIR in ankylosing spondylitis (0.37); the HR was 4.05 for Sjogren syndrome. The SIR for ovarian cancer was increased for polymyositis/dermatomyositis (3.26) while the HR was increased for multiple sclerosis (2.43). The overall SIR for other genital cancers was increased to 1.54 and a very high risk of 35.88 was observed in localized scleroderma. CONCLUSIONS: Breast, endometrial and ovarian cancers were decreased after all AI diseases and most significant changes after individual AI diseases were towards lower risks. Probably treatment related factors explain the findings. For cervical and other genital cancers all significant changes were increased risks.
    Type of Publication: Journal article published
    PubMed ID: 22819787
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    Keywords: brain ; CANCER ; EXPRESSION ; carcinoma ; CELL ; Germany ; LUNG ; PROSTATE ; lung cancer ; LUNG-CANCER ; GENE ; GENE-EXPRESSION ; microarray ; PROTEIN ; PROTEINS ; DRUG ; TISSUE ; SURGERY ; TIME ; FAMILY ; DOMAIN ; CARCINOGENESIS ; TARGET ; LESIONS ; PROGRESSION ; immunohistochemistry ; PATTERNS ; gene expression ; microarrays ; MEMBRANE ; TUMOR PROGRESSION ; METASTASIS ; PROSTATE-CANCER ; SURFACE ; ADHESION ; CELL-ADHESION ; MIGRATION ; CARCINOMAS ; INVOLVEMENT ; adenocarcinoma ; squamous cell carcinoma ; TARGETS ; OVEREXPRESSION ; GASTRIC-CANCER ; ADAM9 ; pancreatic cancer ; BIOPSY ; protein expression ; non-small cell lung cancer ; CELL CARCINOMA ; pancreas ; PANCREATIC-CANCER ; FAMILIES ; DUCTAL ADENOCARCINOMA ; cell adhesion ; GENE FAMILY ; DRUG DISCOVERY ; pancreatic adenocarcinoma ; proteases ; EPITHELIUM ; USA ; SQUAMOUS-CELL ; CIN ; DISINTEGRIN ; WELL ; SCC ; CELL-LUNG-CANCER ; METALLOPROTEASES ; gynecology
    Abstract: Objective. ADAM9 is a member of the ADAM family which is involved in cellular processes like cell adhesion, migration and signalling [M.L. Moss, J.M. White, M.H. Lambert, R.C. Andrews, TACE and other ADAM proteases as targets for drug discovery. Drug Discov. Today 2001; 6:417-426., G. Murphy, The ADAMS: signalling scissors in the turnout microenvironment. Nat. Cancer Rev. 2008; 8:929-941.]. ADAM9 overexpression has been described in many of solid tumours including prostate, renal, pancreas, lung and gastric cancer [R.J. Grutzmann, J. Luttges, B. Sipos, O. Ammerpohl, F. Dobrowolski, I. Alldinger, et al., ADAMS) expression in pancreatic cancer is associated with turnout type and is a prognostic factor in ductal adenocarcinoma. Br. J. Cancer 2004; 90: 1053-1058., C.A. lacobuzio-Donahue, A. Maitra, M. Olsen, A.W. Lowe, N.T. van Heck, C. Rosty, et al., Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays. Am. J. Pathol. 2003; 162: 1151-1162., Y. Shintani, S. Higashiyama, M. Ohta, H. Hirabayashi, S. Yamamoto,T. Yoshimasu, et al., Overexpression of ADAMS) in non-small cell lung cancer correlates with brain metastasis. Cancer Res. 2004; 64:4190-4196., S. Carl-McGrath, U. Lendeckel, M. Ebert, A. Roessner, C. Rocken, The disintegrin-metalloproteinases ADAM9, ADAM12, and ADAM15 are upregulated in gastric cancer. Int. J. Oncol. 2005; 26:17-24., F.R. Fritzsche, K Wassermann, M.Jung, A. Tolle, I. Kristiansen, M. Lein, et al., ADAMS) is highly expressed in renal cell cancer and is associated with turnout progression. BMC Cancer 2008; 8:179.]. The involvement of this protease in cervical carcinogenesis has not been yet investigated. The aim of this study was to evaluate the expression of ADAMS) in normal epithelium, CIN3 lesions and squamous cell Carcinomas (SCC) of the uterine cervix. Methods. Archived paraffin-embedded tissue blocks from biopsy or surgery specimens obtained from 50 subjects with CIN3 and squamous cancer of the cervix were studied by immunohistochemistry using heat-induced epitope retrieval for ADAMS) expression. Results. Weak expression of ADAMS) was found in the normal cervical epithelium with weak cytoplasmatic staining but also membrane immunoreactivity. Evident staining for ADAM9 was detected in 31 out of 36 (86%) CIN3 lesions and in 13 out of 14 (93%) squamous cell carcinomas of the uterine cervix. Staining was Stronger in SCC compared to CIN3 lesions. Moderate staining was detected in 64% (9/14) of SCC and in 36% (13/36) CIN3 lesions. Weak staining was observed in 50% (18/36) of CIN3 lesions and in 29% (4/14) of SCC. The difference in the ADAM9 protein expression between cervical squamous carcinomas and normal epithelium was highly significant. Statistical significance was also found for the increased expression observed in CIN3 lesions versus normal squamous epithelium. Conclusions. Our results show for the first time, that ADAM9 expression is low in the squamous epithelium of the cervix, but is increased in CIN3 lesions as well as SCCs being the increase in both cases statistically significant. (C) 2009 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 19473694
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    Abstract: OBJECTIVE: Cancer cells in the body release soluble and membranous factors that manipulate the tumor environment to facilitate growth and survival. Recent years have provided evidence that small microvesicles that are termed exosomes may play a pivotal role in this process. Exosomes are membrane vesicles with a size of 40-100nm that are released by both tumor and normal cells and can be found in various body fluids. Tumor-derived exosomes carry functional proteins, mRNAs, and miRNAs and could serve as novel platform for tumor diagnosis and prognosis. However, marker proteins that allow enrichment of tumor-derived exosomes over normal exosomes are less well defined. METHODS: We used Western blot analysis and antibody coupled magnetic beads to characterize CD24 and EpCAM as markers for exosomes. We investigated ovarian carcinoma ascites, pleural effusions and serum of breast carcinoma patients. As non-tumor derived control we used exosomes from ascites of liver cirrhosis patients. RESULTS: Exosomes could be isolated from all body fluids and contained marker proteins as well as miRNAs. We observed that CD24 and EpCAM were selectively present on ascites exosomes of tumor patients and copurified together on anti-EpCAM or anti-CD24 magnetic beads. In breast cancer patients CD24 was present but EpCAM was absent from serum exosomes. Instead, the intact EpCAM ectodomain was recovered in a soluble form. We provide evidence that EpCAM can be cleaved from exosomes via serum metalloproteinase(s). CONCLUSION: Loss of EpCAM on serum exosomes may hamper enrichment by immune-affinity isolation. We suggest that CD24 could be an additional marker for the enrichment of tumor-derived exosomes from blood.
    Type of Publication: Journal article published
    PubMed ID: 21601258
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  • 7
    Keywords: CANCER ; GROWTH-FACTOR ; carcinoma ; COHORT ; EPIDEMIOLOGY ; RISK ; RISK-FACTORS ; score ; WOMEN ; OBESITY ; cervical cancer ; HUMAN-PAPILLOMAVIRUS ; SQUAMOUS-CELL CARCINOMA ; adenocarcinoma ; UTERINE CERVIX ; PROJECT ; metabolic syndrome ; COMPLETENESS ; REGRESSION DILUTION ; CONOR ; Squamous cell ; Metabolic factors
    Abstract: Background. Little is known about the association between metabolic risk factors and cervical cancer carcinogenesis. Material and methods. During mean follow-up of 11 years of the Me-Can cohort (N = 288,834) 425 invasive cervical cancer cases were diagnosed. Hazard ratios (HRs) were estimated by the use of Cox proportional hazards regression models for quintiles and standardized z-scores (with a mean of 0 and a SD of 1) of BMI, blood pressure, glucose, cholesterol, triglycerides and MetS score. Risk estimates were corrected for random error in the measurements. Results. BMI (per 1SD increment) was associated with 12%, increase of cervical cancer risk, blood pressure with 25% and triglycerides with 39%, respectively. In models including all metabolic factors, the associations for blood pressure and triglycerides persisted. The metabolic syndrome (MetS) score was associated with 26% increased corrected risk of cervical cancer. Triglycerides were stronger associated with squamous cell carcinoma (HR 1.48; 95% CI, 1.20-1.83) than with adenocarcinoma (0.92, 0.54-1.56). Among older women cholesterol (50-70 years 1.34; 1.00-1.81), triglycerides (50-70 years 1.49, 1.03-2.16 and 〉= 70 years 1.54, 1.09-2.19) and glucose (〉= 70 years 1.87, 1.13-3.11) were associated with increased cervical cancer risk. Conclusion. The presence of obesity, elevated blood pressure and triglycerides were associated with increased risk of cervical cancer.
    Type of Publication: Journal article published
    PubMed ID: 22330614
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    Keywords: RECEPTOR ; RISK ; POLYMORPHISMS ; SUSCEPTIBILITY LOCUS ; VARIANTS ; IDENTIFICATION ; GENOME-WIDE ASSOCIATION ; PROGESTERONE ; GENOTYPE IMPUTATION ; GRANULOSA-CELL TUMOR
    Abstract: OBJECTIVE: Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted. METHODS: Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2185 SNPs from 11 gonadotropin signaling pathway genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations. RESULTS: We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some suggestion of gene-level associations for four gonadotropin signaling pathway genes: INHBB (p=0.045, mucinous), LHCGR (p=0.046, high-grade serous), GNRH (p=0.041, high-grade serous), and FSHB (p=0.036, overall invasive). There was also suggestive evidence for INHA (p=0.060, overall invasive). CONCLUSIONS: Ovarian cancer studies have limited sample numbers, thus fewer genome-wide susceptibility alleles, with only modest associations, have been identified relative to breast and prostate cancers. We have evaluated the majority of ovarian cancer studies with biological samples, to our knowledge, leaving no opportunity for replication. Using both our understanding of biology and powerful gene-level tests, we have identified four putative ovarian cancer loci near INHBB, LHCGR, GNRH, and FSHB that warrant a second look if larger sample sizes and denser genotype chips become available.
    Type of Publication: Journal article published
    PubMed ID: 25528498
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  • 9
    Keywords: DISEASE ; LESIONS ; prevention ; HUMAN-PAPILLOMAVIRUS DNA ; intraepithelial neoplasia ; PROGRAM ; transcriptome ; cytology ; METHYLATION ANALYSIS ; SCRAPES
    Abstract: Objective. Cervical cancer precursor screening by HPV testing has a low positive predictive value for advanced lesion. HPV16 RNA patterns characteristic for HPV16-transformed cells but based on laborious, cost-intensive singleplex NASBA reactions promised high value in triaging HPV16 DNA-positive women. Methods. We developed two high-throughput reverse transcriptase quantitative (RT-q) PCR assays for the HPV16 transcripts E6*I, E1 boolean AND E4 and E1 C and the cellular transcript ubiquitin C and analysed RNA of 158 singly HPV16 DNA-positive cervical cell samples archived in PreservCyt buffer for the presence of transformation-associated HPV16 RNA patterns, i.e., upregulation of E6*I relative to E1 boolean AND E4 and/or presence of E1C. Results. HPV16 RNA pattern analyses classified 85% of 58 samples diagnosed 〈= CIN1 (no cytologically and histologically detectable cervical lesion or CIN grade 1) as negative and 90% of 59 samples diagnosed as 〉= CIN3 (CIN grade 3 or invasive cancer) as positive. Among 41 CIN grade 2 samples representing an intermediate lesion group, 49% were HPV16 RNA patterns-positive. Interestingly, 3 of 4 HPV16 RNA patterns-positive lesions initially diagnosed as 〈= CIN1 at follow-up 5-24 months later had progressed to 〉= CIN2. Conclusions. We successfully developed and validated a second generation of HPV16 RNA patterns assay by rapid RT-qPCR as triage marker for HPV16 DNA-positive women offering clinical utility to distinguish between the need for immediate colposcopy and continued observation. Limited follow-up data suggests that HPV16 RNA patterns-positivity in 〈= CIN1 lesions can predict disease progression.
    Type of Publication: Journal article published
    PubMed ID: 26148764
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  • 10
    Abstract: OBJECTIVES: Tumor-associated autoantibodies (AAbs), produced as an immune response to tumor-associated antigens (TAAs), are a novel pathway of early detection markers. METHODS: We conducted a systematic review on AAbs and ovarian cancer to summarize the diagnostic performance of individual AAbs and AAb panels. A total of 29 studies including 85 AAbs were included; 27 of the studies were conducted in prevalent cases and cancer-free controls and 2 investigations included pre-diagnosis samples. The majority of studies were hypothesis-driven, evaluating AAbs to target TAAs; 10 studies used screening approaches such as serological expression cloning (SEREX) and nucleic acid-programmable protein arrays (NAPPA). RESULTS: The highest sensitivities for individual AAbs were reported for RhoGDI-AAbs (89.5%) and TUBA1C-AAbs (89%); however, specificity levels were relatively low (80% and 75%, respectively). High sensitivities at high specificities were reported for HOXA7-AAbs for detection of moderately differentiated ovarian tumors (66.7% sensitivity at 100% specificity) and IL8-AAbs in stage I-II ovarian cancer (65.5% sensitivity at 98% specificity). A panel of 11 AAbs (ICAM3, CTAG2, p53, STYXL1, PVR, POMC, NUDT11, TRIM39, UHMK1, KSR1, and NXF3) provided 45% sensitivity at 98% specificity for serous ovarian cancer, when at least 2 AAbs were above a threshold of 95% specificity. Twelve of the AAbs identified in this review were investigated in more than one study. Data on diagnostic discrimination by tumor histology and stage at diagnosis are sparse. Limited data suggest select AAb markers improve diagnostic discrimination when combined with markers such as CA125 and HE4. CONCLUSIONS: AAbs for ovarian cancer early detection is an emerging area, and large-scale, prospective investigations considering histology and stage are required for discovery and validation. However, data to date suggests panels of AAbs may eventually reach sufficient diagnostic discrimination to allow earlier detection of disease as a complement to existing markers and transvaginal ultrasound.
    Type of Publication: Journal article published
    PubMed ID: 28800944
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