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Sökning: WFRF:(Cramer DW)

  • Resultat 1-10 av 21
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1.
  • Fortner, Renee T., et al. (författare)
  • Correlates of circulating ovarian cancer early detection markers and their contribution to discrimination of early detection models : results from the EPIC cohort
  • 2017
  • Ingår i: Journal of Ovarian Research. - : BioMed Central (BMC). - 1757-2215 .- 1757-2215. ; 10
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Ovarian cancer early detection markers CA125, CA15.3, HE4, and CA72.4 vary between healthy women, limiting their utility for screening.Methods: We evaluated cross-sectional relationships between lifestyle and reproductive factors and these markers among controls (n = 1910) from a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC). Improvements in discrimination of prediction models adjusting for correlates of the markers were evaluated among postmenopausal women in the nested case-control study (n = 590 cases). Generalized linear models were used to calculate geometric means of CA125, CA15.3, and HE4. CA72.4 above vs. below limit of detection was evaluated using logistic regression. Early detection prediction was modeled using conditional logistic regression.Results: CA125 concentrations were lower, and CA15.3 higher, in post- vs. premenopausal women (p ≤ 0.02). Among postmenopausal women, CA125 was higher among women with higher parity and older age at menopause (ptrend ≤ 0.02), but lower among women reporting oophorectomy, hysterectomy, ever use of estrogen-only hormone therapy, or current smoking (p < 0.01). CA15.3 concentrations were higher among heavier women and in former smokers (p ≤ 0.03). HE4 was higher with older age at blood collection and in current smokers, and inversely associated with OC use duration, parity, and older age at menopause (≤ 0.02). No associations were observed with CA72.4. Adjusting for correlates of the markers in prediction models did not improve the discrimination.Conclusions: This study provides insights into sources of variation in ovarian cancer early detection markers in healthy women and informs about the utility of individualizing marker cutpoints based on epidemiologic factors.
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2.
  • Terry, Kathryn L, et al. (författare)
  • A prospective evaluation of early detection biomarkers for ovarian cancer in the European EPIC cohort
  • 2016
  • Ingår i: Clinical Cancer Research. - : American Association for Cancer Research. - 1078-0432 .- 1557-3265. ; 22:18, s. 4575-4664
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: About 60% of ovarian cancers are diagnosed at late stage, when 5-year survival is less than 30% in contrast to 90% for local disease. This has prompted search for early detection biomarkers. For initial testing, specimens taken months or years before ovarian cancer diagnosis are the best source of information to evaluate early detection biomarkers. Here we evaluate the most promising ovarian cancer screening biomarkers in prospectively collected samples from the European Prospective Investigation into Cancer and Nutrition (EPIC) study.EXPERIMENTAL DESIGN: We measured CA125, HE4, CA72.4 and CA15.3 in 810 invasive epithelial ovarian cancer cases and 1,939 controls. We calculated the sensitivity at 95% and 98% specificity as well as Area under the Receiver Operator Curve (C-statistic) for each marker individually and in combination. Additionally, we evaluated marker performance by stage at diagnosis and time between blood draw and diagnosis.RESULTS: We observed the best discrimination between cases and controls within six months of diagnosis for CA125 (C-statistic=0.92), HE4 (0.84), CA72.4 (0.77), and CA15.3 (0.73). Marker performance declined with longer time between blood draw and diagnosis and for earlier staged disease. However, assessment of discriminatory ability at early stage was limited by small numbers. Combinations of markers performed modestly, but significantly better than any single marker.CONCLUSIONS: CA125 remains the single best marker for the early detection of invasive epithelial ovarian cancer, but can be slightly improved by combining with other markers. Identifying novel markers for ovarian cancer will require studies including larger numbers of early stage cases.
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  • Cramer, Daniel W., et al. (författare)
  • Anti-CA15.3 and Anti-CA125 Antibodies and ovarian cancer risk : Results from the EPIC cohort
  • 2018
  • Ingår i: Cancer Epidemiology Biomarkers and Prevention. - : American Association for Cancer Research. - 1055-9965 .- 1538-7755. ; 27:7, s. 790-804
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Neoplastic and non-neoplastic events may raise levels of mucins, CA15.3, and CA125, and generate antibodies against them, but their impact on epithelial ovarian cancer (EOC) risk has not been fully defined. Methods: CA15.3, CA125, and IgG1 antibodies against them were measured in 806 women who developed EOC and 1,927 matched controls from the European Prospective Investigation of Nutrition and Cancer. Associations between epidemiologic factors and anti-mucin antibodies were evaluated using generalized linear models; EOC risks associated with anti-mucin antibodies, by themselves or in combination with respective antigens, were evaluated using conditional logistic regression. Results: In controls, lower antibodies against both mucins were associated with current smoking; and, in postmenopausal women, higher levels with longer oral contraceptive use and later-age-at and shorter-interval-since last birth. Lower anti-CA15.3 antibodies were associated with higher body mass and, in premenopausal women, more ovulatory cycles. Higher anti-CA15.3 and anti-CA125 antibodies were associated with higher risk for mucinous EOC occurring ≥ 3 years from enrollment. Long-term risk for serous EOC was reduced in women with low CA125 and high anti-CA125 antibodies relative to women with low concentrations of both. Conclusions: We found general support for the hypothesis that anti-mucin antibody levels correlate with risk factors for EOC. Antibodies alone or in combinations with their antigen may predict longer term risk of specific EOC types. Impact: Anti-CA125 and anti-CA15.3 antibodies alone or in perspective of antigens may be informative in the pathogenesis of EOC subtypes, but less useful for informing risk for all EOC.
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5.
  • Fortner, Renée T., et al. (författare)
  • Ovarian cancer early detection by circulating CA125 in the context of anti-CA125 autoantibody levels : Results from the EPIC cohort
  • 2018
  • Ingår i: International Journal of Cancer. - : John Wiley and Sons. - 0020-7136 .- 1097-0215. ; 142:7, s. 1355-1360
  • Tidskriftsartikel (refereegranskat)abstract
    • CA125 is the best ovarian cancer early detection marker to date; however, sensitivity is limited and complementary markers are required to improve discrimination between ovarian cancer cases and non-cases. Anti-CA125 autoantibodies are observed in circulation. Our objective was to evaluate whether these antibodies (1) can serve as early detection markers, providing evidence of an immune response to a developing tumor, and (2) modify the discriminatory capacity of CA125 by either masking CA125 levels (resulting in lower discrimination) or acting synergistically to improve discrimination between cases and non-cases. We investigated these objectives using a nested case–control study within the European Prospective Investigation into Cancer and Nutrition cohort (EPIC) including 250 cases diagnosed within 4 years of blood collection and up to four matched controls. Circulating CA125 antigen and antibody levels were quantified using an electrochemiluminescence assay. Adjusted areas under the curve (aAUCs) by 2-year lag-time intervals were calculated using conditional logistic regression calibrated toward the absolute risk estimates from a pre-existing epidemiological risk model as an offset-variable. Anti-CA125 levels alone did not discriminate cases from controls. For cases diagnosed <2 years after blood collection, discrimination by CA125 antigen was suggestively higher with higher anti-CA125 levels (aAUC, highest antibody tertile: 0.84 [0.76–0.92]; lowest tertile: 0.76 [0.67–0.86]; phet = 0.06). We provide the first evidence of potentially synergistic discrimination effects of CA125 and anti-CA125 antibodies in ovarian early detection. If these findings are replicated, evaluating CA125 in the context of its antibody may improve ovarian cancer early detection.
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6.
  • Kaaks, Rudolf, et al. (författare)
  • Tumor-associated autoantibodies as early detection markers for ovarian cancer? A prospective evaluation
  • 2018
  • Ingår i: International Journal of Cancer. - : John Wiley and Sons. - 0020-7136 .- 1097-0215. ; 143:3, s. 515-526
  • Tidskriftsartikel (refereegranskat)abstract
    • Immuno-proteomic screening has identified several tumor-associated autoantibodies (AAb) that may have diagnostic capacity for invasive epithelial ovarian cancer, with AAbs to P53 proteins and cancer-testis antigens (CTAGs) as prominent examples. However, the early detection potential of these AAbs has been insufficiently explored in prospective studies. We performed ELISA measurements of AAbs to CTAG1A, CTAG2, P53 and NUDT11 proteins, for 194 patients with ovarian cancer and 705 matched controls from the European EPIC cohort, using serum samples collected up to 36 months prior to diagnosis under usual care. CA125 was measured using electrochemo-luminiscence. Diagnostic discrimination statistics were calculated by strata of lead-time between blood collection and diagnosis. With lead times ≤6 months, ovarian cancer detection sensitivity at 0.98 specificity (SE98) varied from 0.19 [95% CI 0.08-0.40] for CTAG1A, CTAG2 and NUDT1 to 0.23 [0.10-0.44] for P53 (0.33 [0.11-0.68] for high-grade serous tumors). However, at longer lead-times, the ability of these AAb markers to distinguish future ovarian cancer cases from controls declined rapidly; at lead times >1 year, SE98 estimates were close to zero (all invasive cases, range: 0.01-0.11). Compared to CA125 alone, combined logistic regression scores of AAbs and CA125 did not improve detection sensitivity at equal level of specificity. The added value of these selected AAbs as markers for ovarian cancer beyond CA125 for early detection is therefore limited.
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7.
  • Kar, Siddhartha P., et al. (författare)
  • Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types
  • 2016
  • Ingår i: Cancer Discovery. - : AMER ASSOC CANCER RESEARCH. - 2159-8274 .- 2159-8290. ; 6:9, s. 1052-1067
  • Tidskriftsartikel (refereegranskat)abstract
    • Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10 -8 seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis. SIGNIFICANCE: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. (C) 2016 AACR.
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  • Lawrenson, Kate, et al. (författare)
  • Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
  • 2016
  • Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
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