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  • 1
    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 4 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 towards 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. This article is protected by copyright. All rights reserved.
    Type of Publication: Journal article published
    PubMed ID: 29159934
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  • 2
    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.
    Type of Publication: Journal article published
    PubMed ID: 29473162
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  • 3
    Keywords: CANCER ; proliferation ; SURVIVAL ; CELL ; COHORT ; POPULATION ; RISK ; GENE ; ASSOCIATION ; SUSCEPTIBILITY ; VARIANTS ; breast cancer ; BREAST-CANCER ; WOMEN ; prostate cancer ; PROSTATE-CANCER ; UNITED-STATES ; VARIANT ; SINGLE NUCLEOTIDE POLYMORPHISMS ; GENOTYPE ; prospective ; SUN EXPOSURE ; vitamin D ; AFRICAN-AMERICAN ; GENE POLYMORPHISMS ; 25-HYDROXYVITAMIN-D ; UK CAUCASIAN POPULATION
    Abstract: Background: Vitamin D is hypothesized to lower the risk of breast cancer by inhibiting cell proliferation via the nuclear vitamin D receptor (VDR). Two common single nucleotide polymorphisms (SNP) in the VDR gene (VDR), rs154441.0 (BsmI), and rs2228570 (FokI), have been inconsistently associated with breast cancer risk. Increased risk has been reported for the FokIff genotype, which encodes a less transcriptionally active isoform of VDR, and reduced risk has been reported for the BsmI BB genotype, a SNP in strong linkage disequilibrium with a 3'-untranslated region, which may influence VDR mRNA stability. Methods: We pooled data from 6 prospective studies in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium to examine associations between these SNPs and breast cancer among 〉6,300 cases and 8,100 controls for each SNP using conditional logistic regression. Results: The odds ratio (OR) for the rs2228570 (FokI) ff versus FF genotype in the overall population was statistically significantly elevated [OR, 1-1.6; 95% confidence interval (95% CI), 1.04-1.28] but was weaker once data from the cohort with previously published positive findings were removed (OR, 1.1.0; 95% CI, 0.981.24). No association was noted between rs1544410 (Bsm I) BB and breast cancer risk overall (OR, 0.98; 95% CI, 0.89-1.09), but the BB genotype was associated with a significantly lower risk of advanced breast cancer (OR, 0.74; 95% CI, 0.60-0.92). Conclusions: Although the evidence for independent contributions of these variants to breast cancer susceptibility remains equivocal, future large studies should integrate genetic variation in VDR with biomarkers of vitamin D status. (Cancer Epidemiol Biomarkers Prev 2009;18(1):297-305)
    Type of Publication: Journal article published
    PubMed ID: 19124512
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  • 4
    Keywords: CANCER ; CELLS ; tumor ; CELL ; Germany ; MODEL ; PROSTATE ; FOLLOW-UP ; COHORT ; cohort study ; POPULATION ; RISK ; TIME ; ASSOCIATION ; FREQUENCIES ; STAGE ; REPRODUCIBILITY ; prostate cancer ; PROSTATE-CANCER ; cancer risk ; DATABASE ; RECRUITMENT ; PROJECT ; CONSUMPTION ; VEGETABLES ; FOOD-INTAKE ; FOOD FREQUENCY QUESTIONNAIRE ; METABOLITE ; PRODUCTS ; prospective studies ; RELATIVE VALIDITY ; bioavailability ; USA ; dietary intake ; prospective ; prospective study ; EPIC-Heidelberg ; CANCERS ; CANCER-RISK ; FOODS ; NOV ; LOW-GRADE ; GERMAN PART ; PLANT FOODS ; hazard ratio ; RANGE ; CRUCIFEROUS VEGETABLES ; Food content ; Glucosinolates ; FRUIT CONSUMPTION
    Abstract: Glucosinolates (GLS) are secondary plant metabolites occurring in cruciferous vegetables. Their biologically active break-down products show cancer preventive properties in animal and cell studies. So far, epidemiologic studies, using consumption of cruciferous vegetables as proxy for GLS intake, yielded inconsistent results. Here, we evaluated the association between dietary intake of GLS in comparison with consumption data of GLS-containing foods and the risk of prostate cancer. The study population comprised 11,405 male participants of the prospective EPIC-Heidelberg cohort study. During a mean follow-up time of 9.4 years, 328 incident cases of prostate cancer occurred. At recruitment, habitual food consumption was assessed by a validated food frequency questionnaire, and intake of individual GLS was estimated by means of a newly compiled database on food content of GLS. Adjusted hazard ratios (HR) for prostate cancer were calculated using the Cox proportional hazard model. Median daily intake of total GLS was 7.9 mg/day (interquartile range 5.1-11.9 mg/day). The risk of prostate cancer decreased significantly over quartiles of total GLS intake (multivariate HR [4th vs. 1st quartile] 0.68, 95% CI 0.48-4.97, P-trend 0.03). Associations with GLS-containing food intake were weaker. Among GLS subgroups, aliphatic GLS showed the strongest inverse association with cancer risk. Analyse stratified by tumor stage and grade gave hint to inverse associations for localized and low-grade cancers. This study shows an inverse association between dietary intake of GLS and the risk of prostate cancer. Because this is the first prospective study using individual GLS intake data, confirmation in other studies is warranted. (C) 2009 UICC
    Type of Publication: Journal article published
    PubMed ID: 19585501
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  • 5
    Keywords: CANCER ; SUPPORT ; COHORT ; ASSOCIATION ; WOMEN ; ESTRADIOL ; BREAST-CANCER RISK ; IGF-1 ; PREGNANCY ; TESTOSTERONE ; female ; sex steroids ; vitamin D ; VITAMIN-D ; androstenedione ; PROGESTERONE
    Abstract: Vitamin D may influence circulating levels of sex steroid hormones in women during reproductive life, but associations in pregnant women have not been explored. Correlation and linear regression models were used to assess the association between sex steroids, (estradiol, progesterone, 17-hydroxyprogesterone, testosterone, and androstenedione), IGF-1, and serum 25-hydroxyvitamin D (25-OHD) concentrations during the first trimester of pregnancy in 106 cancer-free women from the Finnish Maternity Cohort. There was no significant association of serum 25-OHD with any of the hormones measured. One-unit increase in serum 25-OHD concentration was associated with a non-significant 6% increase in estradiol concentrations. Multiparous women had higher levels of vitamin D (40.4 vs. 32.9 nmol/L, p-value = 0.01) than primiparous women. Our study does not support an association between maternal serum 25-OHD levels and sex steroids or IGF-I concentrations during the first trimester of pregnancy
    Type of Publication: Journal article published
    PubMed ID: 21387179
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  • 6
    Abstract: Epidemiological studies suggest that soya consumption as a source of phyto-oestrogens and isoflavones may be associated with a reduced risk of colorectal cancer. However, findings have not yet been synthesised for all groups of phyto-oestrogens. A meta-analysis was conducted to quantify the association between phyto-oestrogens and colorectal cancer risk. Relevant observational studies published up to June 2016 were identified by searching MEDLINE, EMBASE and Cochrane Library databases. Study-specific relative risks (RR) were pooled in both categorical and dose-response meta-analyses. Out of seventeen identified studies, sixteen were included in the meta-analysis. Comparing the highest with the lowest intake category, inverse associations for phyto-oestrogens overall and by subgroup were observed but were statistically significant in case-controls studies and not in cohort studies. The pooled RR in case-control studies were 0.76 (95 % CI 0.69, 0.84), 0.77 (95 % CI 0.69, 0.85) and 0.70 (95 % CI 0.56, 0.89) for phyto-oestrogens, isoflavones and lignans, respectively, whereas the corresponding pooled RR were 0.95 (95 % CI 0.85, 1.06), 0.94 (95 % CI 0.84, 1.05) and 1.00 (95 % CI 0.64, 1.57) in cohort studies. Dose-response analysis yielded an 8 % reduced risk of colorectal neoplasms for every 20 mg/d increase in isoflavones intake in Asians (pooled RR 0.92; 95 % CI 0.86, 0.97). A non-linear inverse association with colorectal cancer risk was found for lignans intake, but no association for circulating enterolactone concentrations was observed. Thus, study heterogeneity precludes a rigorous conclusion regarding an effect of high exposure to isoflavones on risk of colorectal cancer. Current evidence for an association with lignans exposure is limited. Further prospective studies, particularly evaluating lignans, are warranted to clarify the association between different phyto-oestrogens and colorectal cancer risk.
    Type of Publication: Journal article published
    PubMed ID: 28091359
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  • 7
    Abstract: Recently, we identified unique processing patterns of apolipoprotein A2 (ApoA2) in patients with pancreatic cancer. This study provides a first prospective evaluation of an ApoA2 isoform ("ApoA2-ATQ/AT"), alone and in combination with carbohydrate antigen 19-9 (CA19-9), as an early detection biomarker for pancreatic cancer. We performed ELISA measurements of CA19-9 and ApoA2-ATQ/AT in 156 patients with pancreatic cancer and 217 matched controls within the European EPIC cohort, using plasma samples collected up to 60 months prior to diagnosis. The detection discrimination statistics were calculated for risk scores by strata of lag-time. For CA19-9, in univariate marker analyses, C-statistics to distinguish future pancreatic cancer patients from cancer-free individuals were 0.80 for plasma taken 〈/=6 months before diagnosis, and 0.71 for 〉6-18 months; for ApoA2-ATQ/AT, C-statistics were 0.62, and 0.65, respectively. Joint models based on ApoA2-ATQ/AT plus CA19-9 significantly improved discrimination within 〉6-18 months (C = 0.74 vs. 0.71 for CA19-9 alone, p = 0.022) and 〈/=18 months (C = 0.75 vs. 0.74, p = 0.022). At 98% specificity, and for lag times of 〈/=6, 〉6-18 or 〈/=18 months, sensitivities were 57%, 36% and 43% for CA19-9 combined with ApoA2-ATQ/AT, respectively, vs. 50%, 29% and 36% for CA19-9 alone. Compared to CA19-9 alone, the combination of CA19-9 and ApoA2-ATQ/AT may improve detection of pancreatic cancer up to 18 months prior to diagnosis under usual care, and may provide a useful first measure for pancreatic cancer detection prior to imaging. This article is protected by copyright. All rights reserved.
    Type of Publication: Journal article epub ahead of print
    PubMed ID: 30259989
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  • 8
    Abstract: Importance: There is an urgent need to improve lung cancer risk assessment because current screening criteria miss a large proportion of cases. Objective: To investigate whether a lung cancer risk prediction model based on a panel of selected circulating protein biomarkers can outperform a traditional risk prediction model and current US screening criteria. Design, Setting, and Participants: Prediagnostic samples from 108 ever-smoking patients with lung cancer diagnosed within 1 year after blood collection and samples from 216 smoking-matched controls from the Carotene and Retinol Efficacy Trial (CARET) cohort were used to develop a biomarker risk score based on 4 proteins (cancer antigen 125 [CA125], carcinoembryonic antigen [CEA], cytokeratin-19 fragment [CYFRA 21-1], and the precursor form of surfactant protein B [Pro-SFTPB]). The biomarker score was subsequently validated blindly using absolute risk estimates among 63 ever-smoking patients with lung cancer diagnosed within 1 year after blood collection and 90 matched controls from 2 large European population-based cohorts, the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Northern Sweden Health and Disease Study (NSHDS). Main Outcomes and Measures: Model validity in discriminating between future lung cancer cases and controls. Discrimination estimates were weighted to reflect the background populations of EPIC and NSHDS validation studies (area under the receiver-operating characteristics curve [AUC], sensitivity, and specificity). Results: In the validation study of 63 ever-smoking patients with lung cancer and 90 matched controls (mean [SD] age, 57.7 [8.7] years; 68.6% men) from EPIC and NSHDS, an integrated risk prediction model that combined smoking exposure with the biomarker score yielded an AUC of 0.83 (95% CI, 0.76-0.90) compared with 0.73 (95% CI, 0.64-0.82) for a model based on smoking exposure alone (P = .003 for difference in AUC). At an overall specificity of 0.83, based on the US Preventive Services Task Force screening criteria, the sensitivity of the integrated risk prediction (biomarker) model was 0.63 compared with 0.43 for the smoking model. Conversely, at an overall sensitivity of 0.42, based on the US Preventive Services Task Force screening criteria, the integrated risk prediction model yielded a specificity of 0.95 compared with 0.86 for the smoking model. Conclusions and Relevance: This study provided a proof of principle in showing that a panel of circulating protein biomarkers may improve lung cancer risk assessment and may be used to define eligibility for computed tomography screening.
    Type of Publication: Journal article published
    PubMed ID: 30003238
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  • 9
    Keywords: RISK ; GENETIC POLYMORPHISMS ; ASSOCIATION ; POLYMORPHISMS ; nutrition ; ESTROGEN ; PREMENOPAUSAL WOMEN ; MULTIETHNIC COHORT ; ANDROGEN ; SEX-HORMONES ; SHBG GENE
    Abstract: Context: Sex steroids play a central role in breast cancer development. Objective: This study aimed to relate polymorphic variants in 36 candidate genes in the sex steroid pathway to serum concentrations of sex steroid hormones and SHBG. Design: Data on 700 genetic polymorphisms were combined with existing hormone assays and data on breast cancer incidence, within the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Nurses' Health Study (NHS) cohorts; significant findings were reanalyzed in the Multiethnic Cohort (MEC). Setting and Participants: We analyzed data from a pooled sample of 3852 pre- and postmenopausal Caucasian women from EPIC and NHS and 454 postmenopausal women from MEC. Main Outcome Measures: Outcome measures were SHBG, testosterone, dehydroepiandrosterone (DHEAS), androstenedione, estrone (E1), and estradiol (E2) as well as breast cancer risk. Results: Globally significant associations were found among pre- and postmenopausal women combined between levels of SHBG and the SHBG gene and between DHEAS and the FSHR and AKR1C3 genes. Among postmenopausal women, serum E1 and E2 were significantly associated with the genes CYP19 and FSHR, and E1 was associated with ESR1. None of the variants related to serum hormone levels showed any significant association with breast cancer risk. Conclusions: We confirmed associations between serum levels of SHBG and the SHBG gene and of E1 and E2 and the CYP19 and ESR1 genes. Novel associations were observed between FSHR and DHEAS, E1, and E2 and between AKR1C3 and DHEAS.
    Type of Publication: Journal article published
    PubMed ID: 21177793
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  • 10
    Keywords: RISK ; prognosis ; PROGRESSION ; CYCLOPHOSPHAMIDE ; METAANALYSIS ; SINGLE-NUCLEOTIDE POLYMORPHISMS ; EPIRUBICIN ; LOCI ; GENOME-WIDE ASSOCIATION ; GENOTYPE IMPUTATION
    Abstract: Background: Survival after a diagnosis of breast cancer varies considerably between patients, and some of this variation may be because of germline genetic variation. We aimed to identify genetic markers associated with breast cancer-specific survival. Methods: We conducted a large meta-analysis of studies in populations of European ancestry, including 37 954 patients with 2900 deaths from breast cancer. Each study had been genotyped for between 200 000 and 900 000 single nucleotide polymorphisms (SNPs) across the genome; genotypes for nine million common variants were imputed using a common reference panel from the 1000 Genomes Project. We also carried out subtype-specific analyses based on 6881 estrogen receptor (ER)-negative patients (920 events) and 23 059 ER-positive patients (1333 events). All statistical tests were two-sided. Results: We identified one new locus (rs2059614 at 11q24.2) associated with survival in ER-negative breast cancer cases (hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.55 to 2.47, P = 1.91 x 10(-8)). Genotyping a subset of 2113 case patients, of which 300 were ER negative, provided supporting evidence for the quality of the imputation. The association in this set of case patients was stronger for the observed genotypes than for the imputed genotypes. A second locus (rs148760487 at 2q24.2) was associated at genome-wide statistical significance in initial analyses; the association was similar in ER-positive and ER-negative case patients. Here the results of genotyping suggested that the finding was less robust. Conclusions: This is currently the largest study investigating genetic variation associated with breast cancer survival. Our results have potential clinical implications, as they confirm that germline genotype can provide prognostic information in addition to standard tumor prognostic factors.
    Type of Publication: Journal article published
    PubMed ID: 25890600
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