[Show abstract][Hide abstract] ABSTRACT: We performed a multistage genome-wide association study including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT, per-allele odds ratio (OR) = 0.79, 95% confidence interval (CI) 0.74-0.84, P = 3.0 × 10(-12)), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2, OR = 1.46, 95% CI 1.30-1.65, P = 1.1 × 10(-10)), rs9581943 at 13q12.2 (PDX1, OR = 1.15, 95% CI 1.10-1.20, P = 2.4 × 10(-9)) and rs16986825 at 22q12.1 (ZNRF3, OR = 1.18, 95% CI 1.12-1.25, P = 1.2 × 10(-8)). We identified an independent signal in exon 2 of TERT at the established region 5p15.33 (rs2736098, OR = 0.80, 95% CI 0.76-0.85, P = 9.8 × 10(-14)). We also identified a locus at 8q24.21 (rs1561927, P = 1.3 × 10(-7)) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study identified multiple new susceptibility alleles for pancreatic cancer that are worthy of follow-up studies.
[Show abstract][Hide abstract] ABSTRACT: Background We investigated whether prediagnostic reported intake of dairy products and dietary calcium are associated with colorectal cancer (CRC) survival. Methods Data from 3,859 subjects with CRC (42.1% male, mean age at diagnosis 64.2 ± 8.1 years) in the European Investigation into Cancer and Nutrition (EPIC) cohort were analyzed. Intake of dairy products and dietary calcium was assessed at baseline (1992-2000) using validated, country-specific dietary questionnaires. Multivariable Cox regression models were used to calculate hazard ratios (HR) and corresponding 95% confidence intervals (95%-CI) for CRC specific death (n=1,028) and all-cause death (n=1,525) for different quartiles of intake. Results The consumption of total dairy products was not statistically significantly associated with risk of CRC-specific death (adjusted HR Q4 vs. Q1: 1.17 95%-CI 0.97-1.43) nor of all-cause death (Q4 vs. Q1: 1.16 95%-CI 0.98-1.36). Multivariable adjusted HRs for CRC-specific death (Q4 vs. Q1) were 1.21 (95%-CI 0.99-1.48) for milk, 1.09 (95%-CI 0.88-1.34) for yoghurt and 0.93 (95%-CI 0.76-1.14) for cheese. The intake of dietary calcium was not associated with the risk of CRC-specific (adjusted HR Q4 vs. Q1: 1.01 95%-CI 0.81-1.26) nor of all-cause death (Q4 vs. Q1: 1.01 95%-CI 0.84-1.21). Conclusions The prediagnostic reported intake of dairy products and dietary calcium are not associated with disease-specific or all-cause risk of death in patients diagnosed with CRC. Impact The impact of diet on cancer survival is largely unknown. This study shows that despite it's inverse association with CRC risk, the prediagnostic intake of dairy and dietary calcium do not affect CRC survival.
[Show abstract][Hide abstract] ABSTRACT: Principal component analysis (PCA) and cluster analysis are used frequently to derive dietary patterns. Decisions on how many patterns to extract are primarily based on subjective criteria, whereas different solutions vary in their food-group composition and perhaps association with disease outcome. Literature on reliability of dietary patterns is scarce, and previous studies validated only 1 preselected solution. Therefore, we assessed reliability of different pattern solutions ranging from 2 to 6 patterns, derived from the aforementioned methods. A validated food frequency questionnaire was administered at baseline (1993-1997) to 39,678 participants in the European Prospective Investigation into Cancer and Nutrition-The Netherlands (EPIC-NL) cohort. Food items were grouped into 31 food groups for dietary pattern analysis. The cohort was randomly half-split, and dietary pattern solutions derived in 1 sample through PCA were replicated through confirmatory factor analysis in sample 2. For cluster analysis, cluster stability and split-half reproducibility were assessed for various solutions. With PCA, we found the 3-component solution to be best replicated, although all solutions contained ≥1 poorly confirmed component. No quantitative criterion was in agreement with these results. Associations with disease outcome (coronary heart disease) differed between the component solutions. For all cluster solutions, stability was excellent and deviations between split samples was negligible, indicating good reproducibility. All quantitative criteria identified the 2-cluster solution as optimal. Associations with disease outcome were comparable for different cluster solutions. In conclusion, reliability of obtained dietary patterns differed considerably for different solutions using PCA, whereas cluster analysis derived generally stable, reproducible clusters across different solutions. Quantitative criteria for determining the number of patterns to retain were valuable for cluster analysis but not for PCA. Associations with disease risk were influenced by the number of patterns that are retained, especially when using PCA. Therefore, studies on associations between dietary patterns and disease risk should report reasons to choose the number of retained patterns.
[Show abstract][Hide abstract] ABSTRACT: Prospective cohort studies recruit relatively healthy population samples, resulting in lower morbidity and mortality rates than in the source population. This is known as the healthy volunteer effect. The aim of this study was to define the magnitude and the development over time of the healthy volunteer effect in the EPIC-NL cohort.
We studied mortality rates in the EPIC-NL cohort, which comprises 37 551 men and women aged 20-70 years at recruitment in 1993-97. The date and cause of death of deceased participants until 2010 were obtained through linkage with the municipal registry and Statistics Netherlands. Standardized mortality ratios (SMRs) were computed by dividing the observed number of deaths by the number of deaths expected from the general Dutch population. Additionally, standardized incidence ratios were calculated to compare cancer incidence.
After an average follow-up of 14.9 years, 3029 deaths were documented. Overall mortality in men [SMR 73.5%, 95% confidence interval (CI): 68.1-79.3] and women (SMR 65.9%, 95% CI: 63.2-68.6) was lower compared with the general population for the whole follow-up period. The SMRs clearly increased over the follow-up period. Among women, the SMR was lower for death due to cardiovascular diseases than death due to cancer. Cancer incidence was also lower in EPIC-NL than in the general population (SMR 78.3 and 82.7% for men and women, respectively).
The results show a healthy volunteer effect in the EPIC-NL cohort, which tapers off with longer follow-up. Therefore, in the first years of follow-up, power might not be sufficient to detect small associations.
The European Journal of Public Health 04/2014; · 2.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We prospectively evaluated fat intake as predictor of developing breast cancer (BC) subtypes defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 receptor (HER2), in a large (n = 337327) heterogeneous cohort of women, with 10062 BC case patients after 11.5 years, estimating BC hazard ratios (HRs) by Cox proportional hazard modeling. High total and saturated fat were associated with greater risk of ER(+)PR(+) disease (HR = 1.20, 95% confidence interval [CI] = 1.00 to 1.45; HR = 1.28, 95% CI = 1.09 to 1.52; highest vs lowest quintiles) but not ER(-)PR(-) disease. High saturated fat was statistically significantly associated with greater risk of HER2(-) disease. High saturated fat intake particularly increases risk of receptor-positive disease, suggesting saturated fat involvement in the etiology of this BC subtype.
[Show abstract][Hide abstract] ABSTRACT: The (14;18) translocation constitutes both a genetic hallmark and critical early event in the natural history of follicular lymphoma (FL). However, t(14;18) is also detectable in the blood of otherwise healthy persons, and its relationship with progression to disease remains unclear. Here we sought to determine whether t(14;18)-positive cells in healthy individuals represent tumor precursors and whether their detection could be used as an early predictor for FL.
Among 520,000 healthy participants enrolled onto the EPIC (European Prospective Investigation Into Cancer and Nutrition) cohort, we identified 100 who developed FL 2 to 161 months after enrollment. Prediagnostic blood from these and 218 controls were screened for t(14;18) using sensitive polymerase chain reaction-based assays. Results were subsequently validated in an independent cohort (65 case participants; 128 controls). Clonal relationships between t(14;18) cells and FL were also assessed by molecular backtracking of paired prediagnostic blood and tumor samples.
Clonal analysis of t(14;18) junctions in paired prediagnostic blood versus tumor samples demonstrated that progression to FL occurred from t(14;18)-positive committed precursors. Furthermore, healthy participants at enrollment who developed FL up to 15 years later showed a markedly higher t(14;18) prevalence and frequency than controls (P < .001). Altogether, we estimated a 23-fold higher risk of subsequent FL in blood samples associated with a frequency > 10(-4) (odds ratio, 23.17; 95% CI, 9.98 to 67.31; P < .001). Remarkably, risk estimates remained high and significant up to 15 years before diagnosis.
High t(14;18) frequency in blood from healthy individuals defines the first predictive biomarker for FL, effective years before diagnosis.
Journal of Clinical Oncology 03/2014; · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Little is known about the causes of thyroid cancer, but insulin-like growth factor-I (IGF-I) might play an important role in its development due to its mitogenic and anti-apoptotic properties. Methods: This study prospectively investigated the association between serum IGF-I concentrations and risk of differentiated thyroid carcinoma in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition. 345 incident cases of differentiated thyroid carcinoma were individually matched to 735 controls by study centre, sex, and age, date, time, and fasting status at blood collection, follow-up duration, and for women menopausal status, use of exogenous hormones, and phase of menstrual cycle at blood collection. Serum IGF-I concentrations were measured by immunoassay, and risk of differentiated thyroid cancer in relation to IGF-I concentration was estimated using conditional logistic regression. Results: There was a positive association between IGF-I concentrations and risk of differentiated thyroid carcinoma: the odds ratio for a doubling in IGF-I concentration was 1.48 (95% confidence interval: 1.06 - 2.08; ptrend = 0.02). The positive association with IGF-I was stable over time between blood collection and cancer diagnosis. Conclusion: These findings suggest that IGF-I concentrations may be positively associated with risk of differentiated thyroid carcinoma. Impact: This study provides the first prospective evidence of a potential association between circulating IGF-I concentrations and risk of differentiated thyroid carcinoma and may prompt the further investigations needed to confirm the association.
Cancer Epidemiology Biomarkers & Prevention 03/2014; · 4.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background Evidence for the association of alcohol consumption with prognosis after a diagnosis of breast cancer has been inconsistent. We have reviewed and summarised the published evidence and evaluated the association using individual patient data from multiple case cohorts. Materials and Methods A MEDLINE search to identify studies published up to January 2013 was performed. We combined published estimates for survival time in "moderate drinkers" versus non-drinkers. An analysis of individual participant data using Cox regression was carried out using data from eleven case cohorts. Results We identified eleven published studies suitable for inclusion in the meta-analysis. Moderate post-diagnosis alcohol consumption was not associated with overall survival (HR = 0.95, 95% CI 0.85-1.05), but there was some evidence of better survival associated with pre-diagnosis consumption (HR = 0.80, 95% CI 0.73-0.88). Individual data on alcohol consumption for 29,239 cases with 4,839 deaths were available from the eleven case cohorts, all of which had data on ER status. For women with ER-positive disease there was little evidence that pre- or post-diagnosis alcohol consumption is associated with breast cancer-specific mortality, with some evidence of a reduction in all-cause mortality. Based on a single study, moderate post-diagnosis alcohol intake was associated with a small reduction in breast cancer-specific mortality in women with ER-negative disease. There was no association for pre-diagnosis intake in women with ER-negative disease. Impact Considering the totality of the evidence, moderate post-diagnosis alcohol consumption is unlikely to have a major adverse effect on survival of women with breast cancer.
Cancer Epidemiology Biomarkers & Prevention 03/2014; · 4.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In the prediction of time to menopause (TTM), what is the added value of anti-Müllerian hormone (AMH) when mother's age at natural menopause (ANM) is also known?
AMH is a more accurate predictor of individual TTM than mother's age at menopause.
Mother's ANM is considered a proxy for daughter's ANM although studies on its predictive accuracy are non-existent. AMH is a biomarker with a known capacity to predict ANM. However, its added value on top of known predictors, like mother's ANM, is unknown.
Population-based cohort studies were used. To assess any additive predictive value of mother's ANM, 164 mother-daughter pairs were used (Group 1). To assess the added value of AMH, a second group of 150 women in whom AMH and mother's ANM were recorded prior to a 12-year follow-up period during which daughter's ANM was assessed was used (Group 2).
Group 1 consisted of participants of the DOM cohort (an ongoing breast cancer study). Group 2 was a pooled cohort of women with regular menstrual cycles from two independent published studies. Cox proportional hazards analysis estimated uni- and multivariate regression coefficients for female age at study entry, mother's ANM and AMH in the prediction of TTM. Discrimination of models was assessed with C-statistics. Clinical added value of AMH was quantified with a net reclassification index (NRI).
A model with female age and mother's ANM had a c-statistic of 79 and 85% in groups 1 and 2, respectively. Both age and mother's ANM were significantly associated with TTM (HR 1.54 and HR 0.93 for age and mother's ANM in Cohort 1 and HR 1.59 and HR 0.89 in Group 2, respectively. P-value for all <0.001). In Group 2, the multivariate model with age, mother's ANM and AMH had a c-statistic of 92%, and only female age and AMH remained significantly associated with TTM (HR 1.41 P < 0.0001; HR 0.93 P = 0.08 and HR 0.06 P < 0.0001 for age, mother's ANM and AMH, respectively). The mean weighted NRI suggests that a 47% improvement in predictive accuracy is offered by adding AMH to the model of age and mother's ANM. In conclusion, AMH and mother's ANM both have added value in forecasting TTM for the daughter based on her age. In comparison, AMH is a more accurate added predictor of TTM than mother's ANM.
The cohort of women is relatively small and different cohorts of women were pooled.
This study shows that AMH is a more accurate predictor of ANM than mother's ANM. However, before achieving clinical applicability, the certainty with which a woman's prediction is made must improve. The association between mother's ANM and TTM in daughters did not appear to be influenced by whether ANM was recorded by mothers or daughters-an important finding because in the clinical setting daughters usually provide this information.
No funding was received and there were no competing interests in direct relation to this study.
[Show abstract][Hide abstract] ABSTRACT: Cigarette smoking is the best established modifiable risk factor for pancreatic cancer. Genetic factors that underlie smoking-related pancreatic cancer have previously not been examined at the genome-wide level. Taking advantage of the existing GWAS genotype and risk factor data from the Pancreatic Cancer Case Control Consortium, we conducted a discovery study in 2,028 cases and 2,109 controls to examine gene-smoking interactions at pathway/gene/SNP level. Using the likelihood ratio test (LRT) nested in logistic regression models and Ingenuity Pathway Analysis (IPA), we examined 172 KEGG pathways, 3 manually curated gene sets, 3 nicotine-dependency GO pathways, 17,912 genes and 486,114 SNPs. None of the individual pathway/gene/SNP showed significant interaction with smoking after adjusting for multiple comparisons. Six KEGG pathways showed nominal interactions (P <0.05) with smoking, and the top two are the pancreatic secretion and salivary secretion pathways (major contributing genes: RAB8A, PLCB, and CTRB1). Nine genes, i.e. ZBED2, EXO1, PSG2, SLC36A1, CLSTN1, MTHFSD, FAT2, IL10RB, and ATXN2 had Pinteraction <0.0005. Five inter-genic region SNPs and two SNPs of the EVC and KCNIP4 genes had Pinteraction <0.00003. In IPA analysis of genes with nominal interactions with smoking, axonal guidance signaling (P=2.12×10(-7)) and α-adrenergic signaling (P=2.52×10(-5)) genes were significantly overrepresented canonical pathways. Genes contributing to the axon guidance signaling pathway included the SLIT/ROBO signaling genes that were frequently altered in pancreatic cancer. These observations need to be confirmed in additional dataset. Once confirmed, it will open a new avenue to unveiling the etiology of smoking-associated pancreatic cancer.
[Show abstract][Hide abstract] ABSTRACT: To investigate the added diagnostic value of 3.0 Tesla breast MRI over conventional breast imaging in the diagnosis of in situ and invasive breast cancer and to explore the role of routine versus expert reading.
We evaluated MRI scans of patients with nonpalpable BI-RADS 3-5 lesions who underwent dynamic contrast-enhanced 3.0 Tesla breast MRI. Initially, MRI scans were read by radiologists in a routine clinical setting. All histologically confirmed index lesions were re-evaluated by two dedicated breast radiologists. Sensitivity and specificity for the three MRI readings were determined, and the diagnostic value of breast MRI in addition to conventional imaging was assessed. Interobserver reliability between the three readings was evaluated.
MRI examinations of 207 patients were analyzed. Seventy-eight of 207 (37.7%) patients had a malignant lesion, of which 33 (42.3%) patients had pure DCIS and 45 (57.7%) invasive breast cancer. Sensitivity of breast MRI was 66.7% during routine, and 89.3% and 94.7% during expert reading. Specificity was 77.5% in the routine setting, and 61.0% and 33.3% during expert reading. In the routine setting, MRI provided additional diagnostic information over clinical information and conventional imaging, as the Area Under the ROC Curve increased from 0.76 to 0.81. Expert MRI reading was associated with a stronger improvement of the AUC to 0.87. Interobserver reliability between the three MRI readings was fair and moderate.
3.0 T breast MRI of nonpalpable breast lesions is of added diagnostic value for the diagnosis of in situ and invasive breast cancer.
PLoS ONE 01/2014; 9(4):e94233. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Imbalances in tryptophan metabolism have been linked to cancer related immune escape and implicated in several cancers, including lung cancer. Methods: We conducted a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) that included 893 incident lung cancer cases and 1,748 matched controls. Circulating levels of tryptophan and six of its metabolites were measured and evaluated in relation to lung cancer risk. Results: Tryptophan (Ptrend=2x10-5) and the kynurenine/tryptophan ratio (KTR) (Ptrend=4x10-5) were associated with lung cancer risk overall after adjusting for established risk factors. The odds ratios comparing the fifth and first quintiles (OR5thvs.1st) were 0.52 (95% CI: 0.37-0.74) for tryptophan and 1.74 (95% CI: 1.24-2.45) for KTR. After adjusting for plasma methionine (available from previous work, which was strongly correlated with tryptophan), the associations of tryptophan (adjusted Ptrend=0.13) and KTR (Ptrend=0.009) were substantially attenuated. KTR was positively associated with squamous cell carcinoma, the OR5thvs.1st being 2.83 (95% CI: 1.62-4.94, Ptrend=3x10-5) that was only marginally affected by adjusting for methionine. Conclusions: This study indicates that biomarkers of tryptophan metabolism are associated with subsequent lung cancer risk. While this result would seem consistent with the immune system having a role in lung cancer development, the overall associations were dependent on methionine, and further studies are warranted to further elucidate the importance of these metabolites in lung cancer etiology. Impact: This is the first prospective study investigating the tryptophan pathway in relation to lung cancer risk.
Cancer Epidemiology Biomarkers & Prevention 12/2013; · 4.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Obesity and diabetes are potentially alterable risk factors for pancreatic cancer. Genetic factors that modify the associations of obesity and diabetes with pancreatic cancer have previously not been examined at the genome-wide level. Methods: Using GWAS genotype and risk factor data from the Pancreatic Cancer Case Control Consortium, we conducted a discovery study of 2,028 cases and 2,109 controls to examine gene-obesity and gene-diabetes interactions in relation to pancreatic cancer risk by employing the likelihood ratio test (LRT) nested in logistic regression models and Ingenuity Pathway Analysis (IPA). Results: After adjusting for multiple comparisons, a significant interaction of the chemokine signaling pathway with obesity (P=3.29×10^(-6)) and a near significant interaction of calcium signaling pathway with diabetes (P=1.57×10^(-4)) in modifying the risk of pancreatic cancer was observed. These findings were supported by results from IPA analysis of the top genes with nominal interactions. The major contributing genes to the two top pathways include GNGT2, RELA, TIAM1 and GNAS. None of the individual genes or SNPs except one SNP remained significant after adjusting for multiple testing. Notably, SNP rs10818684 of the PTGS1 gene showed an interaction with diabetes (P = 7.91×10^(-7)) at a false discovery rate of 6%. Conclusions: Genetic variations in inflammatory response and insulin resistance may affect the risk of obesity and diabetes-related pancreatic cancer. These observations should be replicated in additional large datasets. Impact: Gene-environment interaction analysis may provide new insights into the genetic susceptibility and molecular mechanisms of obesity- and diabetes-related pancreatic cancer.
Cancer Epidemiology Biomarkers & Prevention 10/2013; · 4.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the diagnostic value of 3-Tesla (T) breast MRI in patients presenting with microcalcifications on mammography.
Between January 2006 and May 2009, 123 patients with mammographically detected BI-RADS 3-5 microcalcifications underwent 3-T breast MRI before undergoing breast biopsy. All MRIs of the histopathologically confirmed index lesions were reviewed by two breast radiologists. The detection rate of invasive carcinoma and ductal carcinoma in situ (DCIS) was evaluated, as well as the added diagnostic value of MRI over mammography and breast ultrasound.
At pathology, 40/123 (33 %) lesions proved malignant; 28 (70 %) DCIS and 12 (30 %) invasive carcinoma. Both observers detected all invasive malignancies at MRI, as well as 79 % (observer 1) and 86 % (observer 2) of in situ lesions. MRI in addition to conventional imaging led to a significant increase in area under the receiver operating characteristic (ROC) curve from 0.67 (95 % CI 0.56-0.79) to 0.79 (95 % CI 0.70-0.88, observer 1) and to 0.80 (95 % CI 0.71-0.89, observer 2), respectively.
3-T breast MRI was shown to add significant value to conventional imaging in patients presenting with suspicious microcalcifications on mammography.
• 3-T MRI is increasingly used for breast imaging in clinical practice. • On 3-T breast MRI up to 86 % of DCIS lesions are detected. • 3-T MRI increases the diagnostic value in patients with mammographically detected microcalcifications.
[Show abstract][Hide abstract] ABSTRACT: Increasing evidence suggests that oral microbiota play a pivotal role in chronic diseases, in addition to the well-established role in periodontal disease. Moreover, recent studies suggest that oral bacteria may also be involved in carcinogenesis; periodontal disease has been linked to several cancers. In this study, we examined whether lifestyle factors have an impact on antibody levels to oral bacteria.
Data on demographic characteristics, lifestyle factors, and medical conditions were obtained at the time of blood sample collection. For the current analysis, we measured antibody levels to 25 oral bacteria in 395 cancer-free individuals using an immunoblot array. Combined total immunoglobin G (IgG) levels were obtained by summing concentrations for all oral bacteria measured.
IgG antibody levels were substantially lower among current and former smokers (1,697 and 1,677 ng/mL, respectively) than never smokers (1,960 ng/mL; p trend = 0.01), but did not vary by other factors, including body mass index, diabetes, physical activity, or by dietary factors, after adjusting for age, sex, education, country, and smoking status. The highest levels of total IgG were found among individuals with low education (2,419 ng/mL).
Our findings on smoking are consistent with previous studies and support the notion that smokers have a compromised humoral immune response. Moreover, other major factors known to be associated with inflammatory markers, including obesity, were not associated with antibody levels to a large number of oral bacteria.
Cancer Causes and Control 07/2013; · 3.20 Impact Factor