Displaying publications 1 - 20 of 109 in total

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  1. Zhang M, Wang Z, Obazee O, Jia J, Childs EJ, Hoskins J, et al.
    Oncotarget, 2016 Oct 11;7(41):66328-66343.
    PMID: 27579533 DOI: 10.18632/oncotarget.11041
    Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10 -15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10 -9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10 -8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 ( NR5A2), chr8q24.21 ( MYC) and chr5p15.33 ( CLPTM1L- TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal ( n = 10) and tumor ( n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10 -8). This finding was validated in a second set of paired ( n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10 -4-2.0x10 -3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.
  2. Duarte-Salles T, Misra S, Stepien M, Plymoth A, Muller D, Overvad K, et al.
    Cancer Prev Res (Phila), 2016 Sep;9(9):758-65.
    PMID: 27339170 DOI: 10.1158/1940-6207.CAPR-15-0434
    We previously identified osteopontin (OPN) as a promising marker for the early detection of hepatocellular carcinoma (HCC). In this study, we investigated the association between prediagnostic circulating OPN levels and HCC incidence in a large population-based cohort. A nested case-control study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. During a mean follow-up of 4.8 years, 100 HCC cases were identified. Each case was matched to two controls and OPN levels were measured in baseline plasma samples. Viral hepatitis, liver function, and α-fetoprotein (AFP) tests were also conducted. Conditional logistic regression models were used to calculate multivariable odds ratio (OR) and 95% confidence intervals (95% CI) for OPN levels in relation to HCC. Receiver operating characteristics curves were constructed to determine the discriminatory accuracy of OPN alone or in combination with other liver biomarkers in the prediction of HCC. OPN levels were positively associated with HCC risk (per 10% increment, ORmultivariable = 1.30; 95% CI, 1.14-1.48). The association was stronger among cases diagnosed within 2 years of follow-up. Adding liver function tests to OPN improved the discriminatory performance for subjects who developed HCC (AUC = 0.86). For cases diagnosed within 2 years, the combination of OPN and AFP was best able to predict HCC risk (AUC = 0.88). The best predictive model for HCC in this low-risk population is OPN in combination with liver function tests. Within 2 years of diagnosis, the combination of OPN and AFP best predicted HCC development, suggesting that measuring OPN and AFP could identify high-risk groups independently of a liver disease diagnosis. Cancer Prev Res; 9(9); 758-65. ©2016 AACR.
  3. Scelo G, Muller DC, Riboli E, Johansson M, Cross AJ, Vineis P, et al.
    Clin Cancer Res, 2018 Nov 15;24(22):5594-5601.
    PMID: 30037816 DOI: 10.1158/1078-0432.CCR-18-1496
    Purpose: Renal cell carcinoma (RCC) has the potential for cure with surgery when diagnosed at an early stage. Kidney injury molecule-1 (KIM-1) has been shown to be elevated in the plasma of RCC patients. We aimed to test whether plasma KIM-1 could represent a means of detecting RCC prior to clinical diagnosis.Experimental Design: KIM-1 concentrations were measured in prediagnostic plasma from 190 RCC cases and 190 controls nested within a population-based prospective cohort study. Cases had entered the cohort up to 5 years before diagnosis, and controls were matched on cases for date of birth, date at blood donation, sex, and country. We applied conditional logistic regression and flexible parametric survival models to evaluate the association between plasma KIM-1 concentrations and RCC risk and survival.Results: The incidence rate ratio (IRR) of RCC for a doubling in KIM-1 concentration was 1.71 [95% confidence interval (CI), 1.44-2.03, P = 4.1 × 10-23], corresponding to an IRR of 63.3 (95% CI, 16.2-246.9) comparing the 80th to the 20th percentiles of the KIM-1 distribution in this sample. Compared with a risk model including known risk factors of RCC (age, sex, country, body mass index, and tobacco smoking status), a risk model additionally including KIM-1 substantially improved discrimination between cases and controls (area under the receiver-operating characteristic curve of 0.8 compared with 0.7). High plasma KIM-1 concentrations were also associated with poorer survival (P = 0.0053).Conclusions: Plasma KIM-1 concentrations could predict RCC incidence up to 5 years prior to diagnosis and were associated with poorer survival. Clin Cancer Res; 24(22); 5594-601. ©2018 AACR.
  4. Steffen A, Huerta JM, Weiderpass E, Bueno-de-Mesquita HB, May AM, Siersema PD, et al.
    Int J Cancer, 2015 Aug 01;137(3):646-57.
    PMID: 25598323 DOI: 10.1002/ijc.29432
    General obesity, as reflected by BMI, is an established risk factor for esophageal adenocarcinoma (EAC), a suspected risk factor for gastric cardia adenocarcinoma (GCC) and appears unrelated to gastric non-cardia adenocarcinoma (GNCC). How abdominal obesity, as commonly measured by waist circumference (WC), relates to these cancers remains largely unexplored. Using measured anthropometric data from 391,456 individuals from the European Prospective Investigation into Cancer and Nutrition (EPIC) study and 11 years of follow-up, we comprehensively assessed the association of anthropometric measures with risk of EAC, GCC and GNCC using multivariable proportional hazards regression. One hundred twenty-four incident EAC, 193 GCC and 224 GNCC were accrued. After mutual adjustment, BMI was unrelated to EAC, while WC showed a strong positive association (highest vs. lowest quintile HR = 1.19; 95% CI, 0.63-2.22 and HR = 3.76; 1.72-8.22, respectively). Hip circumference (HC) was inversely related to EAC after controlling for WC, while WC remained positively associated (HR = 0.35; 0.18-0.68, and HR=4.10; 1.94-8.63, respectively). BMI was not associated with GCC or GNCC. WC was related to higher risks of GCC after adjustment for BMI and more strongly after adjustment for HC (highest vs. lowest quintile HR = 1.91; 1.09-3.37, and HR = 2.23; 1.28-3.90, respectively). Our study demonstrates that abdominal, rather than general, obesity is an indisputable risk factor for EAC and also provides evidence for a protective effect of gluteofemoral (subcutaneous) adipose tissue in EAC. Our study further shows that general obesity is not a risk factor for GCC and GNCC, while the role of abdominal obesity in GCC needs further investigation.
  5. Racine A, Carbonnel F, Chan SS, Hart AR, Bueno-de-Mesquita HB, Oldenburg B, et al.
    Inflamm Bowel Dis, 2016 Feb;22(2):345-54.
    PMID: 26717318 DOI: 10.1097/MIB.0000000000000638
    BACKGROUND: Specific nutrients or foods have been inconsistently associated with ulcerative colitis (UC) or Crohn's disease (CD) risks. Thus, we investigated associations between diet as a whole, as dietary patterns, and UC and CD risks.

    METHODS: Within the prospective EPIC (European Prospective Investigation into Cancer) study, we set up a nested matched case-control study among 366,351 participants with inflammatory bowel disease data, including 256 incident cases of UC and 117 of CD, and 4 matched controls per case. Dietary intake was recorded at baseline from validated food frequency questionnaires. Incidence rate ratios of developing UC and CD were calculated for quintiles of the Mediterranean diet score and a posteriori dietary patterns produced by factor analysis.

    RESULTS: No dietary pattern was associated with either UC or CD risks. However, when excluding cases occurring within the first 2 years after dietary assessment, there was a positive association between a "high sugar and soft drinks" pattern and UC risk (incidence rate ratios for the fifth versus first quintile, 1.68 [1.00-2.82]; Ptrend = 0.02). When considering the foods most associated with the pattern, high consumers of sugar and soft drinks were at higher UC risk only if they had low vegetables intakes.

    CONCLUSIONS: A diet imbalance with high consumption of sugar and soft drinks and low consumption of vegetables was associated with UC risk. Further studies are needed to investigate whether microbiota alterations or other mechanisms mediate this association.

  6. Lesseur C, Diergaarde B, Olshan AF, Wünsch-Filho V, Ness AR, Liu G, et al.
    Nat Genet, 2016 Dec;48(12):1544-1550.
    PMID: 27749845 DOI: 10.1038/ng.3685
    We conducted a genome-wide association study of oral cavity and pharyngeal cancer in 6,034 cases and 6,585 controls from Europe, North America and South America. We detected eight significantly associated loci (P < 5 × 10-8), seven of which are new for these cancer sites. Oral and pharyngeal cancers combined were associated with loci at 6p21.32 (rs3828805, HLA-DQB1), 10q26.13 (rs201982221, LHPP) and 11p15.4 (rs1453414, OR52N2-TRIM5). Oral cancer was associated with two new regions, 2p23.3 (rs6547741, GPN1) and 9q34.12 (rs928674, LAMC3), and with known cancer-related loci-9p21.3 (rs8181047, CDKN2B-AS1) and 5p15.33 (rs10462706, CLPTM1L). Oropharyngeal cancer associations were limited to the human leukocyte antigen (HLA) region, and classical HLA allele imputation showed a protective association with the class II haplotype HLA-DRB1*1301-HLA-DQA1*0103-HLA-DQB1*0603 (odds ratio (OR) = 0.59, P = 2.7 × 10-9). Stratified analyses on a subgroup of oropharyngeal cases with information available on human papillomavirus (HPV) status indicated that this association was considerably stronger in HPV-positive (OR = 0.23, P = 1.6 × 10-6) than in HPV-negative (OR = 0.75, P = 0.16) cancers.
  7. Anantharaman D, Muller DC, Lagiou P, Ahrens W, Holcátová I, Merletti F, et al.
    Int J Epidemiol, 2016 Jun;45(3):752-61.
    PMID: 27197530 DOI: 10.1093/ije/dyw069
    BACKGROUND: Although smoking and HPV infection are recognized as important risk factors for oropharyngeal cancer, how their joint exposure impacts on oropharyngeal cancer risk is unclear. Specifically, whether smoking confers any additional risk to HPV-positive oropharyngeal cancer is not understood.

    METHODS: Using HPV serology as a marker of HPV-related cancer, we examined the interaction between smoking and HPV16 in 459 oropharyngeal (and 1445 oral cavity and laryngeal) cancer patients and 3024 control participants from two large European multi-centre studies. Odds ratios and credible intervals [CrI], adjusted for potential confounders, were estimated using Bayesian logistic regression.

    RESULTS: Both smoking [odds ratio (OR [CrI]: 6.82 [4.52, 10.29]) and HPV seropositivity (OR [CrI]: 235.69 [99.95, 555.74]) were independently associated with oropharyngeal cancer. The joint association of smoking and HPV seropositivity was consistent with that expected on the additive scale (synergy index [CrI]: 1.32 [0.51, 3.45]), suggesting they act as independent risk factors for oropharyngeal cancer.

    CONCLUSIONS: Smoking was consistently associated with increase in oropharyngeal cancer risk in models stratified by HPV16 seropositivity. In addition, we report that the prevalence of oropharyngeal cancer increases with smoking for both HPV16-positive and HPV16-negative persons. The impact of smoking on HPV16-positive oropharyngeal cancer highlights the continued need for smoking cessation programmes for primary prevention of head and neck cancer.

  8. Muller DC, Murphy N, Johansson M, Ferrari P, Tsilidis KK, Boutron-Ruault MC, et al.
    BMC Med, 2016 Jun 14;14:87.
    PMID: 27296932 DOI: 10.1186/s12916-016-0630-6
    BACKGROUND: Life expectancy is increasing in Europe, yet a substantial proportion of adults still die prematurely before the age of 70 years. We sought to estimate the joint and relative contributions of tobacco smoking, hypertension, obesity, physical inactivity, alcohol and poor diet towards risk of premature death.

    METHODS: We analysed data from 264,906 European adults from the EPIC prospective cohort study, aged between 40 and 70 years at the time of recruitment. Flexible parametric survival models were used to model risk of death conditional on risk factors, and survival functions and attributable fractions (AF) for deaths prior to age 70 years were calculated based on the fitted models.

    RESULTS: We identified 11,930 deaths which occurred before the age of 70. The AF for premature mortality for smoking was 31 % (95 % confidence interval (CI), 31-32 %) and 14 % (95 % CI, 12-16 %) for poor diet. Important contributions were also observed for overweight and obesity measured by waist-hip ratio (10 %; 95 % CI, 8-12 %) and high blood pressure (9 %; 95 % CI, 7-11 %). AFs for physical inactivity and excessive alcohol intake were 7 % and 4 %, respectively. Collectively, the AF for all six risk factors was 57 % (95 % CI, 55-59 %), being 35 % (95 % CI, 32-37 %) among never smokers and 74 % (95 % CI, 73-75 %) among current smokers.

    CONCLUSIONS: While smoking remains the predominant risk factor for premature death in Europe, poor diet, overweight and obesity, hypertension, physical inactivity, and excessive alcohol consumption also contribute substantially. Any attempt to minimise premature deaths will ultimately require all six factors to be addressed.

  9. Ordóñez-Mena JM, Schöttker B, Fedirko V, Jenab M, Olsen A, Halkjær J, et al.
    Eur J Epidemiol, 2016 Mar;31(3):311-23.
    PMID: 25977096 DOI: 10.1007/s10654-015-0040-7
    The associations of circulating 25-hydroxyvitamin D [25(OH)D] concentrations with total and site-specific cancer incidence have been examined in several epidemiological studies with overall inconclusive findings. Very little is known about the association of vitamin D with cancer incidence in older populations. We assessed the association of pre-diagnostic serum 25(OH)D levels with incidence of all cancers combined and incidence of lung, colorectal, breast, prostate and lymphoid malignancies among older adults. Pre-diagnostic 25(OH)D concentrations and cancer incidence were available in total for 15,486 older adults (mean age 63, range 50-84 years) participating in two cohort studies: ESTHER (Germany) and TROMSØ (Norway); and a subset of previously published nested-case control data from a another cohort study: EPIC-Elderly (Greece, Denmark, Netherlands, Spain and Sweden) from the CHANCES consortium on health and aging. Cox proportional hazards or logistic regression were used to derive multivariable adjusted hazard and odds ratios, respectively, and their 95% confidence intervals across 25(OH)D categories. Meta-analyses with random effects models were used to pool study-specific risk estimates. Overall, lower 25(OH)D concentrations were not significantly associated with increased incidence of most of the cancers assessed. However, there was some evidence of increased breast cancer and decreased lymphoma risk with higher 25(OH)D concentrations. Our meta-analyses with individual participant data from three large European population-based cohort studies provide at best limited support for the hypothesis that vitamin D may have a major role in cancer development and prevention among European older adults.
  10. Kong SY, Takeuchi M, Hyogo H, McKeown-Eyssen G, Yamagishi S, Chayama K, et al.
    Cancer Epidemiol Biomarkers Prev, 2015 Dec;24(12):1855-63.
    PMID: 26404963 DOI: 10.1158/1055-9965.EPI-15-0422
    BACKGROUND: A large proportion of colorectal cancers are thought to be associated with unhealthy dietary and lifestyle exposures, particularly energy excess, obesity, hyperinsulinemia, and hyperglycemia. It has been suggested that these processes stimulate the production of toxic reactive carbonyls from sugars such as glyceraldehyde. Glyceraldehyde contributes to the production of a group of compounds known as glyceraldehyde-derived advanced glycation end-products (glycer-AGEs), which may promote colorectal cancer through their proinflammatory and pro-oxidative properties. The objective of this study nested within a prospective cohort was to explore the association of circulating glycer-AGEs with risk of colorectal cancer.

    METHODS: A total of 1,055 colorectal cancer cases (colon n = 659; rectal n = 396) were matchced (1:1) to control subjects. Circulating glycer-AGEs were measured by a competitive ELISA. Multivariable conditional logistic regression models were used to calculate ORs and 95% confidence intervals (95% CI), adjusting for potential confounding factors, including smoking, alcohol, physical activity, body mass index, and diabetes status.

    RESULTS: Elevated glycer-AGEs levels were not associated with colorectal cancer risk (highest vs. lowest quartile, 1.10; 95% CI, 0.82-1.49). Subgroup analyses showed possible divergence by anatomical subsites (OR for colon cancer, 0.83; 95% CI, 0.57-1.22; OR for rectal cancer, 1.90; 95% CI, 1.14-3.19; Pheterogeneity = 0.14).

    CONCLUSIONS: In this prospective study, circulating glycer-AGEs were not associated with risk of colon cancer, but showed a positive association with the risk of rectal cancer.

    IMPACT: Further research is needed to clarify the role of toxic products of carbohydrate metabolism and energy excess in colorectal cancer development.

  11. Bhoo-Pathy N, Uiterwaal CS, Dik VK, Jeurnink SM, Bech BH, Overvad K, et al.
    Clin Gastroenterol Hepatol, 2013 Nov;11(11):1486-92.
    PMID: 23756220 DOI: 10.1016/j.cgh.2013.05.029
    BACKGROUND & AIMS: Few modifiable risk factors have been implicated in the etiology of pancreatic cancer. There is little evidence for the effects of caffeinated coffee, decaffeinated coffee, or tea intake on risk of pancreatic cancer. We investigated the association of total coffee, caffeinated coffee, decaffeinated coffee, and tea consumption with risk of pancreatic cancer.

    METHODS: This study was conducted within the European Prospective Investigation into Nutrition and Cancer cohort, comprising male and female participants from 10 European countries. Between 1992 and 2000, there were 477,312 participants without cancer who completed a dietary questionnaire and were followed up to determine pancreatic cancer incidence. Coffee and tea intake was calibrated with a 24-hour dietary recall. Adjusted hazard ratios (HRs) were computed using multivariable Cox regression.

    RESULTS: During a mean follow-up period of 11.6 y, 865 first incidences of pancreatic cancers were reported. When divided into fourths, neither total intake of coffee (HR, 1.03; 95% confidence interval [CI], 0.83-1.27; high vs low intake), decaffeinated coffee (HR, 1.12; 95% CI, 0.76-1.63; high vs low intake), nor tea were associated with risk of pancreatic cancer (HR, 1.22, 95% CI, 0.95-1.56; high vs low intake). Moderately low intake of caffeinated coffee was associated with an increased risk of pancreatic cancer (HR, 1.33; 95% CI, 1.02-1.74), compared with low intake. However, no graded dose response was observed, and the association attenuated after restriction to histologically confirmed pancreatic cancers.

    CONCLUSIONS: Based on an analysis of data from the European Prospective Investigation into Nutrition and Cancer cohort, total coffee, decaffeinated coffee, and tea consumption are not related to the risk of pancreatic cancer.

  12. Bueno-de-Mesquita HB
    Asia Pac J Public Health, 2015 Nov;27(8 Suppl):110S-115S.
    PMID: 26155799 DOI: 10.1177/1010539515594445
    Noncommunicable diseases (NCDs; mainly cancer, cardiovascular diseases, diabetes, and chronic respiratory diseases) are now responsible for more than 35 million deaths per annum in the world; more than 80% of these deaths occur in low- and middle-income countries. Dramatic worldwide changes in lifestyle and in the prevalence and incidence of major chronic diseases lends credence to the causative role of modifiable risk factors. For the elucidation of modifiable risk factors, large-scale prospective cohort studies with biobanks often combined in consortia are of paramount importance. Associations between selected risk factors and development of NCDs will be reviewed. In addition to the contribution of treatment, even larger proportions of NCDs can be prevented had risk factors been reduced to the optimum levels or eliminated. Individual-based approaches should be complemented by administrative regulations.
  13. Navarrete-Muñoz EM, Wark PA, Romaguera D, Bhoo-Pathy N, Michaud D, Molina-Montes E, et al.
    Am J Clin Nutr, 2016 Sep;104(3):760-8.
    PMID: 27510540 DOI: 10.3945/ajcn.116.130963
    BACKGROUND: The consumption of sweet beverages has been associated with greater risk of type 2 diabetes and obesity, which may be involved in the development of pancreatic cancer. Therefore, it has been hypothesized that sweet beverages may increase pancreatic cancer risk as well.

    OBJECTIVE: We examined the association between sweet-beverage consumption (including total, sugar-sweetened, and artificially sweetened soft drink and juice and nectar consumption) and pancreatic cancer risk.

    DESIGN: The study was conducted within the European Prospective Investigation into Cancer and Nutrition cohort. A total of 477,199 participants (70.2% women) with a mean age of 51 y at baseline were included, and 865 exocrine pancreatic cancers were diagnosed after a median follow-up of 11.60 y (IQR: 10.10-12.60 y). Sweet-beverage consumption was assessed with the use of validated dietary questionnaires at baseline. HRs and 95% CIs were obtained with the use of multivariable Cox regression models that were stratified by age, sex, and center and adjusted for educational level, physical activity, smoking status, and alcohol consumption. Associations with total soft-drink consumption were adjusted for juice and nectar consumption and vice versa.

    RESULTS: Total soft-drink consumption (HR per 100 g/d: 1.03; 95% CI: 0.99, 1.07), sugar-sweetened soft-drink consumption (HR per 100 g/d: 1.02; 95% CI: 0.97, 1.08), and artificially sweetened soft-drink consumption (HR per 100 g/d: 1.04; 95% CI: 0.98, 1.10) were not associated with pancreatic cancer risk. Juice and nectar consumption was inversely associated with pancreatic cancer risk (HR per 100 g/d: 0.91; 95% CI: 0.84, 0.99); this association remained statistically significant after adjustment for body size, type 2 diabetes, and energy intake.

    CONCLUSIONS: Soft-drink consumption does not seem to be associated with pancreatic cancer risk. Juice and nectar consumption might be associated with a modest decreased pancreatic cancer risk. Additional studies with specific information on juice and nectar subtypes are warranted to clarify these results.

  14. Leenders M, Siersema PD, Overvad K, Tjønneland A, Olsen A, Boutron-Ruault MC, et al.
    Int J Cancer, 2015 Dec 01;137(11):2705-14.
    PMID: 26077137 DOI: 10.1002/ijc.29640
    Previously, a lower risk of colorectal cancer was observed with fruit and vegetable consumption in the European Prospective Investigation into Cancer and Nutrition within a follow-up period of 9 years which was not fully supported by a recent meta-analysis. Therefore, we were interested in the relation with extended follow-up, also focusing on single subtypes and a variety of intake of fruit and vegetables. Fruit and vegetable consumption was assessed at baseline. After an average of 13 years of follow-up, 3,370 participants were diagnosed with colon or rectal cancer. Diet diversity scores were constructed to quantify variety in fruit and vegetable consumption. A lower risk of colon cancer was observed with higher self-reported consumption of fruit and vegetable combined (HR Q4 vs. Q1 0.87, 95% CI 0.75-1.01, p for trend 0.02), but no consistent association was observed for separate consumption of fruits and vegetables. No associations with risk of rectal cancer were observed. The few observed associations for some fruit and vegetable subtypes with colon cancer risk may have been due to chance. Variety in consumption of fruits and vegetables was not associated with a lower risk of colon or rectal cancer. Although a lower risk of colon cancer is suggested with high consumption of fruit and vegetables, this study does not support a clear inverse association between fruit and vegetable consumption and colon or rectal cancer beyond a follow-up of more than 10 years. Attenuation of the risk estimates from dietary changes over time cannot be excluded, but appears unlikely.
  15. Moy FM, Hoe VC, Hairi NN, Buckley B, Wark PA, Koh D, et al.
    BMC Public Health, 2014;14:611.
    PMID: 24938383 DOI: 10.1186/1471-2458-14-611
    The study on Clustering of Lifestyle risk factors and Understanding its association with Stress on health and wellbeing among school Teachers in Malaysia (CLUSTer) is a prospective cohort study which aims to extensively study teachers in Malaysia with respect to clustering of lifestyle risk factors and stress, and subsequently, to follow-up the population for important health outcomes.
  16. Arnold M, Freisling H, Stolzenberg-Solomon R, Kee F, O'Doherty MG, Ordóñez-Mena JM, et al.
    Eur J Epidemiol, 2016 Sep;31(9):893-904.
    PMID: 27300353 DOI: 10.1007/s10654-016-0169-z
    Recent studies have shown that cancer risk related to overweight and obesity is mediated by time and might be better approximated by using life years lived with excess weight. In this study we aimed to assess the impact of overweight duration and intensity in older adults on the risk of developing different forms of cancer. Study participants from seven European and one US cohort study with two or more weight assessments during follow-up were included (n = 329,576). Trajectories of body mass index (BMI) across ages were estimated using a quadratic growth model; overweight duration (BMI ≥ 25) and cumulative weighted overweight years were calculated. In multivariate Cox models and random effects analyses, a longer duration of overweight was significantly associated with the incidence of obesity-related cancer [overall hazard ratio (HR) per 10-year increment: 1.36; 95 % CI 1.12-1.60], but also increased the risk of postmenopausal breast and colorectal cancer. Additionally accounting for the degree of overweight further increased the risk of obesity-related cancer. Risks associated with a longer overweight duration were higher in men than in women and were attenuated by smoking. For postmenopausal breast cancer, increased risks were confined to women who never used hormone therapy. Overall, 8.4 % of all obesity-related cancers could be attributed to overweight at any age. These findings provide further insights into the role of overweight duration in the etiology of cancer and indicate that weight control is relevant at all ages. This knowledge is vital for the development of effective and targeted cancer prevention strategies.
  17. Campa D, Rizzato C, Stolzenberg-Solomon R, Pacetti P, Vodicka P, Cleary SP, et al.
    Int J Cancer, 2015 Nov 01;137(9):2175-83.
    PMID: 25940397 DOI: 10.1002/ijc.29590
    A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT-CLPTM1L gene region on chromosome 5p15.33. Because this region is characterized by low linkage disequilibrium, we sought to identify whether additional single nucleotide polymorphisms (SNPs) could be related to pancreatic cancer risk, independently of rs401681. We performed an in-depth analysis of genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) genes, in 5,550 subjects with pancreatic cancer and 7,585 controls from the PANcreatic Disease ReseArch (PANDoRA) and the PanScan consortia. We identified a significant association between a variant in TERT and pancreatic cancer risk (rs2853677, odds ratio = 0.85; 95% confidence interval = 0.80-0.90, p = 8.3 × 10(-8)). Additional analysis adjusting rs2853677 for rs401681 indicated that the two SNPs are independently associated with pancreatic cancer risk, as suggested by the low linkage disequilibrium between them (r(2) = 0.07, D' = 0.28). Three additional SNPs in TERT reached statistical significance after correction for multiple testing: rs2736100 (p = 3.0 × 10(-5) ), rs4583925 (p = 4.0 × 10(-5) ) and rs2735948 (p = 5.0 × 10(-5) ). In conclusion, we confirmed that the TERT locus is associated with pancreatic cancer risk, possibly through several independent variants.
  18. Campa D, Matarazzi M, Greenhalf W, Bijlsma M, Saum KU, Pasquali C, et al.
    Int J Cancer, 2019 03 15;144(6):1275-1283.
    PMID: 30325019 DOI: 10.1002/ijc.31928
    Telomere deregulation is a hallmark of cancer. Telomere length measured in lymphocytes (LTL) has been shown to be a risk marker for several cancers. For pancreatic ductal adenocarcinoma (PDAC) consensus is lacking whether risk is associated with long or short telomeres. Mendelian randomization approaches have shown that a score built from SNPs associated with LTL could be used as a robust risk marker. We explored this approach in a large scale study within the PANcreatic Disease ReseArch (PANDoRA) consortium. We analyzed 10 SNPs (ZNF676-rs409627, TERT-rs2736100, CTC1-rs3027234, DHX35-rs6028466, PXK-rs6772228, NAF1-rs7675998, ZNF208-rs8105767, OBFC1-rs9420907, ACYP2-rs11125529 and TERC-rs10936599) alone and combined in a LTL genetic score ("teloscore", which explains 2.2% of the telomere variability) in relation to PDAC risk in 2,374 cases and 4,326 controls. We identified several associations with PDAC risk, among which the strongest were with the TERT-rs2736100 SNP (OR = 1.54; 95%CI 1.35-1.76; p = 1.54 × 10-10 ) and a novel one with the NAF1-rs7675998 SNP (OR = 0.80; 95%CI 0.73-0.88; p = 1.87 × 10-6 , ptrend = 3.27 × 10-7 ). The association of short LTL, measured by the teloscore, with PDAC risk reached genome-wide significance (p = 2.98 × 10-9 for highest vs. lowest quintile; p = 1.82 × 10-10 as a continuous variable). In conclusion, we present a novel genome-wide candidate SNP for PDAC risk (TERT-rs2736100), a completely new signal (NAF1-rs7675998) approaching genome-wide significance and we report a strong association between the teloscore and risk of pancreatic cancer, suggesting that telomeres are a potential risk factor for pancreatic cancer.
  19. Campa D, Pastore M, Gentiluomo M, Talar-Wojnarowska R, Kupcinskas J, Malecka-Panas E, et al.
    Oncotarget, 2016 08 30;7(35):57011-57020.
    PMID: 27486979 DOI: 10.18632/oncotarget.10935
    The CDKN2A (p16) gene plays a key role in pancreatic cancer etiology. It is one of the most commonly somatically mutated genes in pancreatic cancer, rare germline mutations have been found to be associated with increased risk of developing familiar pancreatic cancer and CDKN2A promoter hyper-methylation has been suggested to play a critical role both in pancreatic cancer onset and prognosis. In addition several unrelated SNPs in the 9p21.3 region, that includes the CDNK2A, CDNK2B and the CDNK2B-AS1 genes, are associated with the development of cancer in various organs. However, association between the common genetic variability in this region and pancreatic cancer risk is not clearly understood. We sought to fill this gap in a case-control study genotyping 13 single nucleotide polymorphisms (SNPs) in 2,857 pancreatic ductal adenocarcinoma (PDAC) patients and 6,111 controls in the context of the Pancreatic Disease Research (PANDoRA) consortium. We found that the A allele of the rs3217992 SNP was associated with an increased pancreatic cancer risk (ORhet=1.14, 95% CI 1.01-1.27, p=0.026, ORhom=1.30, 95% CI 1.12-1.51, p=0.00049). This pleiotropic variant is reported to be a mir-SNP that, by changing the binding site of one or more miRNAs, could influence the normal cell cycle progression and in turn increase PDAC risk. In conclusion, we observed a novel association in a pleiotropic region that has been found to be of key relevance in the susceptibility to various types of cancer and diabetes suggesting that the CDKN2A/B locus could represent a genetic link between diabetes and pancreatic cancer risk.
  20. Roura E, Travier N, Waterboer T, de Sanjosé S, Bosch FX, Pawlita M, et al.
    PLoS One, 2016;11(1):e0147029.
    PMID: 26808155 DOI: 10.1371/journal.pone.0147029
    BACKGROUND: In addition to HPV, high parity and hormonal contraceptives have been associated with cervical cancer (CC). However, most of the evidence comes from retrospective case-control studies. The aim of this study is to prospectively evaluate associations between hormonal factors and risk of developing cervical intraepithelial neoplasia grade 3 (CIN3)/carcinoma in situ (CIS) and invasive cervical cancer (ICC).

    METHODS AND FINDINGS: We followed a cohort of 308,036 women recruited in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study. At enrollment, participants completed a questionnaire and provided serum. After a 9-year median follow-up, 261 ICC and 804 CIN3/CIS cases were reported. In a nested case-control study, the sera from 609 cases and 1,218 matched controls were tested for L1 antibodies against HPV types 11,16,18,31,33,35,45,52,58, and antibodies against Chlamydia trachomatis and Human herpesvirus 2. Multivariate analyses were performed to estimate hazard ratios (HR), odds ratios (OR) and corresponding 95% confidence intervals (CI). The cohort analysis showed that number of full-term pregnancies was positively associated with CIN3/CIS risk (p-trend = 0.03). Duration of oral contraceptives use was associated with a significantly increased risk of both CIN3/CIS and ICC (HR = 1.6 and HR = 1.8 respectively for ≥ 15 years versus never use). Ever use of menopausal hormone therapy was associated with a reduced risk of ICC (HR = 0.5, 95%CI: 0.4-0.8). A non-significant reduced risk of ICC with ever use of intrauterine devices (IUD) was found in the nested case-control analysis (OR = 0.6). Analyses restricted to all cases and HPV seropositive controls yielded similar results, revealing a significant inverse association with IUD for combined CIN3/CIS and ICC (OR = 0.7).

    CONCLUSIONS: Even though HPV is the necessary cause of CC, our results suggest that several hormonal factors are risk factors for cervical carcinogenesis. Adherence to current cervical cancer screening guidelines should minimize the increased risk of CC associated with these hormonal risk factors.

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