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Comparison of prognostic models to predict the occurrence of colorectal cancer in asymptomatic individuals: a systematic literature review and external validation in the EPIC and UK Biobank prospective cohort studies.
Smith, T, Muller, DC, Moons, KGM, Cross, AJ, Johansson, M, Ferrari, P, Fagherazzi, G, Peeters, PHM, Severi, G, Hüsing, A, et al
Gut. 2019;(4):672-683
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Abstract
OBJECTIVE To systematically identify and validate published colorectal cancer risk prediction models that do not require invasive testing in two large population-based prospective cohorts. DESIGN Models were identified through an update of a published systematic review and validated in the European Prospective Investigation into Cancer and Nutrition (EPIC) and the UK Biobank. The performance of the models to predict the occurrence of colorectal cancer within 5 or 10 years after study enrolment was assessed by discrimination (C-statistic) and calibration (plots of observed vs predicted probability). RESULTS The systematic review and its update identified 16 models from 8 publications (8 colorectal, 5 colon and 3 rectal). The number of participants included in each model validation ranged from 41 587 to 396 515, and the number of cases ranged from 115 to 1781. Eligible and ineligible participants across the models were largely comparable. Calibration of the models, where assessable, was very good and further improved by recalibration. The C-statistics of the models were largely similar between validation cohorts with the highest values achieved being 0.70 (95% CI 0.68 to 0.72) in the UK Biobank and 0.71 (95% CI 0.67 to 0.74) in EPIC. CONCLUSION Several of these non-invasive models exhibited good calibration and discrimination within both external validation populations and are therefore potentially suitable candidates for the facilitation of risk stratification in population-based colorectal screening programmes. Future work should both evaluate this potential, through modelling and impact studies, and ascertain if further enhancement in their performance can be obtained.
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Comparison of general obesity and measures of body fat distribution in older adults in relation to cancer risk: meta-analysis of individual participant data of seven prospective cohorts in Europe.
Freisling, H, Arnold, M, Soerjomataram, I, O'Doherty, MG, Ordóñez-Mena, JM, Bamia, C, Kampman, E, Leitzmann, M, Romieu, I, Kee, F, et al
British journal of cancer. 2017;(11):1486-1497
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Abstract
BACKGROUND We evaluated the associations of anthropometric indicators of general obesity (body mass index, BMI), an established risk factor of various cancer, and body fat distribution (waist circumference, WC; hip circumference, HC; and waist-to-hip ratio, WHR), which may better reflect metabolic complications of obesity, with total obesity-related and site-specific (colorectal and postmenopausal breast) cancer incidence. METHODS This is a meta-analysis of seven prospective cohort studies participating in the CHANCES consortium including 18 668 men and 24 751 women with a mean age of 62 and 63 years, respectively. Harmonised individual participant data from all seven cohorts were analysed separately and alternatively for each anthropometric indicator using multivariable Cox proportional hazards models. RESULTS After a median follow-up period of 12 years, 1656 first-incident obesity-related cancers (defined as postmenopausal female breast, colorectum, lower oesophagus, cardia stomach, liver, gallbladder, pancreas, endometrium, ovary, and kidney) had occurred in men and women. In the meta-analysis of all studies, associations between indicators of adiposity, per s.d. increment, and risk for all obesity-related cancers combined yielded the following summary hazard ratios: 1.11 (95% CI 1.02-1.21) for BMI, 1.13 (95% CI 1.04-1.23) for WC, 1.09 (95% CI 0.98-1.21) for HC, and 1.15 (95% CI 1.00-1.32) for WHR. Increases in risk for colorectal cancer were 16%, 21%, 15%, and 20%, respectively per s.d. of BMI, WC, HC, and WHR. Effect modification by hormone therapy (HT) use was observed for postmenopausal breast cancer (Pinteraction<0.001), where never HT users showed an ∼20% increased risk per s.d. of BMI, WC, and HC compared to ever users. CONCLUSIONS BMI, WC, HC, and WHR show comparable positive associations with obesity-related cancers combined and with colorectal cancer in older adults. For postmenopausal breast cancer we report evidence for effect modification by HT use.
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Association of CRP genetic variants with blood concentrations of C-reactive protein and colorectal cancer risk.
Nimptsch, K, Aleksandrova, K, Boeing, H, Janke, J, Lee, YA, Jenab, M, Bueno-de-Mesquita, HB, Jansen, EH, Tsilidis, KK, Trichopoulou, A, et al
International journal of cancer. 2015;(5):1181-92
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Abstract
High blood concentrations of C-reactive protein (CRP) have been associated with elevated risk of colorectal cancer in several prospective studies including the European Prospective Investigation into Cancer and Nutrition (EPIC), but it is unknown whether these observations reflect a causal relationship. We aimed to investigate whether CRP genetic variants associated with lifelong higher CRP concentrations translate into higher colorectal cancer risk. We conducted a prospective nested case-control study within EPIC including 727 cases diagnosed between 1992 and 2003 and 727 matched controls selected according to an incidence-density sampling protocol. Baseline CRP concentrations were measured in plasma samples by a high sensitivity assay. Tagging single nucleotide polymorphisms (SNPs) in the CRP gene (rs1205, rs1800947, rs1130864, rs2808630, rs3093077) were identified via HapMap. The causal effect of CRP on colorectal cancer risk was examined in a Mendelian Randomization approach utilizing multiple CRP genetic variants as instrumental variables. The SNPs rs1205, rs1800947, rs1130864 and rs3093077 were significantly associated with CRP concentrations and were incorporated in a CRP allele score which was associated with 13% higher CRP concentrations per allele count (95% confidence interval 8-19%). Using the CRP-score as instrumental variable, genetically twofold higher CRP concentrations were associated with higher risk of colorectal cancer (odds ratio 1.74, 95% confidence interval 1.06-2.85). Similar observations were made using alternative definitions of instrumental variables. Our findings give support to the hypothesis that elevated circulating CRP may play a direct role in the etiology of colorectal cancer.
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Insulin-like growth factor I and risk of breast cancer by age and hormone receptor status-A prospective study within the EPIC cohort.
Kaaks, R, Johnson, T, Tikk, K, Sookthai, D, Tjønneland, A, Roswall, N, Overvad, K, Clavel-Chapelon, F, Boutron-Ruault, MC, Dossus, L, et al
International journal of cancer. 2014;(11):2683-90
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Abstract
Experimental evidence shows cross-talk in mammary cells between estrogen, insulin-like growth factor I (IGF-I) and their respective receptors and possible synergistic effects of estrogen receptor (ER) activation and increased IGF-I signaling with regard to breast tumor development, and epidemiological evidence suggests that circulating IGF-I levels may be related more to the risk of ER-positive than ER-negative breast cancer. Using a case-control study nested within the prospective European EPIC cohort (938 breast cancer cases and 1,394 matched control subjects), we analyzed the relationships of prediagnostic serum IGF-I levels with the risk of estrogen and progesterone receptor-positive and -negative breast tumors. IGF-I levels were positively associated with the risk of ER+ breast tumors overall (pre- and postmenopausal women combined, odds ratio (OR)Q4-Q1 = 1.41 [95% confidence interval (CI) 1.01-1.98] for the highest vs. lowest quartile; OR = 1.17 [95% CI 1.04-1.33] per 1-standard deviation (SD) increase in IGF-I, ptrend = 0.01) and among women who were diagnosed with breast cancer at 50 years or older (ORQ3-Q1 = 1.38 [95% CI 1.01-1.89]; OR = 1.19 [95% CI 1.04-1.36] per 1-SD increase in IGF-I, ptrend = 0.01) but not with receptor-positive disease diagnosed at an earlier age. No statistically significant associations were observed for ER- breast tumors overall and by age at diagnosis. Tests for heterogeneity by receptor status of the tumor were not statistically significant, except for women diagnosed with breast cancer at 50 years or older (phet = 0.03 for ER+/PR+ vs. ER-/PR- disease). Our data add to a global body of evidence indicating that higher circulating IGF-I levels may increase risk specifically of receptor-positive, but not receptor-negative, breast cancer diagnosed at 50 years or older.