Nerea Larrañaga

Lung cancer susceptibility locus at 5p15.33

We carried out a genome-wide association study of lung cancer (3,259 cases and 4,159 controls), followed by replication in 2,899 cases and 5,573 controls. Two uncorrelated disease markers at 5p15.33, rs402710 and rs2736100 were detected by the genome-wide data (P = 2 × 10−7 and P = 4 × 10−6) and replicated by the independent study series (P = 7 × 10−5 and P = 0.016). The susceptibility region contains two genes, TERT and CLPTM1L, suggesting that one or both may have a role in lung cancer etiology.

Fruit and vegetable intake and mortality from ischaemic heart disease: results from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heart study.

AIMS A higher intake of fruits and vegetables has been associated with a lower risk of ischaemic heart disease (IHD), but there is some uncertainty about the interpretation of this association. The objective was to assess the relation between fruit and vegetable intake and risk of mortality from IHD in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heart study. METHODS AND RESULTS After an average of 8.4 years of follow-up, there were 1636 deaths from IHD among 313 074 men and women without previous myocardial infarction or stroke from eight European countries. Participants consuming at least eight portions (80 g each) of fruits and vegetables a day had a 22% lower risk of fatal IHD [relative risk (RR) = 0.78, 95% confidence interval (CI): 0.65-0.95] compared with those consuming fewer than three portions a day. After calibration of fruit and vegetable intake to account for differences in dietary assessment between the participating centres, a one portion (80 g) increment in fruit and vegetable intake was associated with a 4% lower risk of fatal IHD (RR = 0.96, 95% CI: 0.92-1.00, P for trend = 0.033). CONCLUSION Results from this large observational study suggest that a higher intake of fruits and vegetables is associated with a reduced risk of IHD mortality. Whether this association is causal and, if so, the biological mechanism(s) by which fruits and vegetables operate to lower IHD risks remains unclear.

Adherence to the Mediterranean Diet and Risk of Coronary Heart Disease in the Spanish EPIC Cohort Study

No known cohort study has investigated whether the Mediterranean diet can reduce incident coronary heart disease (CHD) events in a Mediterranean population. This study examined the relation between Mediterranean diet adherence and risk of incident CHD events in the 5 Spanish centers of the European Prospective Investigation into Cancer and Nutrition. Analysis included 41,078 participants aged 29-69 years, recruited in 1992-1996 and followed up until December 2004 (mean follow-up:10.4 years). Confirmed incident fatal and nonfatal CHD events were analyzed according to Mediterranean diet adherence, measured by using an 18-unit relative Mediterranean diet score. A total of 609 participants (79% male) had a fatal or nonfatal confirmed acute myocardial infarction (n = 468) or unstable angina requiring revascularization (n = 141). After stratification by center and age and adjustment for recognized CHD risk factors, high compared with low relative Mediterranean diet score was associated with a significant reduction in CHD risk (hazard ratio = 0.60, 95% confidence interval: 0.47, 0.77). A 1-unit increase in relative Mediterranean diet score was associated with a 6% reduced risk of CHD (95% confidence interval: 0.91, 0.97), with similar risk reductions by sex. Mediterranean diet adherence was associated with a significantly reduced CHD risk in this Mediterranean country, supporting its role in primary prevention of CHD in healthy populations.

Evaluation of Human Papillomavirus Antibodies and Risk of Subsequent Head and Neck Cancer

PURPOSE Human papillomavirus type 16 (HPV16) infection is causing an increasing number of oropharyngeal cancers in the United States and Europe. The aim of our study was to investigate whether HPV antibodies are associated with head and neck cancer risk when measured in prediagnostic sera. METHODS We identified 638 participants with incident head and neck cancers (patients; 180 oral cancers, 135 oropharynx cancers, and 247 hypopharynx/larynx cancers) and 300 patients with esophageal cancers as well as 1,599 comparable controls from within the European Prospective Investigation Into Cancer and Nutrition cohort. Prediagnostic plasma samples from patients (collected, on average, 6 years before diagnosis) and control participants were analyzed for antibodies against multiple proteins of HPV16 as well as HPV6, HPV11, HPV18, HPV31, HPV33, HPV45, and HPV52. Odds ratios (ORs) of cancer and 95% CIs were calculated, adjusting for potential confounders. All-cause mortality was evaluated among patients using Cox proportional hazards regression. RESULTS HPV16 E6 seropositivity was present in prediagnostic samples for 34.8% of patients with oropharyngeal cancer and 0.6% of controls (OR, 274; 95% CI, 110 to 681) but was not associated with other cancer sites. The increased risk of oropharyngeal cancer among HPV16 E6 seropositive participants was independent of time between blood collection and diagnosis and was observed more than 10 years before diagnosis. The all-cause mortality ratio among patients with oropharyngeal cancer was 0.30 (95% CI, 0.13 to 0.67), for patients who were HPV16 E6 seropositive compared with seronegative. CONCLUSION HPV16 E6 seropositivity was present more than 10 years before diagnosis of oropharyngeal cancers.

Endogenous sex hormones and endometrial cancer risk in women in the European Prospective Investigation into Cancer and Nutrition (EPIC)

Epidemiological data show that reproductive and hormonal factors are involved in the etiology of endometrial cancer, but there is little data on the association with endogenous sex hormone levels. We analyzed the association between prediagnostic serum concentrations of sex steroids and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition using a nested case–control design of 247 incident endometrial cancer cases and 481 controls, matched on center, menopausal status, age, variables relating to blood collection, and, for premenopausal women, phase of menstrual cycle. Using conditional regression analysis, endometrial cancer risk among postmenopausal women was positively associated with increasing levels of total testosterone, free testosterone, estrone, total estradiol, and free estradiol. The odds ratios (ORs) for the highest versus lowest tertile were 2.66 (95% confidence interval (CI) 1.50–4.72; P=0.002 for a continuous linear trend) for estrone, 2.07 (95% CI 1.20–3.60; P=0.001) for estradiol, and 1.66 (95% CI 0.98–2.82; P=0.001) for free estradiol. For total and free testosterone, ORs for the highest versus lowest tertile were 1.44 (95% CI 0.88–2.36; P=0.05) and 2.05 (95% CI 1.23–3.42; P=0.005) respectively. Androstenedione and dehydroepiandrosterone sulfate were not associated with risk. Sex hormone-binding globulin was significantly inversely associated with risk (OR for the highest versus lowest tertile was 0.57, 95% CI 0.34–0.95; P=0.004). In premenopausal women, serum sex hormone concentrations were not clearly associated with endometrial cancer risk, but numbers were too small to draw firm conclusions. In conclusion, relatively high blood concentrations of estrogens and free testosterone are associated with an increased endometrial cancer risk in postmenopausal women.

Anthropometric factors and risk of endometrial cancer: the European prospective investigation into cancer and nutrition

ObjectiveTo examine the association between anthropometry and endometrial cancer, particularly by menopausal status and exogenous hormone use subgroups.MethodsAmong 223,008 women in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, there were 567 incident endometrial cancer cases during 6.4 years of follow-up. The analysis was performed with Cox proportional hazards modeling.ResultsWeight, body mass index (BMI), waist and hip circumferences and waist–hip ratio (WHR) were strongly associated with increased risk of endometrial cancer. The relative risk (RR) for obese (BMI 30– < 40 kg/m2) compared to normal weight (BMI < 25) women was 1.78, 95% CI = 1.41–2.26, and for morbidly obese women (BMI ≥ 40) was 3.02, 95% CI = 1.66–5.52. The RR for women with a waist circumference of ≥88 cm vs. <80 cm was 1.76, 95% CI = 1.42–2.19. Adult weight gain of ≥20 kg compared with stable weight (±3 kg) increased risk independent of body weight at age 20 (RR = 1.75, 95% CI = 1.11–2.77). These associations were generally stronger for postmenopausal than premenopausal women, and oral contraceptives never-users than ever-users, and much stronger among never-users of hormone replacement therapy compared to ever-users.ConclusionObesity, abdominal adiposity, and adult weight gain were strongly associated with endometrial cancer risk. These associations were particularly evident among never-users of hormone replacement therapy.

Animal foods, protein, calcium and prostate cancer risk: the European Prospective Investigation into Cancer and Nutrition

We examined consumption of animal foods, protein and calcium in relation to risk of prostate cancer among 142 251 men in the European Prospective Investigation into Cancer and Nutrition. Associations were examined using Cox regression, stratified by recruitment centre and adjusted for height, weight, education, marital status and energy intake. After an average of 8.7 years of follow-up, there were 2727 incident cases of prostate cancer, of which 1131 were known to be localised and 541 advanced-stage disease. A high intake of dairy protein was associated with an increased risk, with a hazard ratio for the top versus the bottom fifth of intake of 1.22 (95% confidence interval (CI): 1.07–1.41, Ptrend=0.02). After calibration to allow for measurement error, we estimated that a 35-g day−1 increase in consumption of dairy protein was associated with an increase in the risk of prostate cancer of 32% (95% CI: 1–72%, Ptrend=0.04). Calcium from dairy products was also positively associated with risk, but not calcium from other foods. The results support the hypothesis that a high intake of protein or calcium from dairy products may increase the risk for prostate cancer.

Estimation of Dietary Sources and Flavonoid Intake in a Spanish Adult Population (EPIC-Spain)

BACKGROUND Epidemiologic studies have suggested associations between flavonoid intake and health benefits. Traditional Mediterranean diets consist of a high consumption of plant products rich in flavonoids. OBJECTIVE This study estimates dietary flavonoid intake and main food sources in a Mediterranean population (Spanish adults). DESIGN The study included 40,683 subjects aged 35 to 64 years from northern and southern regions of Spain who were included in the European Prospective Investigation into Cancer and Nutrition study Spanish cohort. Usual food intake was assessed by personal interviews using a computerized version of a validated diet history method. Expanded US Department of Agriculture databases for the flavonoid, isoflavone, and proanthocyanidin content were used. RESULTS The median and mean of total flavonoids were 269.17 and 313.26 mg/day, respectively. The most abundant flavonoid subgroup was proanthocyanidins (60.1%), followed by flavanones (16.9%), flavan-3-ols (10.3%), flavonols (5.9%), anthocyanidins (5.8%), flavones (1.1%), and isoflavones (<0.01%). The main sources of total flavonoid intake were apples (23%), red wine (21%), unspecified fruit (12.8%), and oranges (9.3%). CONCLUSIONS These results should be very useful for evaluating the relationships between flavonoid intake and several diseases.

Anthropometric measures, endogenous sex steroids and breast cancer risk in postmenopausal women: A study within the EPIC cohort

In a large case–control study on breast cancer risk and serum hormone concentrations, nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, we examined to what extent the relationship of excess body weight with breast cancer risk may be explained by changes in sex steroids. Height, weight, waist and hip circumferences, and serum measurements of testosterone [T], androstenedione [Δ4], dehydroepiandrosterone sulphate [DHEAS], estradiol [E2], estrone [E1] and sex‐hormone binding globulin [SHBG] were available for 613 breast cancer cases, and 1,139 matched controls, who were all menopausal at the time of blood donation. Free T [fT] and free E2 [fE2] were calculated using mass action equations. Breast cancer risk was related to body mass index (BMI) (RR = 1.11 [0.99–1.25], per 5 kg/m2 increase in BMI), and waist (RR = 1.12 [1.02–1.24], per 10 cm increase) and hip circumferences (RR = 1.14 [1.02–1.27], per 10 cm increase). The increase in breast cancer risk associated with adiposity was substantially reduced after adjustment for any estrogens, especially for fE2 (from 1.11 [0.99–1.25] to 0.99 [0.87–1.12], from 1.12 [1.02–1.24] to 1.02 [0.92–1.14] and from 1.14 [1.02–1.27] to 1.05 [0.93–1.18] for BMI, waist and hip circumferences, respectively). A modest attenuation in excess risk was observed after adjustment for fT, but the remaining androgens had little effect on the association of body adiposity with breast cancer. Our data indicate that the relationship of adiposity with breast cancer in postmenopausal women could be partially explained by the increases in endogenous estrogens, and by a decrease in levels of SHBG.

CagA+ Helicobacter pylori infection and gastric cancer risk in the EPIC-EURGAST study

Helicobacter pylori (H. pylori), atrophic gastritis, dietary and life‐style factors have been associated with gastric cancer (GC). These factors have been evaluated in a large case–control study nested in the European Prospective Investigation into Cancer and Nutrition carried out in 9 countries, including the Mediterranean area. Participants, enrolled in 1992–1998, provided life‐style and dietary information and a blood sample (360,000; mean follow‐up: 6.1 years). For 233 GC cases diagnosed after enrolment and their 910 controls individually‐matched by center, gender, age and blood donation date H. pylori antibodies (antilysate and antiCagA) and plasma Pepsinogen A (PGA) were measured by ELISA methods. Severe chronic atrophic gastritis (SCAG) was defined as PGA circulating levels <22 μg/l. Overall, in a conditional logistic regression analysis adjusted for education, smoke, weight and consumption of total vegetables, fruit, red and preserved meat, H. pylori seropositivity was associated with GC risk. Subjects showing only antibodies anti‐H. pylori lysate, however, were not at increased risk, while those with antiCagA antibodies had a 3.4‐fold increased risk. Overall, the odds ratio associated with SCAG was 3.3 (95% CI 2.2–5.2). According to site, the risk of noncardia GC associated with CagA seropositivity showed a further increase (OR 6.5; 95% CI 3.3–12.6); on the other hand, a ten‐fold increased risk of cardia GC was associated with SCAG (OR 11.0; 95% CI 3.0–40.9). These results support the causal relationship between H. pylori CagA+ strains infection, and GC in these European populations even after taking into account dietary habits. This association was limited to distal GC, while serologically defined SCAG was strongly associated with cardia GC, thus suggesting a divergent risk pattern for these 2 sites.