Regina G. Ziegler

A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer

We conducted a genome-wide association study (GWAS) of breast cancer by genotyping 528,173 SNPs in 1,145 postmenopausal women of European ancestry with invasive breast cancer and 1,142 controls. We identified four SNPs in intron 2 of FGFR2 (which encodes a receptor tyrosine kinase and is amplified or overexpressed in some breast cancers) that were highly associated with breast cancer and confirmed this association in 1,776 affected individuals and 2,072 controls from three additional studies. Across the four studies, the association with all four SNPs was highly statistically significant (Ptrend for the most strongly associated SNP (rs1219648) = 1.1 × 10−10; population attributable risk = 16%). Four SNPs at other loci most strongly associated with breast cancer in the initial GWAS were not associated in the replication studies. Our summary results from the GWAS are available online in a form that should speed the identification of additional risk loci.

A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1).

We conducted a three-stage genome-wide association study (GWAS) of breast cancer in 9,770 cases and 10,799 controls in the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. In stage 1, we genotyped 528,173 SNPs in 1,145 cases of invasive breast cancer and 1,142 controls. In stage 2, we analyzed 24,909 top SNPs in 4,547 cases and 4,434 controls. In stage 3, we investigated 21 loci in 4,078 cases and 5,223 controls. Two new loci achieved genome-wide significance. A pericentromeric SNP on chromosome 1p11.2 (rs11249433; P = 6.74 × 10−10 adjusted genotype test, 2 degrees of freedom) resides in a large linkage disequilibrium block neighboring NOTCH2 and FCGR1B; this signal was stronger for estrogen-receptor–positive tumors. A second SNP on chromosome 14q24.1 (rs999737; P = 1.74 × 10−7) localizes to RAD51L1, a gene in the homologous recombination DNA repair pathway. We also confirmed associations with loci on chromosomes 2q35, 5p12, 5q11.2, 8q24, 10q26 and 16q12.1.

Nutrition and lung cancer

Epidemiologic evidence on the relationship between nutrition and lung cancer is reviewed. Observational studies of diet and lung cancer, both prospective and retrospective, continue to suggest strongly that increased vegetable and fruit intake is associated with reduced risk in men and women; in various countries; in smokers, ex-smokers, and never-smokers; and for all histologic types of lung cancer. Prospective studies of blood β-carotene levels, arguably the best available biomarker of vegetable and fruit intake, indicate that low levels are predictive of increased lung cancer incidence. However, in a randomized, placebo-controlled clinical trial in male smokers, lung cancer incidence and total mortality were increased significantly among the men receiving β-carotene supplements. If β-carotene can prevent lung carcinogenesis, which the trial cannot rule out, then the dosage, duration of use, method of administration, and/or subpopulation are critical. Ongoing clinical trials, some of which include women, will provide much-needed information. Other carotenoids, other phytochemicals, and associated dietary patterns may explain the beneficial effects of vegetables and fruits and have not been explored adequately in epidemiologic work. Several observational epidemiologic studies, both prospective and retrospective, have indicated that diets high in fat, saturated fat, and cholesterol may increase the risk of lung cancer and that the effect is not mediated through vegetable and fruit intake. The relationship, although not yet established, merits further investigation. Since β-carotene can function as an antioxidant, other micronutrients with this potential, specifically vitamins E and C and selenium, also have been proposed to reduce lung cancer risk. However, the totality of the epidemiologic evidence is not, at present, persuasive for any one of these micronutrients.

The Diesel Exhaust in Miners Study: A Nested Case–Control Study of Lung Cancer and Diesel Exhaust

Background Most studies of the association between diesel exhaust exposure and lung cancer suggest a modest, but consistent, increased risk. However, to our knowledge, no study to date has had quantitative data on historical diesel exposure coupled with adequate sample size to evaluate the exposure–response relationship between diesel exhaust and lung cancer. Our purpose was to evaluate the relationship between quantitative estimates of exposure to diesel exhaust and lung cancer mortality after adjustment for smoking and other potential confounders. Methods We conducted a nested case–control study in a cohort of 12 315 workers in eight non-metal mining facilities, which included 198 lung cancer deaths and 562 incidence density–sampled control subjects. For each case subject, we selected up to four control subjects, individually matched on mining facility, sex, race/ethnicity, and birth year (within 5 years), from all workers who were alive before the day the case subject died. We estimated diesel exhaust exposure, represented by respirable elemental carbon (REC), by job and year, for each subject, based on an extensive retrospective exposure assessment at each mining facility. We conducted both categorical and continuous regression analyses adjusted for cigarette smoking and other potential confounding variables (eg, history of employment in high-risk occupations for lung cancer and a history of respiratory disease) to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Analyses were both unlagged and lagged to exclude recent exposure such as that occurring in the 15 years directly before the date of death (case subjects)/reference date (control subjects). All statistical tests were two-sided. Results We observed statistically significant increasing trends in lung cancer risk with increasing cumulative REC and average REC intensity. Cumulative REC, lagged 15 years, yielded a statistically significant positive gradient in lung cancer risk overall (P trend = .001); among heavily exposed workers (ie, above the median of the top quartile [REC ≥ 1005 μg/m3-y]), risk was approximately three times greater (OR = 3.20, 95% CI = 1.33 to 7.69) than that among workers in the lowest quartile of exposure. Among never smokers, odd ratios were 1.0, 1.47 (95% CI = 0.29 to 7.50), and 7.30 (95% CI = 1.46 to 36.57) for workers with 15-year lagged cumulative REC tertiles of less than 8, 8 to less than 304, and 304 μg/m3-y or more, respectively. We also observed an interaction between smoking and 15-year lagged cumulative REC (P interaction = .086) such that the effect of each of these exposures was attenuated in the presence of high levels of the other. Conclusion Our findings provide further evidence that diesel exhaust exposure may cause lung cancer in humans and may represent a potential public health burden.

Cognitive research enhances accuracy of food frequency questionnaire reports: results of an experimental validation study

OBJECTIVE To test whether changing a food frequency questionnaire (FFQ) on the basis of cognitive theory and testing results in greater accuracy. Accuracy was examined for 4 design issues: a) Grouping: asking about foods in a single vs multiple separate questions; b) different forms of a food: asking consumption frequency of each form of a food (eg, skim, 2%, whole milk) vs a nesting approach--asking frequency of the main food (eg, milk) and proportion of times each form was consumed; c) additions (eg, sugar to coffee): asking independent of the main food vs nested under the main foods; d) units: asking frequency and portion size vs frequency of units (eg, cups of coffee). DESIGN Participants in two randomly assigned groups completed 30 consecutive daily food reports (DFRs), followed by 1 of 2 FFQs that asked about foods consumed in the past month. One was a new, cognitively-based National Cancer Institute (NCI) Diet History Questionnaire; the other was the 1992 NCI-Block Health Habits and History Questionnaire. SUBJECTS/SETTING 623 participants, age range 25 to 70 years, from metropolitan Washington, DC. Statistical analyses performed Accuracy was assessed by comparing DFR and FFQ responses using categorical (percent agreement) and continuous (rank order correlation, discrepancy scores) agreement statistics. RESULTS Grouping: accuracy was greater using separate questions. Different forms of food: accuracy was greater using nesting. Additions: neither approach was consistently superior; accuracy of the addition report was affected by accuracy of the main food report. Units: both approaches were similarly accurate. CONCLUSIONS Accuracy of FFQ reporting can be improved by restructuring questions based on cognitive theory and testing.

Alcohol Consumption and Breast Cancer in the Epidemiologic Follow-up Study of the First National Health and Nutrition Examination Survey

We investigated the relation between alcohol consumption and breast cancer in the Epidemiologic Follow-up Study of the first National Health and Nutrition Examination Survey, a cohort study based on sample of the U.S. population. A total of 7188 women 25 to 74 years of age who were examined during the period 1971 through 1975 were included in the analysis. Information about alcohol consumption was obtained during the base-line interview. The median follow-up period for this cohort was 10 years. One hundred twenty-one cases of breast cancer that developed after the baseline examination were identified through hospital records or death certificates. The relative-risk estimate for any amount of drinking relative to no drinking was 1.5 (95 percent confidence interval, 1.1 to 2.2). The estimates for three levels of consumption, from the lowest to the highest, were 1.4 (confidence interval, 0.9 to 2.3), 1.5 (0.9 to 2.6), and 1.6 (1.0 to 2.7), in comparison to no drinking at all. These relative-risk estimates were not materially affected by adjustment for known risk factors for breast cancer or for several dietary factors. The results of this study, consistent with those of two other cohort studies and a number of case-control studies, suggest that moderate alcohol consumption is associated with an elevation in the risk of breast cancer of 50 to 100 percent.

The landscape of recombination in African Americans

Recombination, together with mutation, gives rise to genetic variation in populations. Here we leverage the recent mixture of people of African and European ancestry in the Americas to build a genetic map measuring the probability of crossing over at each position in the genome, based on about 2.1 million crossovers in 30,000 unrelated African Americans. At intervals of more than three megabases it is nearly identical to a map built in Europeans. At finer scales it differs significantly, and we identify about 2,500 recombination hotspots that are active in people of West African ancestry but nearly inactive in Europeans. The probability of a crossover at these hotspots is almost fully controlled by the alleles an individual carries at PRDM9 (P value < 10−245). We identify a 17-base-pair DNA sequence motif that is enriched in these hotspots, and is an excellent match to the predicted binding target of PRDM9 alleles common in West Africans and rare in Europeans. Sites of this motif are predicted to be risk loci for disease-causing genomic rearrangements in individuals carrying these alleles. More generally, this map provides a resource for research in human genetic variation and evolution.

Etiologic and early marker studies in the prostate, lung, colorectal and ovarian (PLCO) cancer screening trial.

The Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, which is randomizing 74,000 screening arm participants (37,000 men, 37,000 women; ages 55-74) and an equal number of nonscreened controls, is a unique setting for the investigation of the etiology of cancer and other diseases and for the evaluation of potential molecular markers of early disease. At entry, baseline information is collected by questionnaire on dietary intake, tobacco and alcohol use, reproductive history (for women), family history of cancer, use of selected drugs, and other selected risk factors. Blood samples collected at the baseline screening exam are aliquoted to serum, plasma, red blood cell, and buffy coat fractions. At the next two annual screening visits, serum samples are collected. At the third annual reexamination, cryopreserved whole blood is obtained, in addition to serum, plasma, red blood cell, and buffy coat fractions. At the fourth and fifth years, serum, plasma, and buffy coat are collected. All blood samples are shipped to a central repository for long-term storage at -70 degrees C. Dietary questionnaires and buccal cells for DNA analysis are obtained from nonscreened controls. Cancer cases are identified through annual follow-up questionnaires, and all deaths are identified through vital status tracing mechanisms. Procedures are being developed to obtain archival pathologic material for selected cases of cancer and related diseases. Initial investigations are focusing on the etiology of colorectal cancer and on the operative characteristics of tests for the early detection of colorectal and prostate cancer.

Low vitamin D status is associated with physical inactivity, obesity and low vitamin D intake in a large US sample of healthy middle-aged men and women

The aim of this study was to investigate modifiable predictors of vitamin D status in healthy individuals, aged 55-74, and living across the USA. Vitamin D status [serum 25-hydroxyvitamin D (25(OH)D)] was measured along with age and season at blood collection, demographics, anthropometry, physical activity (PA), diet, and other lifestyle factors in 1357 male and 1264 female controls selected from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) cohort. Multivariate linear and logistic regression analyses were used to identify associations with vitamin D status. Three%, 29% and 79% of the population had serum 25(OH)D levels<25, <50 and <80 nmol/L, respectively. The major modifiable predictors of low vitamin D status were low vitamin D dietary and supplement intake, body mass index (BMI) >30 kg/m2, physical inactivity (PA) and low milk and calcium supplement intake. In men, 25(OH)D was determined more by milk intake on cereal and in women, by vitamin D and calcium supplement and menopausal hormone therapy (MHT) use. Thus targeting an increase in vigorous activity and vitamin D and calcium intake and decreasing obesity could be public health interventions independent of sun exposure to improve vitamin D status in middle-aged Americans.

Childhood Soy Intake and Breast Cancer Risk in Asian American Women

Introduction: Historically, breast cancer incidence has been substantially higher in the United States than in Asia. When Asian women migrate to the United States, their breast cancer risk increases over several generations and approaches that for U.S. Whites. Thus, modifiable factors, such as diet, may be responsible. Methods: In this population-based case-control study of breast cancer among women of Chinese, Japanese, and Filipino descent, ages 20 to 55 years, and living in San Francisco-Oakland (California), Los Angeles (California) and Oahu (Hawaii), we interviewed 597 cases (70% of those eligible) and 966 controls (75%) about adolescent and adult diet and cultural practices. For subjects with mothers living in the United States (39% of participants), we interviewed mothers of 99 cases (43% of eligible) and 156 controls (40%) about the daughters childhood exposures. Seventy-three percent of study participants were premenopausal at diagnosis. Results: Comparing highest with lowest tertiles, the multivariate relative risks (95% confidence interval) for childhood, adolescent, and adult soy intake were 0.40 (0.18-0.83; Ptrend = 0.03), 0.80 (0.59-1.08; Ptrend = 0.12), and 0.76 (0.56-1.02; Ptrend = 0.04), respectively. Inverse associations with childhood intake were noted in all three races, all three study sites, and women born in Asia and the United States. Adjustment for measures of westernization attenuated the associations with adolescent and adult soy intake but did not affect the inverse relationship with childhood soy intake. Discussion: Soy intake during childhood, adolescence, and adult life was associated with decreased breast cancer risk, with the strongest, most consistent effect for childhood intake. Soy may be a hormonally related, early-life exposure that influences breast cancer incidence. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1050–9)