Supplementary Methods from CYP19A1 Genetic Variation in Relation to Prostate Cancer Risk and Circulating Sex Hormone Concentrations in Men from the Breast and Prostate Cancer Cohort Consortium

Supplementary Tables 1S-7S, Figure 1S from Haplotype Analysis of the HSD17B1 Gene and Risk of Breast Cancer: A Comprehensive Approach to Multicenter Analyses of Prospective Cohort Studies

Supplementary Methods and Tables 1-4 from Genetic Variation at the CYP19A1 Locus Predicts Circulating Estrogen Levels but not Breast Cancer Risk in Postmenopausal Women

Supplementary Table 1 from CYP19A1 Genetic Variation in Relation to Prostate Cancer Risk and Circulating Sex Hormone Concentrations in Men from the Breast and Prostate Cancer Cohort Consortium

Spina bifida is a birth defect that affects the spines of developing fetuses and infants, and research in the 20th century indicated that chemicals in the herbicide Agent Orange likely led to the birth defect. People with spina bifida [6] can have nerve damage, paralysis, and mental disabilities. During the Vietnam War in the 1960s, the US military employed Agent Orange and other herbicides to destroy enemy crops and forest cover until 1970. Though studies of the link between Agent Orange exposure and birth defects [7] were at first inconclusive, in 1995 the US National Academy of Sciences [8] concluded that one birth defect, spina bifida [6], was associated with paternal Agent Orange exposure. Spina bifida was, by the twenty-first century, the only birth defect that the US Veterans Administration connected to Agent Orange exposure.

Nowadays the ubiquity of telecommunication networks, which underpin and fulfill key aspects of modern day living, is taken for granted. Significant large-scale failures have occurred in the last years affecting telecommunication networks. Traditionally, network robustness analysis has been focused on topological characteristics. Recently approaches also consider the services supported by such networks. In this paper we carry out a robustness analysis of five real backbone telecommunication networks under defined multiple failure scenarios, taking into account the consequences of the loss of established connections. Results show which networks are more robust in response to a specific type of failure.

David J. Hunter1,2,3,6, Peter Kraft2, Kevin B. Jacobs4, David G. Cox1,2, Meredith Yeager5,6, Susan E. Hankinson1, Sholom Wacholder6, Zhaoming Wang5,6, Robert Welch5,6, Amy Hutchinson5,6, Kai Yu6, Nilanjan Chatterjee6, Nick Orr7, Walter C. Willett1,8, Graham A. Colditz9, Regina G. Ziegler6, Christine D. Berg10, Saundra S. Buys11, Catherine A. McCarty12, Heather Spencer Feigelson13, Eugenia E. Calle13, Michael J. Thun13, Richard B. Hayes6, Margaret Tucker6, Daniela S. Gerhard14, Joseph F. Fraumeni Jr.6, Robert N. Hoover6, Gilles Thomas6, and Stephen J Chanock6,7 1Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, 02115 2Program in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 3Broad Institute of Harvard and MIT 4Bioinformed Consulting Services, Gaithersburg, MD 5SAIC-Frederick, NCI-FCRDC, Frederick, MD 6Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services 7Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, DHHS 8Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 9Washington University School of Medicine, St. Louis, MO 10Division of Cancer Prevention, NCI, NIH, DHHS 11Department of Internal Medicine, University of Utah, Salt Lake City, UT 12The Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI 13Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, GA 30329 14Office of Cancer Genomics, NCI, NIH, DHHS

Epidemiologic studies of pancreatic cancer risk have reported null or nonsignificant positive associations for obesity, while associations for height have been null. Waist and hip circumference have been evaluated infrequently. A pooled analysis of 14 cohort studies on 846,340 individuals was conducted; 2,135 individuals were diagnosed with pancreatic cancer during follow-up. Study-specific relative risks (RRs) and 95% confidence intervals (CIs) were calculated by Cox proportional hazards models, and then pooled using a random effects model. Compared to individuals with a body mass index (BMI) at baseline between 21-22.9 kg/m(2) , pancreatic cancer risk was 47% higher (95%CI:23-75%) among obese (BMI ≥ 30 kg/m(2) ) individuals. A positive association was observed for BMI in early adulthood (pooled multivariate [MV]RR = 1.30, 95%CI = 1.09-1.56 comparing BMI ≥ 25 kg/m(2) to a BMI between 21 and 22.9 kg/m(2) ). Compared to individuals who were not overweight in early adulthood (BMI < 25 kg/m(2) ) and not obese at baseline (BMI < 30 kg/m(2) ), pancreatic cancer risk was 54% higher (95%CI = 24-93%) for those who were overweight in early adulthood and obese at baseline. We observed a 40% higher risk among individuals who had gained BMI ≥ 10 kg/m(2) between BMI at baseline and younger ages compared to individuals whose BMI remained stable. Results were either similar or slightly stronger among never smokers. A positive association was observed between waist to hip ratio (WHR) and pancreatic cancer risk (pooled MVRR = 1.35 comparing the highest versus lowest quartile, 95%CI = 1.03-1.78). BMI and WHR were positively associated with pancreatic cancer risk. Maintaining normal body weight may offer a feasible approach to reducing morbidity and mortality from pancreatic cancer.

There is extensive evidence that increases in blood and tissue concentrations of steroid hormones and of insulin-like growth factor I (IGF-I) are associated with breast cancer risk. However, studies of common variation in genes involved in steroid hormone and IGF-I metabolism have yet to provide convincing evidence that such variants predict breast cancer risk. The Breast and Prostate Cancer Cohort Consortium (BPC3) is a collaboration of large US and European cohorts. We genotyped 1416 tagging single nucleotide polymorphisms (SNPs) in 37 steroid hormone metabolism genes and 24 IGF-I pathway genes in 6292 cases of breast cancer and 8135 controls, mostly Caucasian, postmenopausal women from the BPC3. We also imputed 3921 additional SNPs in the regions of interest. None of the SNPs tested was significantly associated with breast cancer risk, after correction for multiple comparisons. The results remained null when cases and controls were stratified by age at diagnosis/recruitment, advanced or nonadvanced disease, body mass index, with or without in situ cases; or restricted to Caucasians. Among 770 estrogen receptor-negative cases, an SNP located 3' of growth hormone receptor (GHR) was marginally associated with increased risk after correction for multiple testing (P(trend) = 1.5 × 10(-4)). We found no significant overall associations between breast cancer and common germline variation in 61 genes involved in steroid hormone and IGF-I metabolism in this large, comprehensive study. Although previous studies have shown that variations in these genes can influence endogenous hormone levels, the magnitude of the effect of single SNPs does not appear to be sufficient to alter breast cancer risk.

The insulin-like growth factor (IGF) pathway has been implicated in prostate development and carcinogenesis. We conducted a comprehensive analysis, utilizing a resequencing and tagging single-nucleotide polymorphism (SNP) approach, between common genetic variation in the IGF1, IGF binding protein (BP) 1, and IGFBP3 genes with IGF-I and IGFBP-3 blood levels, and prostate cancer (PCa) risk, among Caucasians in the NCI Breast and Prostate Cancer Cohort Consortium. We genotyped 14 IGF1 SNPs and 16 IGFBP1/IGFBP3 SNPs to capture common [minor allele frequency (MAF) >or= 5%] variation among Caucasians. For each SNP, we assessed the geometric mean difference in IGF blood levels (N = 5684) across genotypes and the association with PCa risk (6012 PCa cases/6641 controls). We present two-sided statistical tests and correct for multiple comparisons. A non-synonymous IGFBP3 SNP in exon 1, rs2854746 (Gly32Ala), was associated with IGFBP-3 blood levels (P(adj) = 8.8 x 10(-43)) after adjusting for the previously established IGFBP3 promoter polymorphism A-202C (rs2854744); IGFBP-3 blood levels were 6.3% higher for each minor allele. For IGF1 SNP rs4764695, the risk estimates among heterozygotes was 1.01 (99% CI: 0.90-1.14) and 1.20 (99% CI: 1.06-1.37) for variant homozygotes with overall PCa risk. The corrected allelic P-value was 8.7 x 10(-3). IGF-I levels were significantly associated with PCa risk (P(trend) = 0.02) with a 21% increase of PCa risk when compared with the highest quartile to the lowest quartile. We have identified SNPs significantly associated with IGFBP-3 blood levels, but none of these alter PCa risk; however, a novel IGF1 SNP, not associated with IGF-I blood levels, shows preliminary evidence for association with PCa risk among Caucasians.

The insulin-like growth factor (IGF) pathway has been implicated in prostate development and carcinogenesis. We conducted a comprehensive analysis, utilizing a resequencing and tagging single-nucleotide polymorphism (SNP) approach, between common genetic variation in the IGF1 , IGF binding protein ( BP ) 1, and IGFBP3 genes with IGF-I and IGFBP-3 blood levels, and prostate cancer (PCa) risk, among Caucasians in the NCI Breast and Prostate Cancer Cohort Consortium. We genotyped 14 IGF1 SNPs and 16 IGFBP1 / IGFBP3 SNPs to capture common [minor allele frequency (MAF) ≥ 5%] variation among Caucasians. For each SNP, we assessed the geometric mean difference in IGF blood levels ( N = 5684) across genotypes and the association with PCa risk (6012 PCa cases …

Heather S Feigelson, PhD, MPH, Lauren R Teras, MS, W Ryan Diver, MS, Weining Tang, PhD, Alpa V Patel, PhD, Eugenia E Calle, PhD and Mark Bouzyk, PhD Heather S Feigelson, PhD, MPH, Kaiser Permanente Colorado; Lauren R Teras, MS, American Cancer Society; W Ryan Diver, MS, American Cancer Society; Weining Tang, PhD, Emory University; Alpa V Patel, PhD, American Cancer Society; Eugenia E Calle, PhD, American Cancer Society; Mark Bouzyk, PhD, Emory University

A family history of pancreatic cancer is associated with increased risk of pancreatic cancer, but uncertainty remains about the magnitude of this association, whether it varies by age or smoking and whether a family history of other cancers may also be associated with increased risk. We examined family history of 14 cancers and pancreatic cancer mortality among ~1.1 million men and women in Cancer Prevention Study-II (CPS-II). CPS-II participants completed a questionnaire at enrollment in 1982. During follow-up through 2006, there were 7,306 pancreatic cancer deaths. A family history of pancreatic cancer in a parent or sibling was associated with pancreatic cancer mortality [multivariable adjusted rate ratio (RR) = 1.66, 95% confidence interval (CI) 1.43–1.94]. This association was stronger among participants aged under 60 (RR = 2.89, 95% CI 1.67–5.02) than among participants aged 60 or older (RR = 1.61, 95% CI 1.37–1.88). Weaker associations were observed for family history of stomach cancer (RR = 1.23, 95% CI 1.11–1.37), liver cancer (RR = 1.25, 95% CI 1.10–1.43), and colorectal cancer (RR = 1.12, 95% CI 1.01–1.23). Results from this large prospective study indicate family history of pancreatic cancer is associated with a moderate increase in risk of pancreatic cancer, and also identify associations with the family history of certain other cancers which may be useful in generating hypotheses about shared risk factors.

Between 2001 and 2005, Blacks from the United States experienced a 32% higher pancreatic cancer death rate than Whites. Smoking, diabetes, and family history might explain some of this disparity, but prospective analyses are warranted. From 1984 to 2004, there were 6,243 pancreatic cancer deaths among Blacks (n = 48,525) and Whites (n = 1,011,864) in the Cancer Prevention Study II cohort. Multivariate Cox proportional hazards models yielded hazards ratios (HR) for known and suspected risk factors. Population attributable risks were computed and their effect on age-standardized mortality rates were evaluated. Blacks in this cohort had a 42% increased risk of pancreatic cancer mortality compared with Whites (HR, 1.42; 95% confidence intervals (CI), 1.28-1.58). Current smoking increased risk by >60% in both races; although Blacks smoked less intensely, risks were similar to Whites (HR(Black), 1.67; 95% CI, 1.28-2.18; HR(White), 1.82; 95% CI, 1.7-1.95). Obesity was significantly associated with pancreatic cancer mortality in Black men (HR, 1.66; 95% CI, 1.05-2.63), White men (HR, 1.42; 95% CI, 1.25-1.60), and White women (HR, 1.37; 95% CI, 1.22-1.54); results were null in Black women. The population attributable risk due to smoking, family history, diabetes, cholecystectomy, and overweight/obesity was 24.3% in Whites and 21.8% in Blacks. Smoking and overweight/obesity play a substantial a role in pancreatic cancer. Variation in the effect of these factors underscores the need to evaluate disease on the race-sex level. The inability to attribute excess disease in Blacks to currently known risk factors, even when combined with suspected risks, points to yet undetermined factors that play a role in the disease process.

Background: Although many studies have linked elevations in tropospheric ozone to adverse health outcomes, the effect of long-term exposure to ozone on air pollution-related mortality remains uncertain. We examined the potential contribution of exposure to ozone to the risk of death from cardiopulmonary causes and specifically to death from respiratory causes.Methods: Data from the study cohort of the American Cancer Society Cancer Prevention Study II were correlated with air-pollution data from 96 metropolitan statistical areas in the United States. Data were analyzed from 448,850 subjects, with 118,777 deaths in an 18-year follow-up period. Data on daily maximum ozone concentrations were obtained from April 1 to September 30 for the years 1977 through 2000. Data on concentrations of fine particulate matter (particles that are lessthan/equal 2.5 microm in aerodynamic diameter [PM(sub 2.5)]) were obtained for the years 1999 and 2000. Associations between ozone concentrations and the risk of death were evaluated with the use of standard and multilevel Cox regression models.Results: In single-pollutant models, increased concentrations of either PM(sub 2.5) or ozone were significantly associated with an increased risk of death from cardiopulmonary causes. In two-pollutant models, PM(sub 2.5) was associated with the risk of death from cardiovascular causes, whereas ozone was associated with the risk of death from respiratory causes. The estimated relative risk of death from respiratory causes that was associated with an increment in ozone concentration of 10 ppb was 1.040 (95% confidence interval, 1.010 to 1.067). The association of ozone with the risk of death from respiratory causes was insensitive to adjustment for confounders and to the type of statistical model used.Conclusions: In this large study, we were not able to detect an effect of ozone on the risk of death from cardiovascular causes when the concentration of PM(sub 2.5) was taken into account. We did, however, demonstrate a significant increase in the risk of death from respiratory causes in association with an increase in ozone concentration.N Engl J Med 2009;360:1085-95.

BACKGROUND:Vitamin D is hypothesized to lower the risk of breast cancer by inhibiting cell proliferation via the nuclear vitamin D receptor (VDR). Two common single nucleotide polymorphisms (SNP) in the VDR gene (VDR), rs1544410 (BsmI), and rs2228570 (FokI), have been inconsistently associated with breast cancer risk. Increased risk has been reported for the FokI ff genotype, which encodes a less transcriptionally active isoform of VDR, and reduced risk has been reported for the BsmI BB genotype, a SNP in strong linkage disequilibrium with a 3'-untranslated region, which may influence VDR mRNA stability. METHODS:We pooled data from 6 prospective studies in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium to examine associations between these SNPs and breast cancer among >6,300 cases and 8,100 controls for each SNP using conditional logistic regression. RESULTS:The odds ratio (OR) for the rs2228570 (FokI) ff versus FF genotype in the overall population was statistically significantly elevated [OR, 1.16; 95% confidence interval (95% CI), 1.04-1.28] but was weaker once data from the cohort with previously published positive findings were removed (OR, 1.10; 95% CI, 0.98-1.24). No association was noted between rs1544410 (BsmI) BB and breast cancer risk overall (OR, 0.98; 95% CI, 0.89-1.09), but the BB genotype was associated with a significantly lower risk of advanced breast cancer (OR, 0.74; 95% CI, 0.60-0.92). CONCLUSIONS:Although the evidence for independent contributions of these variants to breast cancer susceptibility remains equivocal, future large studies should integrate genetic variation in VDR with biomarkers of vitamin D status.