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1.  Lung Cancer, Cardiopulmonary Mortality, and Long-term Exposure to Fine Particulate Air Pollution 
Context
Associations have been found between day-to-day particulate air pollution and increased risk of various adverse health outcomes, including cardiopulmonary mortality. However, studies of health effects of long-term particulate air pollution have been less conclusive.
Objective
To assess the relationship between long-term exposure to fine particulate air pollution and all-cause, lung cancer, and cardiopulmonary mortality.
Design, Setting, and Participants
Vital status and cause of death data were collected by the American Cancer Society as part of the Cancer Prevention II study, an ongoing prospective mortality study, which enrolled approximately 1.2 million adults in 1982. Participants completed a questionnaire detailing individual risk factor data (age, sex, race, weight, height, smoking history, education, marital status, diet, alcohol consumption, and occupational exposures). The risk factor data for approximately 500000 adults were linked with air pollution data for metropolitan areas throughout the United States and combined with vital status and cause of death data through December 31, 1998.
Main Outcome Measure
All-cause, lung cancer, and cardiopulmonary mortality.
Results
Fine particulate and sulfur oxide–related pollution were associated with all-cause, lung cancer, and cardiopulmonary mortality. Each 10-μg/m3 elevation in fine particulate air pollution was associated with approximately a 4%, 6%, and 8% increased risk of all-cause, cardiopulmonary, and lung cancer mortality, respectively. Measures of coarse particle fraction and total suspended particles were not consistently associated with mortality.
Conclusion
Long-term exposure to combustion-related fine particulate air pollution is an important environmental risk factor for cardiopulmonary and lung cancer mortality.
PMCID: PMC4037163  PMID: 11879110
2.  Are Racial Disparities in Pancreatic Cancer Explained by Smoking and Overweight/Obesity? 
Between 2001–2005, U.S. Blacks experienced a 32% higher pancreatic cancer death rate than Whites. Smoking, diabetes, and family history may explain some of this disparity, but prospective analyses are warranted. From 1984–2004, there were 6,243 pancreatic cancer deaths among Blacks (n=48,252) and Whites (n=1,011,864) in the Cancer Prevention Study II cohort. Multivariate Cox proportional hazards models yielded hazards ratios for known and suspected risk factors. Population attributable risks were computed and their impact on age-standardized mortality rates evaluated. Blacks in this cohort had a 42% increased risk of pancreatic cancer mortality compared to Whites (HR=1.42; 95% CI 1.28 to 1.58). Current smoking increased risk by >60% in both races; although Blacks smoked less intensely, risks were similar to Whites (HRBlack=1.67, 95% CI 1.28 to 2.18; HRWhite=1.82, 95%CI 1.7 to 1.95). Obesity was significantly associated with pancreatic cancer mortality in Black men (HR=1.66, 95% CI 1.05 to 2.63), White men (HR=1.42; 95% CI 1.25 to 1.60) and White women (HR=1.37; 95% CI 1.22 to 1.54); results were null in Black women. The PAR 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 impact 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.
doi:10.1158/1055-9965.EPI-09-0080
PMCID: PMC3630792  PMID: 19723915
3.  A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer 
Nature genetics  2007;39(7):870-874.
We conducted a genome-wide association study (GWAS) of breast cancer by genotyping 528,173 single nucleotide polymorphisms (SNPs) in 1,145 cases of invasive breast cancer among postmenopausal white women, and 1,142 controls. We identified a set of four SNPs in intron 2 of FGFR2, a tyrosine kinase receptor previously shown to be amplified and/or over-expressed in some breast cancers, as highly associated with breast cancer and we confirmed this association in 1,776 cases and 2,072 controls from three additional studies. In both association testing and ancestral recombination graph analysis, FGFR2 haplotypes were associated with risk of breast cancer. 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 chromosomal loci most strongly associated with breast cancer in the initial GWAS were not associated with risk in the three replication studies. Our summary results from the GWAS are freely available online in a form that should speed the identification of additional loci conferring risk.
doi:10.1038/ng2075
PMCID: PMC3493132  PMID: 17529973
4.  A POOLED ANALYSIS OF 14 COHORT STUDIES OF ANTHROPOMETRIC FACTORS AND PANCREATIC CANCER RISK 
Epidemiologic studies of pancreatic cancer risk have reported null or non-significant 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 21–22.9kg/m2, pancreatic cancer risk was 47% higher (95%CI:23–75%) among obese (BMI≥30kg/m2) 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≥25kg/m2 to a BMI between 21–22.9kg/m2). Compared to individuals who were not overweight in early adulthood (BMI<25kg/m2) and not obese at baseline (BMI<30kg/m2), 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 ≥10kg/m2 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.
doi:10.1002/ijc.25794
PMCID: PMC3073156  PMID: 21105029
Pancreatic Cancer; Anthropometry; Pooled Analysis
5.  Comprehensive analysis of common genetic variation in 61 genes related to steroid hormone and insulin-like growth factor-I metabolism and breast cancer risk in the NCI breast and prostate cancer cohort consortium† 
Human Molecular Genetics  2010;19(19):3873-3884.
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 (Ptrend = 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.
doi:10.1093/hmg/ddq291
PMCID: PMC2935856  PMID: 20634197
6.  A comprehensive analysis of common IGF1, IGFBP1 and IGFBP3 genetic variation with prospective IGF-I and IGFBP-3 blood levels and prostate cancer risk among Caucasians† 
Human Molecular Genetics  2010;19(15):3089-3101.
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/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 (Padj = 8.8 × 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 × 10−3. IGF-I levels were significantly associated with PCa risk (Ptrend = 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.
doi:10.1093/hmg/ddq210
PMCID: PMC2901143  PMID: 20484221
7.  Obesity and cancer 
BMJ : British Medical Journal  2007;335(7630):1107-1108.
Substantial evidence supports the link between increasing adiposity and a higher risk of many cancers
doi:10.1136/bmj.39384.472072.80
PMCID: PMC2099565  PMID: 17986715
8.  CYP19A1 genetic variation in relation to prostate cancer risk and circulating sex hormone concentrations in men from the Breast and Prostate Cancer Cohort Consortium 
Sex hormones, in particular the androgens, are important for the growth of the prostate gland and have been implicated in prostate cancer carcinogenesis, yet the determinants of endogenous steroid hormone levels remain poorly understood. Twin studies suggest a heritable component for circulating concentrations of sex hormones, although epidemiological evidence linking steroid hormone gene variants to prostate cancer is limited. Here we report on findings from a comprehensive study of genetic variation at the CYP19A1 locus in relation to prostate cancer risk and to circulating steroid hormone concentrations in men by the Breast and Prostate Cancer Cohort Consortium (BPC3), a large collaborative prospective study. The BPC3 systematically characterised variation in CYP19A1 by targeted resequencing and dense genotyping; selected haplotype-tagging single nucleotide polymorphisms (htSNPs) that efficiently predict common variants in U.S. and European whites, Latinos, Japanese Americans, and Native Hawaiians; and genotyped these htSNPs in 8,166 prostate cancer cases and 9,079 study-, age-, and ethnicity-matched controls. CYP19A1 htSNPs, two common missense variants and common haplotypes were not significantly associated with risk of prostate cancer. However, several htSNPs in linkage disequilibrium blocks 3 and 4 were significantly associated with a 5–10% difference in estradiol concentrations in men (association per copy of the two-SNP haplotype rs749292–rs727479 (A–A) versus noncarriers; P=1 × 10−5), and withinverse, although less marked changes, in free testosterone concentrations. These results suggest that although germline variation in CYP19A1 characterised by the htSNPs produces measurable differences in sex hormone concentrations in men, they do not substantially influence risk for prostate cancer.
doi:10.1158/1055-9965.EPI-09-0496
PMCID: PMC2812905  PMID: 19789370
prostate; cancer; CYP19A1; estradiol; testosterone
9.  A multi-stage genome-wide association in breast cancer identifies two novel risk alleles at 1p11.2 and 14q24.1 (RAD51L1) 
Nature genetics  2009;41(5):579-584.
The Cancer Genetic Markers of Susceptibility (CGEMS) initiative has conducted a three-stage genome-wide association study (GWAS) of breast cancer in 9,770 cases and 10,799 controls. In Stage 1, we genotyped 528,173 single nucleotide polymorphisms (SNPs) in 1,145 cases of invasive breast cancer among postmenopausal white women, and 1,142 controls; in Stage 2, 24,909 SNPs with low p values observed in Stage 1 were analyzed in 4,547 cases and 4,434 controls. In Stage 3 we investigated 21 loci in 4,078 cases and 5,223 controls with low p values from Stage 1 and 2 combined. Two novel loci achieved genome-wide significance. A pericentromeric SNP on chromosome 1p11.2, rs11249433, (p=6.74 × 10-10 adjusted genotype test with 2 degrees of freedom) resides in a large block of linkage disequilibrium neighboring NOTCH2 and FCGR1B and is predominantly associated with estrogen receptor-positive breast cancer. A second SNP, rs999737 on chromosome 14q24.1 (p=1.74 × 10−7), localizes to RAD51L1, a gene in the homologous recombination DNA repair pathway, a prior candidate pathway for breast cancer susceptibility. We confirmed previously reported markers on chromosome 2q35, 5q11.2, 5p12, 8q24, 10q26, and 16q12.1. Our results underscore the importance of large-scale replication in the identification of low penetrance breast cancer alleles.
doi:10.1038/ng.353
PMCID: PMC2928646  PMID: 19330030
10.  SnoRNA U50 is a candidate tumor suppressor gene at 6q14.3 with a mutation associated with clinically significant prostate cancer 
Human molecular genetics  2008;17(7):1031-1042.
Deletion of chromosome 6q14-q22 is common in multiple human cancers including prostate cancer, and chromosome 6 transferred into cancer cells induces senescence and reduces cell growth, tumorigenicity and metastasis, indicating the existence of one or more tumor suppressor genes in 6q. To identify the 6q tumor suppressor gene, we first narrowed the common region of deletion to a 2.5-Mb interval at 6q14-15. Of the 11 genes located in this minimal deletion region and expressed in normal prostates, only snoRNA U50 was mutated, demonstrated transcriptional downregulation, and inhibited colony formation in prostate cancer cells. The mutation, a homozygous 2-bp (TT) deletion, was found in 2 of 30 prostate cancer cell lines/xenografts and 9 of 89 localized prostate cancers (11 of 119 or 9% cancers). Two of 89 (2%) patients with prostate cancer also showed the same mutation in their germline DNA, but none of 104 cancer-free control men did. The homozygous deletion abolished U50 function in a colony formation assay. Analysis of 1371 prostate cancer cases and 1371 matched control men from a case-control study nested in a prospective cohort showed that, although a germline heterozygous genotype of the deletion was detected in both patients and controls at similar frequencies, the homozygosity of the deletion was significantly associated with clinically significant prostate cancer (odds ratio = 2.9, 95% confidence interval = 1.17 – 7.21). These findings establish snoRNA U50 as a reasonable candidate for the 6q tumor suppressor gene in prostate cancer and likely in other types of cancers.
doi:10.1093/hmg/ddm375
PMCID: PMC2923223  PMID: 18202102
11.  Cancer Incidence and Mortality After Gastric Bypass Surgery 
Obesity (Silver Spring, Md.)  2009;17(4):796-802.
Despite weight loss recommendations to prevent cancer, cancer outcome studies after intentional weight loss are limited. Recently, reduced cancer mortality following bariatric surgery has been reported. This study tested whether reduced cancer mortality following gastric bypass was due to decreased incidence. Cancer incidence and mortality data through 2007 from the Utah Cancer Registry (UCR) were compared between 6,596 Utah patients who had gastric bypass (1984–2002) and 9,442 severely obese persons who had applied for Utah Driver’s Licenses (1984–2002). Study outcomes included incidence, case-fatality, and mortality for cancer by site and stage at diagnosis of all gastric bypass patients, compared to nonoperated severely obese controls. Follow-up was over a 24-year period (mean 12.5 years). Total cancer incidence was significantly lower in the surgical group compared to controls (hazard ratio (HR) = 0.76; confidence interval (CI) 95%, 0.65–0.89; P = 0.0006). Lower incidence in surgery patients vs. controls was primarily due to decreased incidence of cancer diagnosed at regional or distant stages. Cancer mortality was 46% lower in the surgery group compared to controls (HR = 0.54; CI 95%, 0.37–0.78; P = 0.001). Although the apparent protective effect of surgery on risk of developing cancer was limited to cancers likely known to be obesity related, the inverse association for mortality was seen for all cancers. Significant reduction in total cancer mortality in gastric bypass patients compared with severely obese controls was associated with decreased incidence, primarily among subjects with advanced cancers. These findings suggest gastric bypass results in lower cancer risk, presumably related to weight loss, supporting recommendations for reducing weight to lower cancer risk.
doi:10.1038/oby.2008.610
PMCID: PMC2859193  PMID: 19148123
12.  Tobacco‐related disease mortality among men who switched from cigarettes to spit tobacco 
Tobacco Control  2007;16(1):22-28.
Background
Although several epidemiological studies have examined the mortality among users of spit tobacco, none have compared mortality of former cigarette smokers who substitute spit tobacco for cigarette smoking (“switchers”) and smokers who quit using tobacco entirely.
Methods
A cohort of 116 395 men were identified as switchers (n = 4443) or cigarette smokers who quit using tobacco entirely (n = 111 952) when enrolled in the ongoing US American Cancer Society Cancer Prevention Study II. From 1982 to 31 December 2002, 44 374 of these men died. The mortality hazard ratios (HR) of tobacco‐related diseases, including lung cancer, coronary heart disease, stroke and chronic obstructive pulmonary disease, were estimated using Cox proportional hazards regression modelling adjusted for age and other demographic variables, as well as variables associated with smoking history, including number of years smoked, number of cigarettes smoked and age at quitting.
Results
After 20 years of follow‐up, switchers had a higher rate of death from any cause (HR 1.08, 95% confidence interval (CI) 1.01 to 1.15), lung cancer (HR 1.46, 95% CI 1.24 to 1.73), coronary heart disease (HR 1.13, 95% CI 1.00 to 1.29) and stroke (HR 1.24, 95% CI 1.01 to 1.53) than those who quit using tobacco entirely.
Conclusion
The risks of dying from major tobacco‐related diseases were higher among former cigarette smokers who switched to spit tobacco after they stopped smoking than among those who quit using tobacco entirely.
doi:10.1136/tc.2006.018069
PMCID: PMC2598436  PMID: 17297069
13.  No Association of SNPs in One-Carbon Metabolism Genes with Prostate Cancer Risk 
One-carbon metabolism mediates the inter-conversion of folates for the synthesis of precursors used in DNA synthesis, repair and methylation. Inadequate folate nutrition or compromised metabolism can disrupt these processes and facilitate carcinogenesis. In this study, we investigated associations of 39 candidate SNPs in nine one-carbon metabolism genes with risk of prostate cancer using 1,144 cases and 1,144 controls from the Cancer Prevention Study-II Nutrition Cohort. None of these SNPs were significantly associated with prostate cancer risk, either overall or in cases with advanced prostate cancer. Thus, our findings do not support the hypothesis that common genetic variation in one-carbon metabolism genes influences prostate cancer risk.
doi:10.1158/1055-9965.EPI-08-0789
PMCID: PMC2645230  PMID: 19064578
14.  Nicotinic Receptor Gene Variants Influence Susceptibility to Heavy Smoking 
Heavy smoking is a strong predictor of nicotine dependence, which is a major impediment to smoking cessation. Although both heavy smoking and nicotine dependence are highly heritable, previous attempts to identify genes influencing these phenotypes have been largely unsuccessful until very recently. We studied 1,452 heavy smokers (defined as smoking at least 30 cigarettes per day for at least 5 years) and 1,395 light smokers (defined as smoking <5 cigarettes per day for at least 1 year) to investigate the association of common variants in nicotinic receptor subunit genes with smoking behavior. Compared to the most common allele, two separate groups of SNPs in the CHRNA5-CHRNA3-CHRNB4 gene cluster were associated with heavy smoking with a very high statistical significance. One group of eight SNPs, that included a nonsynonymous SNP in the CHRNA5 gene, was in strong linkage disequilibrium and associated with increased risk of heavy smoking. A second group of SNPs not strongly correlated with the first was associated with decreased risk of heavy smoking. Analyses that combined both groups of SNPs found associations with heavy smoking that varied by more than two-fold. Our findings identify two loci in the CHRNA5-CHRNA3-CHRNB4 gene cluster that predict smoking behavior and provide strong evidence for the involvement of the α5 nicotinic receptor in heavy smoking.
doi:10.1158/1055-9965.EPI-08-0585
PMCID: PMC2614129  PMID: 19029397
15.  Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2 
Ahmed, Shahana | Thomas, Gilles | Ghoussaini, Maya | Healey, Catherine S | Humphreys, Manjeet K | Platte, Radka | Morrison, Jonathan | Maranian, Melanie | Pooley, Karen A | Luben, Robert | Eccles, Diana | Evans, D Gareth | Fletcher, Olivia | Johnson, Nichola | Silva, Isabel dos Santos | Peto, Julian | Stratton, Michael R | Rahman, Nazneen | Jacobs, Kevin | Prentice, Ross | Anderson, Garnet L | Rajkovic, Aleksandar | Curb, J David | Ziegler, Regina G | Berg, Christine D | Buys, Saundra S | McCarty, Catherine A | Feigelson, Heather Spencer | Calle, Eugenia E | Thun, Michael J | Diver, W Ryan | Bojesen, Stig | Nordestgaard, Børge G | Flyger, Henrik | Dörk, Thilo | Schürmann, Peter | Hillemanns, Peter | Karstens, Johann H | Bogdanova, Natalia V | Antonenkova, Natalia N | Zalutsky, Iosif V | Bermisheva, Marina | Fedorova, Sardana | Khusnutdinova, Elza | Kang, Daehee | Yoo, Keun-Young | Noh, Dong Young | Ahn, Sei-Hyun | Devilee, Peter | van Asperen, Christi J | Tollenaar, R A E M | Seynaeve, Caroline | Garcia-Closas, Montserrat | Lissowska, Jolanta | Brinton, Louise | Peplonska, Beata | Nevanlinna, Heli | Heikkinen, Tuomas | Aittomäki, Kristiina | Blomqvist, Carl | Hopper, John L | Southey, Melissa C | Smith, Letitia | Spurdle, Amanda B | Schmidt, Marjanka K | Broeks, Annegien | van Hien, Richard R | Cornelissen, Sten | Milne, Roger L | Ribas, Gloria | González-Neira, Anna | Benitez, Javier | Schmutzler, Rita K | Burwinkel, Barbara | Bartram, Claus R | Meindl, Alfons | Brauch, Hiltrud | Justenhoven, Christina | Hamann, Ute | Chang-Claude, Jenny | Hein, Rebecca | Wang-Gohrke, Shan | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kosma, Veli-Matti | Kataja, Vesa | Olson, Janet E | Wang, Xianshu | Fredericksen, Zachary | Giles, Graham G | Severi, Gianluca | Baglietto, Laura | English, Dallas R | Hankinson, Susan E | Cox, David G | Kraft, Peter | Vatten, Lars J | Hveem, Kristian | Kumle, Merethe | Sigurdson, Alice | Doody, Michele | Bhatti, Parveen | Alexander, Bruce H | Hooning, Maartje J | van den Ouweland, Ans M W | Oldenburg, Rogier A | Schutte, Mieke | Hall, Per | Czene, Kamila | Liu, Jianjun | Li, Yuqing | Cox, Angela | Elliott, Graeme | Brock, Ian | Reed, Malcolm W R | Shen, Chen-Yang | Yu, Jyh-Cherng | Hsu, Giu-Cheng | Chen, Shou-Tung | Anton-Culver, Hoda | Ziogas, Argyrios | Andrulis, Irene L | Knight, Julia A | kConFab | Beesley, Jonathan | Goode, Ellen L | Couch, Fergus | Chenevix-Trench, Georgia | Hoover, Robert N | Ponder, Bruce A J | Hunter, David J | Pharoah, Paul D P | Dunning, Alison M | Chanock, Stephen J | Easton, Douglas F
Nature genetics  2009;41(5):585-590.
Genome-wide association studies (GWAS) have identified seven breast cancer susceptibility loci, but these explain only a small fraction of the familial risk of the disease. Five of these loci were identified through a two-stage GWAS involving 390 familial cases and 364 controls in the first stage, and 3,990 cases and 3,916 controls in the second stage1. To identify additional loci, we tested over 800 promising associations from this GWAS in a further two stages involving 37,012 cases and 40,069 controls from 33 studies in the CGEMS collaboration and Breast Cancer Association Consortium. We found strong evidence for additional susceptibility loci on 3p (rs4973768: per-allele OR = 1.11, 95% CI = 1.08–1.13, P = 4.1 × 10−23) and 17q (rs6504950: per-allele OR = 0.95, 95% CI = 0.92–0.97, P = 1.4 × 10−8). Potential causative genes include SLC4A7 and NEK10 on 3p and COX11 on 17q.
doi:10.1038/ng.354
PMCID: PMC2748125  PMID: 19330027
16.  Serum 25-hydroxyvitamin D concentrations and postmenopausal breast cancer risk: a nested case control study in the Cancer Prevention Study-II Nutrition Cohort 
Introduction
Vitamin D status measured during adulthood has been inversely associated with breast cancer risk in some, but not all, studies. Vitamin D has been hypothesized to prevent breast cancer through genomic and non-genomic actions in cell-cycle regulation.
Methods
A subset (n = 21,965) of female participants from the prospective Cancer Prevention Study-II (CPS-II) Nutrition Cohort provided a blood sample from 1998-2001 and were followed through 2005. We measured serum 25-hydroxyvitamin D (25(OH)D) in 516 verified incident cases and 516 controls, matched on birth date (± 6 months), date of blood draw (± 6 months) and race. Information on medical history, risk factors and lifestyle was available from repeated questionnaires. We computed multi-variable odds ratios (OR) and 95% confidence intervals (95% CI) for the association between 25(OH)D quintile and breast cancer risk using unconditional logistic regression, controlling for matching factors and additional confounders.
Results
We observed no association between 25(OH)D and breast cancer (OR = 1.09, 95% CI 0.70-1.68, P = 0.60) for the top vs bottom quintile. Using a priori cut-points, the OR was 0.86 (95% CI 0.59-1.26), for ≥75 vs <50 nmol/L. Results were not different when the first two years of follow-up were excluded, or in analyses stratified by season, latitude, BMI, postmenopausal hormone use, or by tumor grade or estrogen receptor status.
Conclusions
These results do not support an association between adulthood serum 25(OH)D and postmenopausal breast cancer. We cannot rule out an association with 25(OH)D status earlier in life.
doi:10.1186/bcr2356
PMCID: PMC2750126  PMID: 19715600
17.  Genetic polymorphisms of the GNRH1 and GNRHR genes and risk of breast cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3) 
BMC Cancer  2009;9:257.
Background
Gonadotropin releasing hormone (GNRH1) triggers the release of follicle stimulating hormone and luteinizing hormone from the pituitary. Genetic variants in the gene encoding GNRH1 or its receptor may influence breast cancer risk by modulating production of ovarian steroid hormones. We studied the association between breast cancer risk and polymorphisms in genes that code for GNRH1 and its receptor (GNRHR) in the large National Cancer Institute Breast and Prostate Cancer Cohort Consortium (NCI-BPC3).
Methods
We sequenced exons of GNRH1 and GNRHR in 95 invasive breast cancer cases. Resulting single nucleotide polymorphisms (SNPs) were genotyped and used to identify haplotype-tagging SNPs (htSNPS) in a panel of 349 healthy women. The htSNPs were genotyped in 5,603 invasive breast cancer cases and 7,480 controls from the Cancer Prevention Study-II (CPS-II), European Prospective Investigation on Cancer and Nutrition (EPIC), Multiethnic Cohort (MEC), Nurses' Health Study (NHS), and Women's Health Study (WHS). Circulating levels of sex steroids (androstenedione, estradiol, estrone and testosterone) were also measured in 4713 study subjects.
Results
Breast cancer risk was not associated with any polymorphism or haplotype in the GNRH1 and GNRHR genes, nor were there any statistically significant interactions with known breast cancer risk factors. Polymorphisms in these two genes were not strongly associated with circulating hormone levels.
Conclusion
Common variants of the GNRH1 and GNRHR genes are not associated with risk of invasive breast cancer in Caucasians.
doi:10.1186/1471-2407-9-257
PMCID: PMC2729775  PMID: 19640273
18.  Genetic variation in candidate obesity genes ADRB2, ADRB3, GHRL, HSD11B1, IRS1, IRS2, and SHC1 and risk for breast cancer in the Cancer Prevention Study II 
Introduction
Obesity has consistently been associated with postmenopausal breast cancer risk. Proteins that are secreted by adipose tissue or are involved in regulating body mass may play a role in breast tumor development.
Methods
We conducted a nested case-control study among postmenopausal women from the American Cancer Society Cancer Prevention Study II Nutrition Cohort to determine whether genes associated with obesity increase risk for breast cancer. Tagging single nucleotide polymorphisms (SNPs) were selected to capture common variation across seven candidate genes that encode adipose-related proteins: ADRB2, ADRB3, GHRL, HSD11B1, IRS1, IRS2, and SHC1. Thirty-nine SNPs were genotyped in 648 cases and 659 controls. Logistic regression models were used to examine the association between each tagging SNP and risk for breast cancer while adjusting for matching factors and potential confounders. We also examined whether these SNPs were associated with measures of adult adiposity.
Results
Two out of five tagging SNPs in HSD11B1 were associated with breast cancer (rs11807619, P = 0.006; rs932335, P = 0.0001). rs11807619 and rs932335 were highly correlated (r2 = 0.74) and, when modeled as a haplotype, only haplotypes containing the rs932335 C allele were associated with breast cancer. The rs932335 C allele was associated with a nearly twofold increased risk for breast cancer (odds ratio = 1.83, 95% confidence interval = 1.01–3.33 for C/C versus G/G). Three of the 11 SNPs for IRS2 were associated with breast cancer (rs4773082, P = 0.007; rs2289046, P = 0.016; rs754204, P = 0.03). When these three SNPs were examined as a haplotype, only the haplotype that included the G allele of rs2289046 was associated with breast cancer (odds ratio = 0.76, 95% confidence interval = 0.63–0.92 for TGC versus CAT). IRS2 rs2289046, rs754204, and rs12584136 were also associated with adult weight gain but only among cases. None of the other SNPs in any gene investigated were associated with breast cancer or adiposity.
Conclusion
Our findings suggest that these tagging SNPs in HSD11B1 and IRS2 mark regions of the genome that may harbor risk alleles for breast cancer, and these associations are probably independent of adiposity.
doi:10.1186/bcr2114
PMCID: PMC2575528  PMID: 18611262
19.  IGF-1, IGFBP-1, and IGFBP-3 Polymorphisms Predict Circulating IGF Levels but Not Breast Cancer Risk: Findings from the Breast and Prostate Cancer Cohort Consortium (BPC3) 
PLoS ONE  2008;3(7):e2578.
IGF-1 has been shown to promote proliferation of normal epithelial breast cells, and the IGF pathway has also been linked to mammary carcinogenesis in animal models. We comprehensively examined the association between common genetic variation in the IGF1, IGFBP1, and IGFBP3 genes in relation to circulating IGF-I and IGFBP-3 levels and breast cancer risk within the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). This analysis included 6,912 breast cancer cases and 8,891 matched controls (n = 6,410 for circulating IGF-I and 6,275 for circulating IGFBP-3 analyses) comprised primarily of Caucasian women drawn from six large cohorts. Linkage disequilibrium and haplotype patterns were characterized in the regions surrounding IGF1 and the genes coding for two of its binding proteins, IGFBP1 and IGFBP3. In total, thirty haplotype-tagging single nucleotide polymorphisms (htSNP) were selected to provide high coverage of common haplotypes; the haplotype structure was defined across four haplotype blocks for IGF1 and three for IGFBP1 and IGFBP3. Specific IGF1 SNPs individually accounted for up to 5% change in circulating IGF-I levels and individual IGFBP3 SNPs were associated up to 12% change in circulating IGFBP-3 levels, but no associations were observed between these polymorphisms and breast cancer risk. Logistic regression analyses found no associations between breast cancer and any htSNPs or haplotypes in IGF1, IGFBP1, or IGFBP3. No effect modification was observed in analyses stratified by menopausal status, family history of breast cancer, body mass index, or postmenopausal hormone therapy, or for analyses stratified by stage at diagnosis or hormone receptor status. In summary, the impact of genetic variation in IGF1 and IGFBP3 on circulating IGF levels does not appear to substantially influence breast cancer risk substantially among primarily Caucasian postmenopausal women.
doi:10.1371/journal.pone.0002578
PMCID: PMC2440354  PMID: 18596909
20.  Recreational Physical Activity and Risk of Parkinson’s Disease 
Purpose
To investigate associations between recreational physical activity and Parkinson’s disease (PD) risk.
Methods
We prospectively followed 143,325 participants in the Cancer Prevention Study II Nutrition Cohort from 1992 to 2001 (mean age at baseline = 63). Recreational physical activity was estimated at baseline from the reported number of hours per week on average spent performing light intensity activities (walking, dancing) and moderate to vigorous intensity activities (jogging/running, lap swimming, tennis/racquetball, bicycling/stationary bike, aerobics/calisthenics). Incident cases of PD (n = 413) were confirmed by treating physicians and medical record review. Relative risks (RR) were estimated using proportional hazards models, adjusting for age, gender, smoking, and other risk factors.
Results
Risk of PD declined in the highest categories of baseline recreational activity. The RR comparing the highest category of total recreational activity (men ≥ 23 metabolic equivalent task-h/wk [MET-h/wk], women ≥ 18.5 MET-h/wk) to no activity was 0.8 (95% CI: 0.6, 1.2; p trend = 0.07). When light activity and moderate to vigorous activity were examined separately, only the latter was found to be associated with PD risk. The RR comparing the highest category of moderate to vigorous activity (men ≥ 16 MET-h/wk, women ≥ 11.5 MET-h/wk) to the lowest (0 MET-h/wk) was 0.6 (95% CI: 0.4, 1.0; p trend = 0.02). These results did not differ significantly by gender. The results were similar when we excluded cases with symptom onset in the first four years of follow-up.
Conclusions
Our results may be explained either by a reduction in PD risk through moderate to vigorous activity, or by decreased baseline recreational activity due to preclinical PD.
doi:10.1002/mds.21772
PMCID: PMC2387117  PMID: 17960818
Parkinson’s disease; epidemiology; cohort study; behavioral risk factors; physical activity
21.  Dairy products and risk of Parkinson’s disease 
American journal of epidemiology  2007;165(9):998-1006.
The authors prospectively investigated the association between dairy intake and risk of Parkinson’s disease among 57,689 men and 73,175 women from the Cancer Prevention Study II Nutrition Cohort from the American Cancer Society. A total of 250 men and 138 women with Parkinson’s disease were identified during the follow-up (1992–2001). Dairy consumption was positively associated with the risk of Parkinson’s disease: compared with the lowest intake quintile, the corresponding relative risks (RRs) for quintiles 2–5 were 1.4, 1.4, 1.4, and 1.6 (95 percent confidence interval (CI): 1.1–2.2; p for trend=0.05). A higher risk among dairy consumers was found in both men and women, although the association in women appeared non-linear. The meta-analysis of all prospective studies confirmed a moderately elevated risk of Parkinson’s disease among individuals with high dairy consumption: the RRs between extreme intake categories were 1.6 (95 percent CI: 1.3–2.0) for men and women combined, 1.8 for men (95 percent CI: 1.4–2.4), and 1.3 for women (95 percent CI: 0.8–2.1). These data suggest that dairy consumption may increase the risk of Parkinson’s disease, particularly in men. More studies are needed to further examine these findings and to explore the underlying mechanisms.
doi:10.1093/aje/kwk089
PMCID: PMC2232901  PMID: 17272289
dairy; diet; milk; Parkinson’s disease
22.  Vitamin D pathway gene polymorphisms, diet, and risk of postmenopausal breast cancer: a nested case-control study 
Breast Cancer Research  2007;9(1):R9.
Introduction
Vitamin D receptor (VDR) polymorphisms have been inconsistently associated with breast cancer risk. Whether risk is influenced by polymorphisms in other vitamin D metabolism genes and whether calcium or vitamin D intake modifies risk by genotype have not been evaluated.
Methods
We conducted a nested case-control study within the Cancer Prevention Study II Nutrition Cohort of associations between breast cancer and four VDR single-nucleotide polymorphisms (SNPs), Bsm1,Apa1,Taq1, and Fok1, a poly(A) microsatellite, and associated haplotypes (baTL and BAtS). We also examined one SNP in the 24-hydroxylase gene (CYP24A1) and two in the vitamin D-binding protein (group-specific component [GC]) gene. Participants completed a questionnaire on diet and medical history at baseline in 1992. This study includes 500 postmenopausal breast cancer cases and 500 controls matched by age, race/ethnicity, and date of blood collection.
Results
Incident breast cancer was not associated with any genotype examined. However, women with the Bsm1 bb SNP who consumed greater than the median intake of total calcium (≥902 mg/day) had lower odds of breast cancer compared to women with the Bb or BB genotype and less than the median calcium intake (odds ratio 0.61, 95% confidence interval 0.38 to 0.96; pinteraction = 0.01). Similar interactions were observed for Taq1 (T allele) and the poly(A) (LL) repeat.
Conclusion
We found no overall association between selected vitamin D pathway genes and postmenopausal breast cancer risk. However, certain VDR gene polymorphisms were associated with lower risk in women consuming high levels of calcium, suggesting that dietary factors may modify associations by VDR genotype.
doi:10.1186/bcr1642
PMCID: PMC1851389  PMID: 17244366
23.  A comprehensive analysis of the androgen receptor gene and risk of breast cancer: results from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3) 
Breast Cancer Research  2006;8(5):R54.
Introduction
Androgens have been hypothesised to influence risk of breast cancer through several possible mechanisms, including their conversion to estradiol or their binding to the oestrogen receptor and/or androgen receptor (AR) in the breast. Here, we report on the results of a large and comprehensive study of the association between genetic variation in the AR gene and risk of breast cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3).
Methods
The underlying genetic variation was determined by first sequencing the coding regions of the AR gene in a panel of 95 advanced breast cancer cases. Second, a dense set of markers from the public database was genotyped in a panel of 349 healthy women. The linkage disequilibrium relationships (blocks) across the gene were then identified, and haplotype-tagging single nucleotide polymorphisms (htSNPs) were selected to capture the common genetic variation across the locus. The htSNPs were then genotyped in the nested breast cancer cases and controls from the Cancer Prevention Study II, European Prospective Investigation into Cancer and Nutrition, Multiethnic Cohort, Nurses' Health Study, and Women's Health Study cohorts (5,603 breast cancer cases and 7,480 controls).
Results
We found no association between any genetic variation (SNP, haplotype, or the exon 1 CAG repeat) in the AR gene and risk of breast cancer, nor were any statistical interactions with known breast cancer risk factors observed.
Conclusion
Among postmenopausal Caucasian women, common variants of the AR gene are not associated with risk of breast cancer.
doi:10.1186/bcr1602
PMCID: PMC1779488  PMID: 16987421
24.  Polymorphisms in the vascular endothelial growth factor gene and breast cancer in the Cancer Prevention Study II cohort 
Breast Cancer Research  2006;8(2):R22.
Introduction
Vascular endothelial growth factor (VEGF) plays a central role in promoting angiogenesis and is over-expressed in breast cancer. At least four polymorphisms in the VEGF gene have been associated with changes in VEGF expression levels: -2578C/A, -1154G/A and -634G/C are all located in the promoter region; and +936C/T is located in the 3'-untranslated region.
Method
We examined the association between these four VEGF polymorphisms and risk for breast cancer among postmenopausal women in CPS-II (Cancer Prevention Study II) Nutrition Cohort. This cohort was established in 1992 and participants were invited to provide a blood sample between 1998 and 2001. Included in this analysis were 501 postmenopausal women who provided a blood sample and were diagnosed with breast cancer between 1992 and 2001 (cases). Control individuals were 504 cancer-free postmenopausal women matched to the cases with respect to age, race/ethnicity, and date of blood collection (controls).
Results
We found no association between any of the polymorphisms examined and overall breast cancer risk. However, associations were markedly different in separate analyses of invasive cancer (n = 380) and in situ cancer (n = 107). The -2578C and -1154G alleles, which are both hypothesized to increase expression of VEGF, were associated with increased risk for invasive breast cancer (odds ratio [OR] 1.46, 95% confidence interval [CI] 1.00–2.14 for -2578 CC versus AA; OR 1.64, 95% CI 1.02–2.64 for -1154 GG versus AA) but they were not associated with risk for in situ cancer. The +936C allele, which is also hypothesized to increase VEGF expression, was not clearly associated with invasive breast cancer (OR 1.21, 95% CI 0.88–1.67 for +936 CC versus TT/CT), but it was associated with reduced risk for in situ cancer (OR 0.59, 95% CI 0.37–0.93 for CC versus TT/CT). The -634 C/G polymorphism was not associated with either invasive or in situ cancer.
Conclusion
Our findings provide limited support for the hypothesis that the -2578C and -1154G VEGF alleles are associated with increased risk for invasive but not in situ breast cancer in postmenopausal women.
doi:10.1186/bcr1400
PMCID: PMC1557725  PMID: 16613616
25.  A prospective study of XRCC1 (X-ray cross-complementing group 1) polymorphisms and breast cancer risk 
Breast Cancer Research  2005;7(6):R1168-R1173.
Introduction
The gene XRCC1 (X-ray repair cross-complementing group 1) encodes a protein involved in DNA base excision repair. Two non-synonymous polymorphisms in XRCC1 (Arg194Trp and Arg399Gln) have been shown to alter DNA repair capacity in some studies in vitro. However, results of previous association studies of these two XRCC1 variants and breast cancer have been inconsistent. We examined the association between polymorphisms in XRCC1 and breast cancer in the American Cancer Society Cancer Prevention Study II (CPS-II) Nutrition Cohort, a large prospective study of cancer incidence in the USA.
Methods
Among the 21,965 women who were cancer-free in 1992 and gave blood between 1998 and 2001, 502 postmenopausal breast cancer cases were diagnosed between 1992 and 2001; 502 controls were matched to cases on age, race/ethnicity, and date of blood collection. Genotyping on DNA extracted from buffy coat was performed with Taqman. Conditional logistic regression was used to examine the association between each polymorphism and breast cancer risk controlling for breast cancer risk factors. We also examined whether factors associated with DNA damage, such as smoking and antioxidant intake, modified the association between XRCC1 polymorphisms and breast cancer.
Results
We observed a significant inverse association between Trp194 carriers (Trp/Trp and Trp/Arg) compared with Trp194 non-carriers in relation to breast cancer (Arg/Arg) (odds ratio (OR) 0.62, 95% confidence interval (CI) 0.40 to 0.95). The inverse association between breast cancer and Trp194 carriers compared with non-carriers was slightly stronger among smokers (OR 0.47, 95% CI 0.24 to 0.94) than never smokers (OR 0.78, 95% CI 0.43 to 1.40). An increased risk associated with the Arg399Gln polymorphism (Gln/Gln versus Arg/Arg) was observed only among women who reported ever smoking cigarettes (OR 2.76, 95% CI 1.36 to 5.63), and not in women who were lifelong non-smokers (OR 0.64, 95% CI 0.33 to 1.26). No other factor examined modified the association between XRCC1 polymorphisms and breast cancer risk.
Conclusion
Our results support the hypothesis that genetic variation in XRCC1, particularly in Arg194Trp, may influence postmenopausal breast cancer risk. In our study, genetic variation in XRCC1 Arg399Gln was associated with breast cancer risk only among women with a history of smoking cigarettes.
doi:10.1186/bcr1355
PMCID: PMC1410742  PMID: 16457697

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