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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  Genetic Variation in the HSD17B1 Gene and Risk of Prostate Cancer 
PLoS Genetics  2005;1(5):e68.
Steroid hormones are believed to play an important role in prostate carcinogenesis, but epidemiological evidence linking prostate cancer and steroid hormone genes has been inconclusive, in part due to small sample sizes or incomplete characterization of genetic variation at the locus of interest. Here we report on the results of a comprehensive study of the association between HSD17B1 and prostate cancer by the Breast and Prostate Cancer Cohort Consortium, a large collaborative study. HSD17B1 encodes 17β-hydroxysteroid dehydrogenase 1, an enzyme that converts dihydroepiandrosterone to the testosterone precursor Δ5-androsterone-3β,17β-diol and converts estrone to estradiol. The Breast and Prostate Cancer Cohort Consortium researchers systematically characterized variation in HSD17B1 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 8,290 prostate cancer cases and 9,367 study-, age-, and ethnicity-matched controls. We found no evidence that HSD17B1 htSNPs (including the nonsynonymous coding SNP S312G) or htSNP haplotypes were associated with risk of prostate cancer or tumor stage in the pooled multiethnic sample or in U.S. and European whites. Analyses stratified by age, body mass index, and family history of disease found no subgroup-specific associations between these HSD17B1 htSNPs and prostate cancer. We found significant evidence of heterogeneity in associations between HSD17B1 haplotypes and prostate cancer across ethnicity: one haplotype had a significant (p < 0.002) inverse association with risk of prostate cancer in Latinos and Japanese Americans but showed no evidence of association in African Americans, Native Hawaiians, or whites. However, the smaller numbers of Latinos and Japanese Americans in this study makes these subgroup analyses less reliable. These results suggest that the germline variants in HSD17B1 characterized by these htSNPs do not substantially influence the risk of prostate cancer in U.S. and European whites.
Synopsis
Steroid hormones such as estrogen and testosterone are hypothesized to play a role in the development of cancer. This is the first substantive paper from the Breast and Prostate Cancer Cohort Consortium, a large, international study designed to assess the effect of variation in genes that influence hormone production and activity on the risk of breast and prostate cancer. The investigators first constructed a detailed map of genetic variation spanning HSD17B1, a gene involved in the production of estrogen and testosterone. This enabled them to efficiently measure common variation across the whole gene, capturing information about both known variants with a plausible function and unknown variants with an unknown function. Because of the results with a large number of study participants, the investigators could rule out strong associations between common HSD17B1 variants and risk of prostate cancer among U.S. and European whites. While this sheds some light on the carcinogenic effects of one enzyme involved in the complex process of steroid hormone production, it remains to be determined whether variants in other genes play a more important role or if the combined effects of several genes within these pathways have a larger impact.
doi:10.1371/journal.pgen.0010068
PMCID: PMC1287955  PMID: 16311626
17.  Genetic Variation in the HSD17B1 Gene and Risk of Prostate Cancer 
PLoS Genetics  2005;1(5):e68.
Steroid hormones are believed to play an important role in prostate carcinogenesis, but epidemiological evidence linking prostate cancer and steroid hormone genes has been inconclusive, in part due to small sample sizes or incomplete characterization of genetic variation at the locus of interest. Here we report on the results of a comprehensive study of the association between HSD17B1 and prostate cancer by the Breast and Prostate Cancer Cohort Consortium, a large collaborative study. HSD17B1 encodes 17β-hydroxysteroid dehydrogenase 1, an enzyme that converts dihydroepiandrosterone to the testosterone precursor Δ5-androsterone-3β,17β-diol and converts estrone to estradiol. The Breast and Prostate Cancer Cohort Consortium researchers systematically characterized variation in HSD17B1 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 8,290 prostate cancer cases and 9,367 study-, age-, and ethnicity-matched controls. We found no evidence that HSD17B1 htSNPs (including the nonsynonymous coding SNP S312G) or htSNP haplotypes were associated with risk of prostate cancer or tumor stage in the pooled multiethnic sample or in U.S. and European whites. Analyses stratified by age, body mass index, and family history of disease found no subgroup-specific associations between these HSD17B1 htSNPs and prostate cancer. We found significant evidence of heterogeneity in associations between HSD17B1 haplotypes and prostate cancer across ethnicity: one haplotype had a significant (p < 0.002) inverse association with risk of prostate cancer in Latinos and Japanese Americans but showed no evidence of association in African Americans, Native Hawaiians, or whites. However, the smaller numbers of Latinos and Japanese Americans in this study makes these subgroup analyses less reliable. These results suggest that the germline variants in HSD17B1 characterized by these htSNPs do not substantially influence the risk of prostate cancer in U.S. and European whites.
Synopsis
Steroid hormones such as estrogen and testosterone are hypothesized to play a role in the development of cancer. This is the first substantive paper from the Breast and Prostate Cancer Cohort Consortium, a large, international study designed to assess the effect of variation in genes that influence hormone production and activity on the risk of breast and prostate cancer. The investigators first constructed a detailed map of genetic variation spanning HSD17B1, a gene involved in the production of estrogen and testosterone. This enabled them to efficiently measure common variation across the whole gene, capturing information about both known variants with a plausible function and unknown variants with an unknown function. Because of the results with a large number of study participants, the investigators could rule out strong associations between common HSD17B1 variants and risk of prostate cancer among U.S. and European whites. While this sheds some light on the carcinogenic effects of one enzyme involved in the complex process of steroid hormone production, it remains to be determined whether variants in other genes play a more important role or if the combined effects of several genes within these pathways have a larger impact.
doi:10.1371/journal.pgen.0010068
PMCID: PMC1287955  PMID: 16311626
18.  Cigarette tar yields in relation to mortality from lung cancer in the cancer prevention study II prospective cohort, 1982-8 
BMJ : British Medical Journal  2004;328(7431):72.
Objective To assess the risk of lung cancer in smokers of medium tar filter cigarettes compared with smokers of low tar and very low tar filter cigarettes.
Design Analysis of the association between the tar rating of the brand of cigarette smoked in 1982 and mortality from lung cancer over the next six years. Multivariate proportional hazards analyses used to assess hazard ratios, with adjustment for age at enrolment, race, educational level, marital status, blue collar employment, occupational exposure to asbestos, intake of vegetables, citrus fruits, and vitamins, and, in analyses of current and former smokers, for age when they started to smoke and number of cigarettes smoked per day.
Setting Cancer prevention study II (CPS-II).
Participants 364 239 men and 576 535 women, aged ≥ 30 years, who had either never smoked, were former smokers, or were currently smoking a specific brand of cigarette when they were enrolled in the cancer prevention study.
Main outcome measure Death from primary cancer of the lung among participants who had never smoked, former smokers, smokers of very low tar (≤ 7 mg tar/cigarette) filter, low tar (8-14 mg) filter, high tar (≥ 22 mg) non-filter brands and medium tar conventional filter brands (15-21 mg).
Results Irrespective of the tar level of their current brand, all current smokers had a far greater risk of lung cancer than people who had stopped smoking or had never smoked. Compared with smokers of medium tar (15-21 mg) filter cigarettes, risk was higher among men and women who smoked high tar (≥ 22 mg) non-filter brands (hazard ratio 1.44, 95% confidence interval 1.20 to 1.73, and 1.64, 1.26 to 2.15, respectively). There was no difference in risk among men who smoked brands rated as very low tar (1.17, 0.95 to 1.45) or low tar (1.02, 0.90 to 1.16) compared with those who smoked medium tar brands. The same was seen for women (0.98, 0.80 to 1.21, and 0.95, 0.82 to 1.11, respectively).
Conclusion The increase in lung cancer risk is similar in people who smoke medium tar cigarettes (15-21 mg), low tar cigarettes (8-14 mg), or very low tar cigarettes (≤ 7 mg). Men and women who smoke non-filtered cigarettes with tar ratings ≥ 22 mg have an even higher risk of lung cancer.
doi:10.1136/bmj.37936.585382.44
PMCID: PMC314045  PMID: 14715602
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

Results 1-25 (27)