PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (263)
 

Clipboard (0)
None

Select a Filter Below

Journals
more »
Year of Publication
more »
1.  Genome-wide interaction study of smoking and bladder cancer risk 
Carcinogenesis  2014;35(8):1737-1744.
Summary
Our GWAS of smoking and bladder cancer risk based on data from 5,424 cases and 10,162 controls suggest that exploring additive and multiplicative gene–environment interactions can identify novel susceptibility loci that are associated with risk for different subgroups.
Bladder cancer is a complex disease with known environmental and genetic risk factors. We performed a genome-wide interaction study (GWAS) of smoking and bladder cancer risk based on primary scan data from 3002 cases and 4411 controls from the National Cancer Institute Bladder Cancer GWAS. Alternative methods were used to evaluate both additive and multiplicative interactions between individual single nucleotide polymorphisms (SNPs) and smoking exposure. SNPs with interaction P values < 5 × 10− 5 were evaluated further in an independent dataset of 2422 bladder cancer cases and 5751 controls. We identified 10 SNPs that showed association in a consistent manner with the initial dataset and in the combined dataset, providing evidence of interaction with tobacco use. Further, two of these novel SNPs showed strong evidence of association with bladder cancer in tobacco use subgroups that approached genome-wide significance. Specifically, rs1711973 (FOXF2) on 6p25.3 was a susceptibility SNP for never smokers [combined odds ratio (OR) = 1.34, 95% confidence interval (CI) = 1.20–1.50, P value = 5.18 × 10− 7]; and rs12216499 (RSPH3-TAGAP-EZR) on 6q25.3 was a susceptibility SNP for ever smokers (combined OR = 0.75, 95% CI = 0.67–0.84, P value = 6.35 × 10− 7). In our analysis of smoking and bladder cancer, the tests for multiplicative interaction seemed to more commonly identify susceptibility loci with associations in never smokers, whereas the additive interaction analysis identified more loci with associations among smokers—including the known smoking and NAT2 acetylation interaction. Our findings provide additional evidence of gene–environment interactions for tobacco and bladder cancer.
doi:10.1093/carcin/bgu064
PMCID: PMC4123644  PMID: 24662972
2.  A genome-wide association study of marginal zone lymphoma shows association to the HLA region 
Vijai, Joseph | Wang, Zhaoming | Berndt, Sonja I | Skibola, Christine F | Slager, Susan L | de Sanjose, Silvia | Melbye, Mads | Glimelius, Bengt | Bracci, Paige M | Conde, Lucia | Birmann, Brenda M | Wang, Sophia S | Brooks-Wilson, Angela R | Lan, Qing | de Bakker, Paul I W | Vermeulen, Roel C H | Portlock, Carol | Ansell, Stephen M | Link, Brian K | Riby, Jacques | North, Kari E | Gu, Jian | Hjalgrim, Henrik | Cozen, Wendy | Becker, Nikolaus | Teras, Lauren R | Spinelli, John J | Turner, Jenny | Zhang, Yawei | Purdue, Mark P | Giles, Graham G | Kelly, Rachel S | Zeleniuch-Jacquotte, Anne | Ennas, Maria Grazia | Monnereau, Alain | Bertrand, Kimberly A | Albanes, Demetrius | Lightfoot, Tracy | Yeager, Meredith | Chung, Charles C | Burdett, Laurie | Hutchinson, Amy | Lawrence, Charles | Montalvan, Rebecca | Liang, Liming | Huang, Jinyan | Ma, Baoshan | Villano, Danylo J | Maria, Ann | Corines, Marina | Thomas, Tinu | Novak, Anne J | Dogan, Ahmet | Liebow, Mark | Thompson, Carrie A | Witzig, Thomas E | Habermann, Thomas M | Weiner, George J | Smith, Martyn T | Holly, Elizabeth A | Jackson, Rebecca D | Tinker, Lesley F | Ye, Yuanqing | Adami, Hans-Olov | Smedby, Karin E | De Roos, Anneclaire J | Hartge, Patricia | Morton, Lindsay M | Severson, Richard K | Benavente, Yolanda | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | McKay, James | Staines, Anthony | Diver, W Ryan | Vajdic, Claire M | Armstrong, Bruce K | Kricker, Anne | Zheng, Tongzhang | Holford, Theodore R | Severi, Gianluca | Vineis, Paolo | Ferri, Giovanni M | Ricco, Rosalia | Miligi, Lucia | Clavel, Jacqueline | Giovannucci, Edward | Kraft, Peter | Virtamo, Jarmo | Smith, Alex | Kane, Eleanor | Roman, Eve | Chiu, Brian C H | Fraumeni, Joseph F | Wu, Xifeng | Cerhan, James R | Offit, Kenneth | Chanock, Stephen J | Rothman, Nathaniel | Nieters, Alexandra
Nature communications  2015;6:5751.
Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P=3.95×10−15) and HLA-B (rs2922994, P=2.43×10−9) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility.
doi:10.1038/ncomms6751
PMCID: PMC4287989  PMID: 25569183
3.  Genetic risk variants associated with in situ breast cancer 
Introduction
Breast cancer in situ (BCIS) diagnoses, a precursor lesion for invasive breast cancer, comprise about 20 % of all breast cancers (BC) in countries with screening programs. Family history of BC is considered one of the strongest risk factors for BCIS.
Methods
To evaluate the association of BC susceptibility loci with BCIS risk, we genotyped 39 single nucleotide polymorphisms (SNPs), associated with risk of invasive BC, in 1317 BCIS cases, 10,645 invasive BC cases, and 14,006 healthy controls in the National Cancer Institute’s Breast and Prostate Cancer Cohort Consortium (BPC3). Using unconditional logistic regression models adjusted for age and study, we estimated the association of SNPs with BCIS using two different comparison groups: healthy controls and invasive BC subjects to investigate whether BCIS and BC share a common genetic profile.
Results
We found that five SNPs (CDKN2BAS-rs1011970, FGFR2-rs3750817, FGFR2-rs2981582, TNRC9-rs3803662, 5p12-rs10941679) were significantly associated with BCIS risk (P value adjusted for multiple comparisons <0.0016). Comparing invasive BC and BCIS, the largest difference was for CDKN2BAS-rs1011970, which showed a positive association with BCIS (OR = 1.24, 95 % CI: 1.11–1.38, P = 1.27 x 10−4) and no association with invasive BC (OR = 1.03, 95 % CI: 0.99–1.07, P = 0.06), with a P value for case-case comparison of 0.006. Subgroup analyses investigating associations with ductal carcinoma in situ (DCIS) found similar associations, albeit less significant (OR = 1.25, 95 % CI: 1.09–1.42, P = 1.07 x 10−3). Additional risk analyses showed significant associations with invasive disease at the 0.05 level for 28 of the alleles and the OR estimates were consistent with those reported by other studies.
Conclusions
Our study adds to the knowledge that several of the known BC susceptibility loci are risk factors for both BCIS and invasive BC, with the possible exception of rs1011970, a putatively functional SNP situated in the CDKN2BAS gene that may be a specific BCIS susceptibility locus.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-015-0596-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-015-0596-x
PMCID: PMC4487950  PMID: 26070784
4.  Physical Activity and Risk of Endometrial Adenocarcinoma in the Nurses’ Health Study 
Studies suggest greater physical activity may reduce endometrial cancer risk. However, the role of the timing, duration, and intensity of activity is unclear. We therefore examined recent and past recreational activities in relation to incident endometrial adenocarcinoma, and compared the importance of total and moderate- or vigorous-intensity activities, as well as walking. We analyzed data from 71,570 women in the Nurses’ Health Study, a prospective cohort that assessed activity in 1986, with updates every 2–4 years. Cox proportional hazards models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs). During follow-up from 1986–2008 (1.2 million person-years), 777 invasive endometrial adenocarcinoma cases were documented. In multivariable models, compared with <3 MET-hrs/wk (<1 hr/wk walking), women engaged in moderate (9–<18 MET-hrs/wk: RR=0.61, 95% CI: 0.48–0.78) or high (≥27 MET-hrs/wk: RR=0.73, 95% CI: 0.58–0.92) amounts of recent total recreational activity were at reduced risk (P-trend=0.001). Past total activity was unassociated with risk. Greater recent moderate- or vigorous-intensity activity was associated with reduced risk (≥4 vs 0 hrs/wk: RR=0.65, 95% CI: 0.47–0.88, P-trend=0.002). Among women who did not perform any vigorous activity, recent walking was associated with reduced risk (≥3 vs <0.5 hrs/wk: RR=0.65, 95% CI: 0.45–0.93, P-trend=0.01), and faster walking pace was independently associated with risk reduction. After additional adjustment for body mass index, all associations were statistically non-significant. Greater recent physical activity may reduce endometrial adenocarcinoma risk, including activity of moderate duration and intensity such as walking. This relation is largely mediated or confounded by body mass index.
doi:10.1002/ijc.28599
PMCID: PMC3960316  PMID: 24213924
physical activity; exercise; endometrial cancer; endometrial adenocarcinoma; prospective study
5.  Prostate Cancer (PCa) Risk Variants and Risk of Fatal PCa in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium 
European urology  2014;65(6):1069-1075.
Background
Screening and diagnosis of prostate cancer (PCa) is hampered by an inability to predict who has the potential to develop fatal disease and who has indolent cancer. Studies have identified multiple genetic risk loci for PCa incidence, but it is unknown whether they could be used as biomarkers for PCa-specific mortality (PCSM).
Objective
To examine the association of 47 established PCa risk single-nucleotide polymorphisms (SNPs) with PCSM.
Design, setting, and participants
We included 10 487 men who had PCa and 11 024 controls, with a median follow-up of 8.3 yr, during which 1053 PCa deaths occurred.
Outcome measurements and statistical analysis
The main outcome was PCSM. The risk allele was defined as the allele associated with an increased risk for PCa in the literature. We used Cox proportional hazards regression to calculate the hazard ratios of each SNP with time to progression to PCSM after diagnosis. We also used logistic regression to calculate odds ratios for each risk SNP, comparing fatal PCa cases to controls.
Results and limitations
Among the cases, we found that 8 of the 47 SNPs were significantly associated (p < 0.05) with time to PCSM. The risk allele of rs11672691 (intergenic) was associated with an increased risk for PCSM, while 7 SNPs had risk alleles inversely associated (rs13385191 [C2orf43], rs17021918 [PDLIM5], rs10486567 [JAZF1], rs6465657 [LMTK2], rs7127900 (intergenic), rs2735839 [KLK3], rs10993994 [MSMB], rs13385191 [C2orf43]). In the case-control analysis, 22 SNPs were associated (p < 0.05) with the risk of fatal PCa, but most did not differentiate between fatal and nonfatal PCa. Rs11672691 and rs10993994 were associated with both fatal and nonfatal PCa, while rs6465657, rs7127900, rs2735839, and rs13385191 were associated with nonfatal PCa only.
Conclusions
Eight established risk loci were associated with progression to PCSM after diagnosis. Twenty-two SNPs were associated with fatal PCa incidence, but most did not differentiate between fatal and nonfatal PCa. The relatively small magnitudes of the associations do not translate well into risk prediction, but these findings merit further follow-up, because they may yield important clues about the complex biology of fatal PCa. Patient summary: In this report, we assessed whether established PCa risk variants could predict PCSM. We found eight risk variants associated with PCSM: One predicted an increased risk of PCSM, while seven were associated with decreased risk. Larger studies that focus on fatal PCa are needed to identify more markers that could aid prediction.
doi:10.1016/j.eururo.2013.12.058
PMCID: PMC4006298  PMID: 24411283
Prostate cancer; Risk single nucleotide polymorphisms; Prostate cancer mortality; Genetic epidemiology
6.  Insulin-like Growth Factor Pathway Genetic Polymorphisms, Circulating IGF1 and IGFBP3, and Prostate Cancer Survival 
Background
The insulin-like growth factor (IGF) signaling pathway has been implicated in prostate cancer (PCa) initiation, but its role in progression remains unknown.
Methods
Among 5887 PCa patients (704 PCa deaths) of European ancestry from seven cohorts in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium, we conducted Cox kernel machine pathway analysis to evaluate whether 530 tagging single nucleotide polymorphisms (SNPs) in 26 IGF pathway-related genes were collectively associated with PCa mortality. We also conducted SNP-specific analysis using stratified Cox models adjusting for multiple testing. In 2424 patients (313 PCa deaths), we evaluated the association of prediagnostic circulating IGF1 and IGFBP3 levels and PCa mortality. All statistical tests were two-sided.
Results
The IGF signaling pathway was associated with PCa mortality (P = .03), and IGF2-AS and SSTR2 were the main contributors (both P = .04). In SNP-specific analysis, 36 SNPs were associated with PCa mortality with P trend less than .05, but only three SNPs in the IGF2-AS remained statistically significant after gene-based corrections. Two were in linkage disequilibrium (r 2 = 1 for rs1004446 and rs3741211), whereas the third, rs4366464, was independent (r 2 = 0.03). The hazard ratios (HRs) per each additional risk allele were 1.19 (95% confidence interval [CI] = 1.06 to 1.34; P trend = .003) for rs3741211 and 1.44 (95% CI = 1.20 to 1.73; P trend < .001) for rs4366464. rs4366464 remained statistically significant after correction for all SNPs (P trend.corr = .04). Prediagnostic IGF1 (HRhighest vs lowest quartile = 0.71; 95% CI = 0.48 to 1.04) and IGFBP3 (HR = 0.93; 95% CI = 0.65 to 1.34) levels were not associated with PCa mortality.
Conclusions
The IGF signaling pathway, primarily IGF2-AS and SSTR2 genes, may be important in PCa survival.
doi:10.1093/jnci/dju085
PMCID: PMC4081624  PMID: 24824313
7.  A Genome-Wide Association Study Identifies Variants in Casein Kinase II (CSNK2A2) to be Associated with Leukocyte Telomere Length in a Punjabi Sikh Diabetic Cohort 
Background
Telomere length is a heritable trait and short telomere length has been associated with multiple chronic diseases. We investigated the relationship of relative leukocyte telomere length (RTL) with cardiometabolic risk and performed the first GWAS and meta-analysis to identify variants influencing RTL in a population of Sikhs from South Asia.
Methods and Results
Our results revealed a significant independent association of shorter RTL with type 2 diabetes (T2D) and heart disease. Our discovery GWAS (n=1,616) was followed by Stage 1 replication of 25 top signals (P<10−6) in an additional Sikhs (n=2,397). On combined discovery and Stage 1 meta-analysis (n= 4013), we identified a novel RTL locus at chromosome 16q21 represented by an intronic variant (rs74019828) in the CSNK2A2 gene (β −0.38, P=4.5×10−8). We further tested 3 top variants by genotyping in UKCVD (Caucasians n=2,952) for Stage 2. Next we performed in silico replication of 139 top signals (p<10−5) in UKTWIN, NHS, PLCO and MDACC (n=10,033) and joint meta-analysis (n=16,998). The observed signal in CSNK2A2 was confined to South Asians and could not be replicated in Caucasians due to significant difference in allele frequencies (P<0.001). CSNK2A2 phosphorylates TRF1 and plays an important role for regulation of telomere length homoeostasis.
Conclusions
By identification of a novel signal in telomere pathway genes, our study provides new molecular insight into the underlying mechanism that may regulate telomere length and its association with human aging and cardiometabolic pathophysiology.
doi:10.1161/CIRCGENETICS.113.000412
PMCID: PMC4106467  PMID: 24795349
telomere genetics; type 2 diabetes mellitus; Genome Wide Association Study; cardiovascular disease
8.  Multilocus Heterozygosity and Coronary Heart Disease: Nested Case-Control Studies in Men and Women 
PLoS ONE  2015;10(5):e0124847.
Background
Generalized allelic heterozygosity has been proposed to improve reproductive fitness and has been associated with higher blood pressure, but its association with chronic disease is not well characterized.
Methods
Using the Affymetrix Genome-Wide Human 6.0 array, we performed whole genome scans in parallel case-control studies of coronary heart disease (CHD) nested in the Health Professionals Follow-up Study and Nurses’ Health Study. We examined ~700,000 single nucleotide polymorphisms (SNPs) in 435 men with incident CHD and 878 matched controls and 435 women with incident CHD with 931 matched controls. We examined the relationship of genome-wide heterozygosity with risk of incident of CHD and with baseline levels of cardiovascular risk factors.
Results
In both cohorts, approximately 227650 (SD 2000) SNPs were heterozygous. The number of heterozygous SNPs was not related to risk of CHD in either men or women (adjusted odds ratios per 2000 heterozygous SNPs 1.01 [95% confidence interval, 0.91-1.13] in women and 0.94 [0.84-1.06] in men). We also found no consistent associations of genome-wide heterozygosity with levels of lipids, inflammatory markers, adhesion molecules, homocysteine, adiponectin, or body-mass index.
Conclusions
In these parallel nested case-control studies, we found no relationship of multilocus heterozygosity with risk of CHD or its major risk factors. Studies in other populations are needed to rule out associations with lower levels of heterozygosity.
doi:10.1371/journal.pone.0124847
PMCID: PMC4430477  PMID: 25970579
9.  Pleiotropic effects of genetic risk variants for other cancers on colorectal cancer risk: PAGE, GECCO, and CCFR Consortia 
Gut  2013;63(5):800-807.
Objective
Genome-wide association studies (GWAS) have identified a large number of single nucleotide polymorphisms (SNPs) associated with a wide array of cancer sites. Several of these variants demonstrate associations with multiple cancers, suggesting pleiotropic effects and shared biological mechanisms across some cancers. We hypothesized that SNPs previously associated with other cancers may additionally be associated with colorectal cancer. In a large-scale study, we examined 171 SNPs previously associated with 18 different cancers for their associations with colorectal cancer.
Design
We examined 13,338 colorectal cancer cases and 40,967 controls from three consortia: Population Architecture using Genetics and Epidemiology (PAGE), Genetic Epidemiology of Colorectal Cancer (GECCO), and the Colon Cancer Family Registry (CCFR). Study-specific logistic regression results, adjusted for age, sex, principal components of genetic ancestry, and/or study specific factors (as relevant) were combined using fixed-effect meta-analyses to evaluate the association between each SNP and colorectal cancer risk. A Bonferroni-corrected p-value of 2.92×10−4 was used to determine statistical significance of the associations.
Results
Two correlated SNPs— rs10090154 and rs4242382—in Region 1 of chromosome 8q24, a prostate cancer susceptibility region, demonstrated statistically significant associations with colorectal cancer risk. The most significant association was observed with rs4242382 (meta-analysis OR=1.12; 95% CI: 1.07–1.18; P=1.74×10−5), which also demonstrated similar associations across racial/ethnic populations and anatomical sub-sites.
Conclusion
This is the first study to clearly demonstrate Region 1 of chromosome 8q24 as a susceptibility locus for colorectal cancer, thus adding colorectal cancer to the list of cancer sites linked to this particular multi-cancer risk region at 8q24.
doi:10.1136/gutjnl-2013-305189
PMCID: PMC3918490  PMID: 23935004
colorectal cancer; pleiotropy; genome-wide association study; single nucleotide polymorphism
10.  Methodological challenges in Mendelian randomization 
Epidemiology (Cambridge, Mass.)  2014;25(3):427-435.
We give critical attention to the assumptions underlying Mendelian randomization analysis and their biological plausibility. Several scenarios violating the Mendelian randomization assumptions are described, including settings with inadequate phenotype definition, the setting of time-varying exposures, the presence of gene-environment interaction, the existence of measurement error, the possibility of reverse causation, and the presence of linkage disequilibrium. Data analysis examples are given illustrating that the inappropriate use of instrumental variable techniques when the Mendelian randomization assumptions are violated can lead to biases of enormous magnitude. To help address some of the strong assumptions being made, three possible approaches are suggested. First, the original proposal of Katan (Lancet. 1986; 1:507-508) for Mendelian randomization was not to use instrumental variable techniques to obtain estimates, but merely to examine genotype-outcome associations to test for the presence of an effect of the exposure on the outcome. We show that this more modest goal and approach can circumvent many, though not all of, the potential biases described. Second, we discuss the use of sensitivity analysis in evaluating the consequences of violations in the assumptions and attempts to correct for those violations. Third, we suggest that a focus on negative, rather than positive, Mendelian randomization results may turn out to be more reliable.
doi:10.1097/EDE.0000000000000081
PMCID: PMC3981897  PMID: 24681576
11.  Insulin-like Growth Factor Pathway Genetic Polymorphisms, Circulating IGF1 and IGFBP3, and Prostate Cancer Survival 
Background
The insulin-like growth factor (IGF) signaling pathway has been implicated in prostate cancer (PCa) initiation, but its role in progression remains unknown.
Methods
Among 5887 PCa patients (704 PCa deaths) of European ancestry from seven cohorts in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium, we conducted Cox kernel machine pathway analysis to evaluate whether 530 tagging single nucleotide polymorphisms (SNPs) in 26 IGF pathway-related genes were collectively associated with PCa mortality. We also conducted SNP-specific analysis using stratified Cox models adjusting for multiple testing. In 2424 patients (313 PCa deaths), we evaluated the association of prediagnostic circulating IGF1 and IGFBP3 levels and PCa mortality. All statistical tests were two-sided.
Results
The IGF signaling pathway was associated with PCa mortality (P = .03), and IGF2-AS and SSTR2 were the main contributors (both P = .04). In SNP-specific analysis, 36 SNPs were associated with PCa mortality with P trend less than .05, but only three SNPs in the IGF2-AS remained statistically significant after gene-based corrections. Two were in linkage disequilibrium (r 2 = 1 for rs1004446 and rs3741211), whereas the third, rs4366464, was independent (r 2 = 0.03). The hazard ratios (HRs) per each additional risk allele were 1.19 (95% confidence interval [CI] = 1.06 to 1.34; P trend = .003) for rs3741211 and 1.44 (95% CI = 1.20 to 1.73; P trend < .001) for rs4366464. rs4366464 remained statistically significant after correction for all SNPs (P trend.corr = .04). Prediagnostic IGF1 (HRhighest vs lowest quartile = 0.71; 95% CI = 0.48 to 1.04) and IGFBP3 (HR = 0.93; 95% CI = 0.65 to 1.34) levels were not associated with PCa mortality.
Conclusions
The IGF signaling pathway, primarily IGF2-AS and SSTR2 genes, may be important in PCa survival.
doi:10.1093/jnci/dju218
PMCID: PMC4111284
12.  Genome-wide association study identifies multiple susceptibility loci for diffuse large B-cell lymphoma 
Cerhan, James R | Berndt, Sonja I | Vijai, Joseph | Ghesquières, Hervé | McKay, James | Wang, Sophia S | Wang, Zhaoming | Yeager, Meredith | Conde, Lucia | de Bakker, Paul I W | Nieters, Alexandra | Cox, David | Burdett, Laurie | Monnereau, Alain | Flowers, Christopher R | De Roos, Anneclaire J | Brooks-Wilson, Angela R | Lan, Qing | Severi, Gianluca | Melbye, Mads | Gu, Jian | Jackson, Rebecca D | Kane, Eleanor | Teras, Lauren R | Purdue, Mark P | Vajdic, Claire M | Spinelli, John J | Giles, Graham G | Albanes, Demetrius | Kelly, Rachel S | Zucca, Mariagrazia | Bertrand, Kimberly A | Zeleniuch-Jacquotte, Anne | Lawrence, Charles | Hutchinson, Amy | Zhi, Degui | Habermann, Thomas M | Link, Brian K | Novak, Anne J | Dogan, Ahmet | Asmann, Yan W | Liebow, Mark | Thompson, Carrie A | Ansell, Stephen M | Witzig, Thomas E | Weiner, George J | Veron, Amelie S | Zelenika, Diana | Tilly, Hervé | Haioun, Corinne | Molina, Thierry Jo | Hjalgrim, Henrik | Glimelius, Bengt | Adami, Hans-Olov | Bracci, Paige M | Riby, Jacques | Smith, Martyn T | Holly, Elizabeth A | Cozen, Wendy | Hartge, Patricia | Morton, Lindsay M | Severson, Richard K | Tinker, Lesley F | North, Kari E | Becker, Nikolaus | Benavente, Yolanda | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | Staines, Anthony | Lightfoot, Tracy | Crouch, Simon | Smith, Alex | Roman, Eve | Diver, W Ryan | Offit, Kenneth | Zelenetz, Andrew | Klein, Robert J | Villano, Danylo J | Zheng, Tongzhang | Zhang, Yawei | Holford, Theodore R | Kricker, Anne | Turner, Jenny | Southey, Melissa C | Clavel, Jacqueline | Virtamo, Jarmo | Weinstein, Stephanie | Riboli, Elio | Vineis, Paolo | Kaaks, Rudolph | Trichopoulos, Dimitrios | Vermeulen, Roel C H | Boeing, Heiner | Tjonneland, Anne | Angelucci, Emanuele | Di Lollo, Simonetta | Rais, Marco | Birmann, Brenda M | Laden, Francine | Giovannucci, Edward | Kraft, Peter | Huang, Jinyan | Ma, Baoshan | Ye, Yuanqing | Chiu, Brian C H | Sampson, Joshua | Liang, Liming | Park, Ju-Hyun | Chung, Charles C | Weisenburger, Dennis D | Chatterjee, Nilanjan | Fraumeni, Joseph F | Slager, Susan L | Wu, Xifeng | de Sanjose, Silvia | Smedby, Karin E | Salles, Gilles | Skibola, Christine F | Rothman, Nathaniel | Chanock, Stephen J
Nature genetics  2014;46(11):1233-1238.
doi:10.1038/ng.3105
PMCID: PMC4213349  PMID: 25261932
13.  Genome-wide association study identifies multiple loci associated with both mammographic density and breast cancer risk 
Nature communications  2014;5:5303.
Mammographic density reflects the amount of stromal and epithelial tissues in relation to adipose tissue in the breast and is a strong risk factor for breast cancer. Here we report the results from meta-analysis of genome-wide association studies (GWAS) of three mammographic density phenotypes: dense area, non-dense area and percent density in up to 7,916 women in stage 1 and an additional 10,379 women in stage 2. We identify genome-wide significant (P<5×10−8) loci for dense area (AREG, ESR1, ZNF365, LSP1/TNNT3, IGF1, TMEM184B, SGSM3/MKL1), non-dense area (8p11.23) and percent density (PRDM6, 8p11.23, TMEM184B). Four of these regions are known breast cancer susceptibility loci, and four additional regions were found to be associated with breast cancer (P<0.05) in a large meta-analysis. These results provide further evidence of a shared genetic basis between mammographic density and breast cancer and illustrate the power of studying intermediate quantitative phenotypes to identify putative disease susceptibility loci.
doi:10.1038/ncomms6303
PMCID: PMC4320806  PMID: 25342443
14.  Common germline polymorphisms associated with breast cancer-specific survival 
Pirie, Ailith | Guo, Qi | Kraft, Peter | Canisius, Sander | Eccles, Diana M | Rahman, Nazneen | Nevanlinna, Heli | Chen, Constance | Khan, Sofia | Tyrer, Jonathan | Bolla, Manjeet K | Wang, Qin | Dennis, Joe | Michailidou, Kyriaki | Lush, Michael | Dunning, Alison M | Shah, Mitul | Czene, Kamila | Darabi, Hatef | Eriksson, Mikael | Lambrechts, Dieter | Weltens, Caroline | Leunen, Karin | van Ongeval, Chantal | Nordestgaard, Børge G | Nielsen, Sune F | Flyger, Henrik | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Blomqvist, Carl | Aittomäki, Kristiina | Fagerholm, Rainer | Muranen, Taru A | Olsen, Janet E | Hallberg, Emily | Vachon, Celine | Knight, Julia A | Glendon, Gord | Mulligan, Anna Marie | Broeks, Annegien | Cornelissen, Sten | Haiman, Christopher A | Henderson, Brian E | Schumacher, Frederick | Le Marchand, Loic | Hopper, John L | Tsimiklis, Helen | Apicella, Carmel | Southey, Melissa C | Cross, Simon S | Reed, Malcolm WR | Giles, Graham G | Milne, Roger L | McLean, Catriona | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Hooning, Maartje J | Hollestelle, Antoinette | Martens, John WM | van den Ouweland, Ans MW | Marme, Federick | Schneeweiss, Andreas | Yang, Rongxi | Burwinkel, Barbara | Figueroa, Jonine | Chanock, Stephen J | Lissowska, Jolanta | Sawyer, Elinor J | Tomlinson, Ian | Kerin, Michael J | Miller, Nicola | Brenner, Hermann | Butterbach, Katja | Holleczek, Bernd | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Li, Jingmei | Brand, Judith S | Humphreys, Keith | Devilee, Peter | Tollenaar, Robert AEM | Seynaeve, Caroline | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Ficarazzi, Filomena | Beckmann, Matthias W | Hein, Alexander | Ekici, Arif B | Balleine, Rosemary | Phillips, Kelly-Anne | Benitez, Javier | Zamora, M Pilar | Perez, Jose Ignacio Arias | Menéndez, Primitiva | Jakubowska, Anna | Lubinski, Jan | Gronwald, Jacek | Durda, Katarzyna | Hamann, Ute | Kabisch, Maria | Ulmer, Hans Ulrich | Rüdiger, Thomas | Margolin, Sara | Kristensen, Vessela | Nord, Siljie | Evans, D Gareth | Abraham, Jean | Earl, Helena | Poole, Christopher J | Hiller, Louise | Dunn, Janet A | Bowden, Sarah | Yang, Rose | Campa, Daniele | Diver, W Ryan | Gapstur, Susan M | Gaudet, Mia M | Hankinson, Susan | Hoover, Robert N | Hüsing, Anika | Kaaks, Rudolf | Machiela, Mitchell J | Willett, Walter | Barrdahl, Myrto | Canzian, Federico | Chin, Suet-Feung | Caldas, Carlos | Hunter, David J | Lindstrom, Sara | Garcia-Closas, Montserrat | Couch, Fergus J | Chenevix-Trench, Georgia | Mannermaa, Arto | Andrulis, Irene L | Hall, Per | Chang-Claude, Jenny | Easton, Douglas F | Bojesen, Stig E | Cox, Angela | Fasching, Peter A | Pharoah, Paul DP | Schmidt, Marjanka K
Introduction
Previous studies have identified common germline variants nominally associated with breast cancer survival. These associations have not been widely replicated in further studies. The purpose of this study was to evaluate the association of previously reported SNPs with breast cancer-specific survival using data from a pooled analysis of eight breast cancer survival genome-wide association studies (GWAS) from the Breast Cancer Association Consortium.
Methods
A literature review was conducted of all previously published associations between common germline variants and three survival outcomes: breast cancer-specific survival, overall survival and disease-free survival. All associations that reached the nominal significance level of P value <0.05 were included. Single nucleotide polymorphisms that had been previously reported as nominally associated with at least one survival outcome were evaluated in the pooled analysis of over 37,000 breast cancer cases for association with breast cancer-specific survival. Previous associations were evaluated using a one-sided test based on the reported direction of effect.
Results
Fifty-six variants from 45 previous publications were evaluated in the meta-analysis. Fifty-four of these were evaluated in the full set of 37,954 breast cancer cases with 2,900 events and the two additional variants were evaluated in a reduced sample size of 30,000 samples in order to ensure independence from the previously published studies. Five variants reached nominal significance (P <0.05) in the pooled GWAS data compared to 2.8 expected under the null hypothesis. Seven additional variants were associated (P <0.05) with ER-positive disease.
Conclusions
Although no variants reached genome-wide significance (P <5 x 10−8), these results suggest that there is some evidence of association between candidate common germline variants and breast cancer prognosis. Larger studies from multinational collaborations are necessary to increase the power to detect associations, between common variants and prognosis, at more stringent significance levels.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-015-0570-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-015-0570-7
PMCID: PMC4484708  PMID: 25897948
15.  Genome-Wide Association Study of Breast Cancer in Latinas Identifies Novel Protective Variants on 6q25 
Nature communications  2014;5:5260.
The genetic contributions to breast cancer development among Latinas are not well understood. Here, we carry out a genome-wide association study of breast cancer in Latinas and identify a genome-wide significant risk variant, located 5’ of the Estrogen Receptor 1 gene (ESR1) (6q25 region). The minor allele for this variant is strongly protective (rs140068132: OR 0.60, 95%CI 0.53-0.67, P=9×10−18), originates from Indigenous Americans, and is uncorrelated with previously reported risk variants at 6q25. The association is stronger for estrogen receptor negative disease (OR 0.34 95% CI 0.21-0.54) than estrogen receptor positive disease (OR 0.63 95% CI 0.49-0.80) (P heterogeneity=0.01) and is also associated with mammographic breast density, a strong risk factor for breast cancer (P=0.001). rs140068132 is located within several transcription factor binding sites and electrophoretic mobility shift assays with MCF-7 nuclear protein demonstrate differential binding of the G/A alleles at this locus. These results highlight the importance of conducting research in diverse populations.
doi:10.1038/ncomms6260
PMCID: PMC4204111  PMID: 25327703
16.  The 19q12 bladder cancer GWAS signal: association with cyclin E function and aggressive disease 
Fu, Yi-Ping | Kohaar, Indu | Moore, Lee E. | Lenz, Petra | Figueroa, Jonine D. | Tang, Wei | Porter-Gill, Patricia | Chatterjee, Nilanjan | Scott-Johnson, Alexandra | Garcia-Closas, Montserrat | Muchmore, Brian | Baris, Dalsu | Paquin, Ashley | Ylaya, Kris | Schwenn, Molly | Apolo, Andrea B. | Karagas, Margaret R. | Tarway, McAnthony | Johnson, Alison | Mumy, Adam | Schned, Alan | Guedez, Liliana | Jones, Michael A. | Kida, Masatoshi | Monawar Hosain, GM | Malats, Nuria | Kogevinas, Manolis | Tardon, Adonina | Serra, Consol | Carrato, Alfredo | Garcia-Closas, Reina | Lloreta, Josep | Wu, Xifeng | Purdue, Mark | Andriole, Gerald L. | Grubb, Robert L. | Black, Amanda | Landi, Maria T. | Caporaso, Neil E. | Vineis, Paolo | Siddiq, Afshan | Bueno-de-Mesquita, H. Bas | Trichopoulos, Dimitrios | Ljungberg, Börje | Severi, Gianluca | Weiderpass, Elisabete | Krogh, Vittorio | Dorronsoro, Miren | Travis, Ruth C. | Tjønneland, Anne | Brennan, Paul | Chang-Claude, Jenny | Riboli, Elio | Prescott, Jennifer | Chen, Constance | De Vivo, Immaculata | Govannucci, Edward | Hunter, David | Kraft, Peter | Lindstrom, Sara | Gapstur, Susan M. | Jacobs, Eric J. | Diver, W. Ryan | Albanes, Demetrius | Weinstein, Stephanie J. | Virtamo, Jarmo | Kooperberg, Charles | Hohensee, Chancellor | Rodabough, Rebecca J. | Cortessis, Victoria K. | Conti, David V. | Gago-Dominguez, Manuela | Stern, Mariana C. | Pike, Malcolm C. | Van Den Berg, David | Yuan, Jian-Min | Haiman, Christopher A. | Cussenot, Olivier | Cancel-Tassin, Geraldine | Roupret, Morgan | Comperat, Eva | Porru, Stefano | Carta, Angela | Pavanello, Sofia | Arici, Cecilia | Mastrangelo, Giuseppe | Grossman, H. Barton | Wang, Zhaoming | Deng, Xiang | Chung, Charles C. | Hutchinson, Amy | Burdette, Laurie | Wheeler, William | Fraumeni, Joseph | Chanock, Stephen J. | Hewitt, Stephen M. | Silverman, Debra T. | Rothman, Nathaniel | Prokunina-Olsson, Ludmila
Cancer research  2014;74(20):5808-5818.
A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell cycle protein. We performed genetic fine mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r2≥0.7) associated with increased bladder cancer risk. From this group we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWAS, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele odds ratio (OR) =1.18 (95%CI=1.09-1.27, p=4.67×10−5 vs. OR =1.01 (95%CI=0.93-1.10, p=0.79) for non-aggressive disease, with p=0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (p=0.013) and, independently, with each rs7257330-A risk allele (ptrend=0.024). Over-expression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E over-expression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models.
doi:10.1158/0008-5472.CAN-14-1531
PMCID: PMC4203382  PMID: 25320178
Aggressive bladder cancer; cyclin E; cell cycle; single nucleotide polymorphism; GWAS
17.  Parent-of-origin specific allelic associations among 106 genomic loci for age at menarche 
Perry, John RB | Day, Felix | Elks, Cathy E | Sulem, Patrick | Thompson, Deborah J | Ferreira, Teresa | He, Chunyan | Chasman, Daniel I | Esko, Tõnu | Thorleifsson, Gudmar | Albrecht, Eva | Ang, Wei Q | Corre, Tanguy | Cousminer, Diana L | Feenstra, Bjarke | Franceschini, Nora | Ganna, Andrea | Johnson, Andrew D | Kjellqvist, Sanela | Lunetta, Kathryn L | McMahon, George | Nolte, Ilja M | Paternoster, Lavinia | Porcu, Eleonora | Smith, Albert V | Stolk, Lisette | Teumer, Alexander | Tšernikova, Natalia | Tikkanen, Emmi | Ulivi, Sheila | Wagner, Erin K | Amin, Najaf | Bierut, Laura J | Byrne, Enda M | Hottenga, Jouke-Jan | Koller, Daniel L | Mangino, Massimo | Pers, Tune H | Yerges-Armstrong, Laura M | Zhao, Jing Hua | Andrulis, Irene L | Anton-Culver, Hoda | Atsma, Femke | Bandinelli, Stefania | Beckmann, Matthias W | Benitez, Javier | Blomqvist, Carl | Bojesen, Stig E | Bolla, Manjeet K | Bonanni, Bernardo | Brauch, Hiltrud | Brenner, Hermann | Buring, Julie E | Chang-Claude, Jenny | Chanock, Stephen | Chen, Jinhui | Chenevix-Trench, Georgia | Collée, J. Margriet | Couch, Fergus J | Couper, David | Coveillo, Andrea D | Cox, Angela | Czene, Kamila | D’adamo, Adamo Pio | Smith, George Davey | De Vivo, Immaculata | Demerath, Ellen W | Dennis, Joe | Devilee, Peter | Dieffenbach, Aida K | Dunning, Alison M | Eiriksdottir, Gudny | Eriksson, Johan G | Fasching, Peter A | Ferrucci, Luigi | Flesch-Janys, Dieter | Flyger, Henrik | Foroud, Tatiana | Franke, Lude | Garcia, Melissa E | García-Closas, Montserrat | Geller, Frank | de Geus, Eco EJ | Giles, Graham G | Gudbjartsson, Daniel F | Gudnason, Vilmundur | Guénel, Pascal | Guo, Suiqun | Hall, Per | Hamann, Ute | Haring, Robin | Hartman, Catharina A | Heath, Andrew C | Hofman, Albert | Hooning, Maartje J | Hopper, John L | Hu, Frank B | Hunter, David J | Karasik, David | Kiel, Douglas P | Knight, Julia A | Kosma, Veli-Matti | Kutalik, Zoltan | Lai, Sandra | Lambrechts, Diether | Lindblom, Annika | Mägi, Reedik | Magnusson, Patrik K | Mannermaa, Arto | Martin, Nicholas G | Masson, Gisli | McArdle, Patrick F | McArdle, Wendy L | Melbye, Mads | Michailidou, Kyriaki | Mihailov, Evelin | Milani, Lili | Milne, Roger L | Nevanlinna, Heli | Neven, Patrick | Nohr, Ellen A | Oldehinkel, Albertine J | Oostra, Ben A | Palotie, Aarno | Peacock, Munro | Pedersen, Nancy L | Peterlongo, Paolo | Peto, Julian | Pharoah, Paul DP | Postma, Dirkje S | Pouta, Anneli | Pylkäs, Katri | Radice, Paolo | Ring, Susan | Rivadeneira, Fernando | Robino, Antonietta | Rose, Lynda M | Rudolph, Anja | Salomaa, Veikko | Sanna, Serena | Schlessinger, David | Schmidt, Marjanka K | Southey, Mellissa C | Sovio, Ulla | Stampfer, Meir J | Stöckl, Doris | Storniolo, Anna M | Timpson, Nicholas J | Tyrer, Jonathan | Visser, Jenny A | Vollenweider, Peter | Völzke, Henry | Waeber, Gerard | Waldenberger, Melanie | Wallaschofski, Henri | Wang, Qin | Willemsen, Gonneke | Winqvist, Robert | Wolffenbuttel, Bruce HR | Wright, Margaret J | Boomsma, Dorret I | Econs, Michael J | Khaw, Kay-Tee | Loos, Ruth JF | McCarthy, Mark I | Montgomery, Grant W | Rice, John P | Streeten, Elizabeth A | Thorsteinsdottir, Unnur | van Duijn, Cornelia M | Alizadeh, Behrooz Z | Bergmann, Sven | Boerwinkle, Eric | Boyd, Heather A | Crisponi, Laura | Gasparini, Paolo | Gieger, Christian | Harris, Tamara B | Ingelsson, Erik | Järvelin, Marjo-Riitta | Kraft, Peter | Lawlor, Debbie | Metspalu, Andres | Pennell, Craig E | Ridker, Paul M | Snieder, Harold | Sørensen, Thorkild IA | Spector, Tim D | Strachan, David P | Uitterlinden, André G | Wareham, Nicholas J | Widen, Elisabeth | Zygmunt, Marek | Murray, Anna | Easton, Douglas F | Stefansson, Kari | Murabito, Joanne M | Ong, Ken K
Nature  2014;514(7520):92-97.
Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality1. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation2,3, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P<5×10−8) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1/WDR25, MKRN3/MAGEL2 and KCNK9) demonstrating parent-of-origin specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signaling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.
doi:10.1038/nature13545
PMCID: PMC4185210  PMID: 25231870
18.  A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer 
Al Olama, Ali Amin | Kote-Jarai, Zsofia | Berndt, Sonja I. | Conti, David V. | Schumacher, Fredrick | Han, Ying | Benlloch, Sara | Hazelett, Dennis J. | Wang, Zhaoming | Saunders, Ed | Leongamornlert, Daniel | Lindstrom, Sara | Jugurnauth-Little, Sara | Dadaev, Tokhir | Tymrakiewicz, Malgorzata | Stram, Daniel O. | Rand, Kristin | Wan, Peggy | Stram, Alex | Sheng, Xin | Pooler, Loreall C. | Park, Karen | Xia, Lucy | Tyrer, Jonathan | Kolonel, Laurence N. | Le Marchand, Loic | Hoover, Robert N. | Machiela, Mitchell J. | Yeager, Merideth | Burdette, Laurie | Chung, Charles C. | Hutchinson, Amy | Yu, Kai | Goh, Chee | Ahmed, Mahbubl | Govindasami, Koveela | Guy, Michelle | Tammela, Teuvo L.J. | Auvinen, Anssi | Wahlfors, Tiina | Schleutker, Johanna | Visakorpi, Tapio | Leinonen, Katri A. | Xu, Jianfeng | Aly, Markus | Donovan, Jenny | Travis, Ruth C. | Key, Tim J. | Siddiq, Afshan | Canzian, Federico | Khaw, Kay-Tee | Takahashi, Atsushi | Kubo, Michiaki | Pharoah, Paul | Pashayan, Nora | Weischer, Maren | Nordestgaard, Borge G. | Nielsen, Sune F. | Klarskov, Peter | Røder, Martin Andreas | Iversen, Peter | Thibodeau, Stephen N. | McDonnell, Shannon K | Schaid, Daniel J | Stanford, Janet L. | Kolb, Suzanne | Holt, Sarah | Knudsen, Beatrice | Coll, Antonio Hurtado | Gapstur, Susan M. | Diver, W. Ryan | Stevens, Victoria L. | Maier, Christiane | Luedeke, Manuel | Herkommer, Kathleen | Rinckleb, Antje E. | Strom, Sara S. | Pettaway, Curtis | Yeboah, Edward D. | Tettey, Yao | Biritwum, Richard B. | Adjei, Andrew A. | Tay, Evelyn | Truelove, Ann | Niwa, Shelley | Chokkalingam, Anand P. | Cannon-Albright, Lisa | Cybulski, Cezary | Wokołorczyk, Dominika | Kluźniak, Wojciech | Park, Jong | Sellers, Thomas | Lin, Hui-Yi | Isaacs, William B. | Partin, Alan W. | Brenner, Hermann | Dieffenbach, Aida Karina | Stegmaier, Christa | Chen, Constance | Giovannucci, Edward L. | Ma, Jing | Stampfer, Meir | Penney, Kathryn L. | Mucci, Lorelei | John, Esther M. | Ingles, Sue A. | Kittles, Rick A. | Murphy, Adam B. | Pandha, Hardev | Michael, Agnieszka | Kierzek, Andrzej M. | Blot, William | Signorello, Lisa B. | Zheng, Wei | Albanes, Demetrius | Virtamo, Jarmo | Weinstein, Stephanie | Nemesure, Barbara | Carpten, John | Leske, Cristina | Wu, Suh-Yuh | Hennis, Anselm | Kibel, Adam S. | Rybicki, Benjamin A. | Neslund-Dudas, Christine | Hsing, Ann W. | Chu, Lisa | Goodman, Phyllis J. | Klein, Eric A | Zheng, S. Lilly | Batra, Jyotsna | Clements, Judith | Spurdle, Amanda | Teixeira, Manuel R. | Paulo, Paula | Maia, Sofia | Slavov, Chavdar | Kaneva, Radka | Mitev, Vanio | Witte, John S. | Casey, Graham | Gillanders, Elizabeth M. | Seminara, Daniella | Riboli, Elio | Hamdy, Freddie C. | Coetzee, Gerhard A. | Li, Qiyuan | Freedman, Matthew L. | Hunter, David J. | Muir, Kenneth | Gronberg, Henrik | Neal, David E. | Southey, Melissa | Giles, Graham G. | Severi, Gianluca | Cook, Michael B. | Nakagawa, Hidewaki | Wiklund, Fredrik | Kraft, Peter | Chanock, Stephen J. | Henderson, Brian E. | Easton, Douglas F. | Eeles, Rosalind A. | Haiman, Christopher A.
Nature genetics  2014;46(10):1103-1109.
Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of >10 million SNPs in 43,303prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three novel susceptibility loci were revealed at P<5×10-8; 15 variants were identified among men of European ancestry, 7 from multiethnic analyses and one was associated with early-onset prostate cancer. These 23 variants, in combination with the known prostate cancer risk variants, explain 33% of the familial risk of the disease in European ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the utility of combining ancestrally diverse populations to discover risk loci for disease.
doi:10.1038/ng.3094
PMCID: PMC4383163  PMID: 25217961
19.  Elevated circulating branched chain amino acids are an early event in pancreatic adenocarcinoma development 
Nature medicine  2014;20(10):1193-1198.
Most patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with advanced disease and survive less than 12 months1. PDAC has been linked with obesity and glucose intolerance2-4, but whether changes in circulating metabolites are associated with early cancer progression is unknown. To better understand metabolic derangements associated with early disease, we profiled metabolites in prediagnostic plasma from pancreatic cancer cases and matched controls from four prospective cohort studies. We find that elevated plasma levels of branched chain amino acids (BCAAs) are associated with a greater than 2–fold increased risk of future pancreatic cancer diagnosis. This elevated risk was independent of known predisposing factors, with the strongest association observed among subjects with samples collected 2 to 5 years prior to diagnosis when occult disease is likely present. We show that plasma BCAAs are also elevated in mice with early stage pancreatic cancers driven by mutant Kras expression, and that breakdown of tissue protein accounts for the increase in plasma BCAAs that accompanies early stage disease. Together, these findings suggest that increased whole–body protein breakdown is an early event in development of PDAC.
doi:10.1038/nm.3686
PMCID: PMC4191991  PMID: 25261994
20.  Genome-wide association study of breast cancer in Latinas identifies novel protective variants on 6q25 
Nature Communications  2014;5:5260.
The genetic contributions to breast cancer development among Latinas are not well understood. Here we carry out a genome-wide association study of breast cancer in Latinas and identify a genome-wide significant risk variant, located 5′ of the Estrogen Receptor 1 gene (ESR1; 6q25 region). The minor allele for this variant is strongly protective (rs140068132: odds ratio (OR) 0.60, 95% confidence interval (CI) 0.53–0.67, P=9 × 10−18), originates from Indigenous Americans and is uncorrelated with previously reported risk variants at 6q25. The association is stronger for oestrogen receptor-negative disease (OR 0.34, 95% CI 0.21–0.54) than oestrogen receptor-positive disease (OR 0.63, 95% CI 0.49–0.80; P heterogeneity=0.01) and is also associated with mammographic breast density, a strong risk factor for breast cancer (P=0.001). rs140068132 is located within several transcription factor-binding sites and electrophoretic mobility shift assays with MCF-7 nuclear protein demonstrate differential binding of the G/A alleles at this locus. These results highlight the importance of conducting research in diverse populations.
Genome-wide association studies (GWAS) have revealed gene variants associated with breast cancer, but their association with breast cancer development in Latinas is not clear. Here, the authors carry out a GWAS of breast cancer in Latinas and identify a significant protective variant of Indigenous American origin in the 6q25 region.
doi:10.1038/ncomms6260
PMCID: PMC4204111  PMID: 25327703
21.  Case-Control Study of Platelet Glycoprotein Receptor Ib and IIb/IIIa Expression in Patients with Acute and Chronic Cerebrovascular Disease 
PLoS ONE  2015;10(3):e0119810.
Background
Animal models have been instrumental in defining thrombus formation, including the role of platelet surface glycoprotein (GP) receptors, in acute ischemic stroke (AIS). However, the involvement of GP receptors in human ischemic stroke pathophysiology and their utility as biomarkers for ischemic stroke risk and severity requires elucidation.
Aims
To determine whether platelet GPIb and GPIIb/IIIa receptors are differentially expressed in patients with AIS and chronic cerebrovascular disease (CCD) compared with healthy volunteers (HV) and to identify predictors of GPIb and GPIIb/IIIa expression.
Methods
This was a case—control study of 116 patients with AIS or transient ischemic attack (TIA), 117 patients with CCD, and 104 HV who were enrolled at our University hospital from 2010 to 2013. Blood sampling was performed once in the CCD and HV groups, and at several time points in patients with AIS or TIA. Linear regression and analysis of variance were used to analyze correlations between platelet GPIb and GPIIb/IIIa receptor numbers and demographic and clinical parameters.
Results
GPIb and GPIIb/IIIa receptor numbers did not significantly differ between the AIS, CCD, and HV groups. GPIb receptor expression level correlated significantly with the magnitude of GPIIb/IIIa receptor expression and the neutrophil count. In contrast, GPIIb/IIIa receptor numbers were not associated with peripheral immune-cell sub-population counts. C-reactive protein was an independent predictor of GPIIb/IIIa (not GPIb) receptor numbers.
Conclusions
Platelet GPIb and GPIIb/IIIa receptor numbers did not distinguish between patient or control groups in this study, negating their potential use as a biomarker for predicting stroke risk.
doi:10.1371/journal.pone.0119810
PMCID: PMC4352011  PMID: 25748430
22.  Genome-wide association study identifies multiple loci associated with bladder cancer risk 
Figueroa, Jonine D. | Ye, Yuanqing | Siddiq, Afshan | Garcia-Closas, Montserrat | Chatterjee, Nilanjan | Prokunina-Olsson, Ludmila | Cortessis, Victoria K. | Kooperberg, Charles | Cussenot, Olivier | Benhamou, Simone | Prescott, Jennifer | Porru, Stefano | Dinney, Colin P. | Malats, Núria | Baris, Dalsu | Purdue, Mark | Jacobs, Eric J. | Albanes, Demetrius | Wang, Zhaoming | Deng, Xiang | Chung, Charles C. | Tang, Wei | Bas Bueno-de-Mesquita, H. | Trichopoulos, Dimitrios | Ljungberg, Börje | Clavel-Chapelon, Françoise | Weiderpass, Elisabete | Krogh, Vittorio | Dorronsoro, Miren | Travis, Ruth | Tjønneland, Anne | Brenan, Paul | Chang-Claude, Jenny | Riboli, Elio | Conti, David | Gago-Dominguez, Manuela | Stern, Mariana C. | Pike, Malcolm C. | Van Den Berg, David | Yuan, Jian-Min | Hohensee, Chancellor | Rodabough, Rebecca | Cancel-Tassin, Geraldine | Roupret, Morgan | Comperat, Eva | Chen, Constance | De Vivo, Immaculata | Giovannucci, Edward | Hunter, David J. | Kraft, Peter | Lindstrom, Sara | Carta, Angela | Pavanello, Sofia | Arici, Cecilia | Mastrangelo, Giuseppe | Kamat, Ashish M. | Lerner, Seth P. | Barton Grossman, H. | Lin, Jie | Gu, Jian | Pu, Xia | Hutchinson, Amy | Burdette, Laurie | Wheeler, William | Kogevinas, Manolis | Tardón, Adonina | Serra, Consol | Carrato, Alfredo | García-Closas, Reina | Lloreta, Josep | Schwenn, Molly | Karagas, Margaret R. | Johnson, Alison | Schned, Alan | Armenti, Karla R. | Hosain, G.M. | Andriole, Gerald | Grubb, Robert | Black, Amanda | Ryan Diver, W. | Gapstur, Susan M. | Weinstein, Stephanie J. | Virtamo, Jarmo | Haiman, Chris A. | Landi, Maria T. | Caporaso, Neil | Fraumeni, Joseph F. | Vineis, Paolo | Wu, Xifeng | Silverman, Debra T. | Chanock, Stephen | Rothman, Nathaniel
Human Molecular Genetics  2013;23(5):1387-1398.
Candidate gene and genome-wide association studies (GWAS) have identified 11 independent susceptibility loci associated with bladder cancer risk. To discover additional risk variants, we conducted a new GWAS of 2422 bladder cancer cases and 5751 controls, followed by a meta-analysis with two independently published bladder cancer GWAS, resulting in a combined analysis of 6911 cases and 11 814 controls of European descent. TaqMan genotyping of 13 promising single nucleotide polymorphisms with P < 1 × 10−5 was pursued in a follow-up set of 801 cases and 1307 controls. Two new loci achieved genome-wide statistical significance: rs10936599 on 3q26.2 (P = 4.53 × 10−9) and rs907611 on 11p15.5 (P = 4.11 × 10−8). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 × 10−7) and rs4510656 on 6p22.3 (P = 6.98 × 10−7); these require further studies for confirmation. In conclusion, our study has identified new susceptibility alleles for bladder cancer risk that require fine-mapping and laboratory investigation, which could further understanding into the biological underpinnings of bladder carcinogenesis.
doi:10.1093/hmg/ddt519
PMCID: PMC3919005  PMID: 24163127
23.  PREMENOPAUSAL PLASMA FERRITIN LEVELS, HFE POLYMORPHISMS, AND RISK OF BREAST CANCER IN THE NURSES’ HEALTH STUDY II 
Background
Evidence from the Nurses’ Health Study II (NHSII) suggests that red meat consumption is associated with increased breast cancer risk in premenopausal women. Iron may be responsible by contributing to oxidative stress or effects on immune function.
Methods
We conducted a case-control study nested within the NHSII examining prediagnostic plasma ferritin (n=795 cases, 795 controls), 15 hemochromatosis gene (HFE) SNPs (n=765 cases, 1,368 controls), and breast cancer risk. Cases were diagnosed after providing blood samples between 1996 and 1999. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for ferritin levels by conditional logistic regression and for HFE SNPs by unconditional logistic regression.
Results
We did not observe a significant association between ferritin levels and breast cancer (top vs. bottom quartile multivariate OR: 1.05, 95% CI: 0.77–1.45, P-value for trend: 0.77). Results did not change when restricted to women who were premenopausal at blood draw, and were similar when cases were examined by hormone receptor status and menopausal status at diagnosis. No HFE SNPs were significantly associated with breast cancer in a log-additive manner. Among controls, ferritin levels were nominally associated with SNPs rs9366637 (P-value for trend: 0.04), rs6918586 (P-value for trend: 0.06) and rs13161 (P-value for trend: 0.07), but results did not remain significant after adjusting for multiple testing.
Conclusions
Ferritin levels and HFE SNPs were not associated with breast cancer risk in this population.
Impact
Components of red meat other than iron are likely responsible for its positive association with breast cancer in premenopausal women.
doi:10.1158/1055-9965.EPI-13-0907
PMCID: PMC3951649  PMID: 24443403
plasma ferritin; HFE polymorphisms; breast cancer; biomarker; iron
24.  Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer 
Wolpin, Brian M. | Rizzato, Cosmeri | Kraft, Peter | Kooperberg, Charles | Petersen, Gloria M. | Wang, Zhaoming | Arslan, Alan A. | Beane-Freeman, Laura | Bracci, Paige M. | Buring, Julie | Canzian, Federico | Duell, Eric J. | Gallinger, Steven | Giles, Graham G. | Goodman, Gary E. | Goodman, Phyllis J. | Jacobs, Eric J. | Kamineni, Aruna | Klein, Alison P. | Kolonel, Laurence N. | Kulke, Matthew H. | Li, Donghui | Malats, Núria | Olson, Sara H. | Risch, Harvey A. | Sesso, Howard D. | Visvanathan, Kala | White, Emily | Zheng, Wei | Abnet, Christian C. | Albanes, Demetrius | Andreotti, Gabriella | Austin, Melissa A. | Barfield, Richard | Basso, Daniela | Berndt, Sonja I. | Boutron-Ruault, Marie-Christine | Brotzman, Michelle | Büchler, Markus W. | Bueno-de-Mesquita, H. Bas | Bugert, Peter | Burdette, Laurie | Campa, Daniele | Caporaso, Neil E. | Capurso, Gabriele | Chung, Charles | Cotterchio, Michelle | Costello, Eithne | Elena, Joanne | Funel, Niccola | Gaziano, J. Michael | Giese, Nathalia A. | Giovannucci, Edward L. | Goggins, Michael | Gorman, Megan J. | Gross, Myron | Haiman, Christopher A. | Hassan, Manal | Helzlsouer, Kathy J. | Henderson, Brian E. | Holly, Elizabeth A. | Hu, Nan | Hunter, David J. | Innocenti, Federico | Jenab, Mazda | Kaaks, Rudolf | Key, Timothy J. | Khaw, Kay-Tee | Klein, Eric A. | Kogevinas, Manolis | Krogh, Vittorio | Kupcinskas, Juozas | Kurtz, Robert C. | LaCroix, Andrea | Landi, Maria T. | Landi, Stefano | Le Marchand, Loic | Mambrini, Andrea | Mannisto, Satu | Milne, Roger L. | Nakamura, Yusuke | Oberg, Ann L. | Owzar, Kouros | Patel, Alpa V. | Peeters, Petra H. M. | Peters, Ulrike | Pezzilli, Raffaele | Piepoli, Ada | Porta, Miquel | Real, Francisco X. | Riboli, Elio | Rothman, Nathaniel | Scarpa, Aldo | Shu, Xiao-Ou | Silverman, Debra T. | Soucek, Pavel | Sund, Malin | Talar-Wojnarowska, Renata | Taylor, Philip R. | Theodoropoulos, George E. | Thornquist, Mark | Tjønneland, Anne | Tobias, Geoffrey S. | Trichopoulos, Dimitrios | Vodicka, Pavel | Wactawski-Wende, Jean | Wentzensen, Nicolas | Wu, Chen | Yu, Herbert | Yu, Kai | Zeleniuch-Jacquotte, Anne | Hoover, Robert | Hartge, Patricia | Fuchs, Charles | Chanock, Stephen J. | Stolzenberg-Solomon, Rachael S. | Amundadottir, Laufey T.
Nature genetics  2014;46(9):994-1000.
We performed a multistage genome-wide association study (GWAS) including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT; per-allele odds ratio [OR] = 0.79; 95% confidence interval [CI] = 0.74–0.84; P = 3.0×10−12), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2; OR = 1.46; 95% CI = 1.30–1.65; P = 1.1×10−10), rs9581943 at 13q12.2 (PDX1; OR = 1.15; 95% CI = 1.10–1.20; P = 2.4×10−9), and rs16986825 at 22q12.1 (ZNRF3; OR = 1.18; 95% CI = 1.12–1.25; P = 1.2×10−8). An independent signal was identified in exon 2 of TERT at the established region 5p15.33 (rs2736098; OR = 0.80; 95% CI = 0.76–0.85; P = 9.8×10−14). We also identified a locus at 8q24.21 (rs1561927; P = 1.3×10−7) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study has identified multiple new susceptibility alleles for pancreatic cancer worthy of follow-up studies.
doi:10.1038/ng.3052
PMCID: PMC4191666  PMID: 25086665
25.  Joint analysis of three genome-wide association studies of esophageal squamous cell carcinoma in Chinese populations 
Wu, Chen | Wang, Zhaoming | Song, Xin | Feng, Xiao-Shan | Abnet, Christian C. | He, Jie | Hu, Nan | Zuo, Xian-Bo | Tan, Wen | Zhan, Qimin | Hu, Zhibin | He, Zhonghu | Jia, Weihua | Zhou, Yifeng | Yu, Kai | Shu, Xiao-Ou | Yuan, Jian-Min | Zheng, Wei | Zhao, Xue-Ke | Gao, She-Gan | Yuan, Zhi-Qing | Zhou, Fu-You | Fan, Zong-Min | Cui, Ji-Li | Lin, Hong-Li | Han, Xue-Na | Li, Bei | Chen, Xi | Dawsey, Sanford M. | Liao, Linda | Lee, Maxwell P. | Ding, Ti | Qiao, You-Lin | Liu, Zhihua | Liu, Yu | Yu, Dianke | Chang, Jiang | Wei, Lixuan | Gao, Yu-Tang | Koh, Woon-Puay | Xiang, Yong-Bing | Tang, Ze-Zhong | Fan, Jin-Hu | Han, Jing-Jing | Zhou, Sheng-Li | Zhang, Peng | Zhang, Dong-Yun | Yuan, Yuan | Huang, Ying | Liu, Chunling | Zhai, Kan | Qiao, Yan | Jin, Guangfu | Guo, Chuanhai | Fu, Jianhua | Miao, Xiaoping | Lu, Changdong | Yang, Haijun | Wang, Chaoyu | Wheeler, William A. | Gail, Mitchell | Yeager, Meredith | Yuenger, Jeff | Guo, Er-Tao | Li, Ai-Li | Zhang, Wei | Li, Xue-Min | Sun, Liang-Dan | Ma, Bao-Gen | Li, Yan | Tang, Sa | Peng, Xiu-Qing | Liu, Jing | Hutchinson, Amy | Jacobs, Kevin | Giffen, Carol | Burdette, Laurie | Fraumeni, Joseph F. | Shen, Hongbing | Ke, Yang | Zeng, Yixin | Wu, Tangchun | Kraft, Peter | Chung, Charles C. | Tucker, Margaret A. | Hou, Zhi-Chao | Liu, Ya-Li | Hu, Yan-Long | Liu, Yu | Wang, Li | Yuan, Guo | Chen, Li-Sha | Liu, Xiao | Ma, Teng | Meng, Hui | Sun, Li | Li, Xin-Min | Li, Xiu-Min | Ku, Jian-Wei | Zhou, Ying-Fa | Yang, Liu-Qin | Wang, Zhou | Li, Yin | Qige, Qirenwang | Yang, Wen-Jun | Lei, Guang-Yan | Chen, Long-Qi | Li, En-Min | Yuan, Ling | Yue, Wen-Bin | Wang, Ran | Wang, Lu-Wen | Fan, Xue-Ping | Zhu, Fang-Heng | Zhao, Wei-Xing | Mao, Yi-Min | Zhang, Mei | Xing, Guo-Lan | Li, Ji-Lin | Han, Min | Ren, Jing-Li | Liu, Bin | Ren, Shu-Wei | Kong, Qing-Peng | Li, Feng | Sheyhidin, Ilyar | Wei, Wu | Zhang, Yan-Rui | Feng, Chang-Wei | Wang, Jin | Yang, Yu-Hua | Hao, Hong-Zhang | Bao, Qi-De | Liu, Bao-Chi | Wu, Ai-Qun | Xie, Dong | Yang, Wan-Cai | Wang, Liang | Zhao, Xiao-Hang | Chen, Shu-Qing | Hong, Jun-Yan | Zhang, Xue-Jun | Freedman, Neal D | Goldstein, Alisa M. | Lin, Dongxin | Taylor, Philip R. | Wang, Li-Dong | Chanock, Stephen J.
Nature genetics  2014;46(9):1001-1006.
We conducted a joint (pooled) analysis of three genome-wide association studies (GWAS) 1-3 of esophageal squamous cell carcinoma (ESCC) in ethnic Chinese (5,337 ESCC cases and 5,787 controls) with 9,654 ESCC cases and 10,058 controls for follow-up. In a logistic regression model adjusted for age, sex, study, and two eigenvectors, two new loci achieved genome-wide significance, marked by rs7447927 at 5q31.2 (per-allele odds ratio (OR) = 0.85, 95% CI 0.82-0.88; P=7.72x10−20) and rs1642764 at 17p13.1 (per-allele OR= 0.88, 95% CI 0.85-0.91; P=3.10x10−13). rs7447927 is a synonymous single nucleotide polymorphism (SNP) in TMEM173 and rs1642764 is an intronic SNP in ATP1B2, near TP53. Furthermore, a locus in the HLA class II region at 6p21.32 (rs35597309) achieved genome-wide significance in the two populations at highest risk for ESSC (OR=1.33, 95% CI 1.22-1.46; P=1.99x10−10). Our joint analysis identified new ESCC susceptibility loci overall as well as a new locus unique to the ESCC high risk Taihang Mountain region.
doi:10.1038/ng.3064
PMCID: PMC4212832  PMID: 25129146

Results 1-25 (263)