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1.  Identification of FGFR4-activating mutations in human rhabdomyosarcomas that promote metastasis in xenotransplanted models  
The Journal of Clinical Investigation  2009;119(11):3395-3407.
Rhabdomyosarcoma (RMS) is a childhood cancer originating from skeletal muscle, and patient survival is poor in the presence of metastatic disease. Few determinants that regulate metastasis development have been identified. The receptor tyrosine kinase FGFR4 is highly expressed in RMS tissue, suggesting a role in tumorigenesis, although its functional importance has not been defined. Here, we report the identification of mutations in FGFR4 in human RMS tumors that lead to its activation and present evidence that it functions as an oncogene in RMS. Higher FGFR4 expression in RMS tumors was associated with advanced-stage cancer and poor survival, while FGFR4 knockdown in a human RMS cell line reduced tumor growth and experimental lung metastases when the cells were transplanted into mice. Moreover, 6 FGFR4 tyrosine kinase domain mutations were found among 7 of 94 (7.5%) primary human RMS tumors. The mutants K535 and E550 increased autophosphorylation, Stat3 signaling, tumor proliferation, and metastatic potential when expressed in a murine RMS cell line. These mutants also transformed NIH 3T3 cells and led to an enhanced metastatic phenotype. Finally, murine RMS cell lines expressing the K535 and E550 FGFR4 mutants were substantially more susceptible to apoptosis in the presence of a pharmacologic FGFR inhibitor than the control cell lines expressing the empty vector or wild-type FGFR4. Together, our results demonstrate that mutationally activated FGFR4 acts as an oncogene, and these are what we believe to be the first known mutations in a receptor tyrosine kinase in RMS. These findings support the potential therapeutic targeting of FGFR4 in RMS.
doi:10.1172/JCI39703
PMCID: PMC2769177  PMID: 19809159
3.  Scanning for Clues to Better Use Selective Estrogen Receptor Modulators 
Cancer discovery  2013;3(7):728-729.
Summary
Ingle and colleagues present timely findings identifying genetic variants associated with response to selective estrogen receptor modulator therapy that when substantiated in follow-up may represent an important step towards understanding estrogen-dependent induction of BRCA1 expression and advancing individualized preventive medicine in women at high risk for developing breast cancer.
doi:10.1158/2159-8290.CD-13-0251
PMCID: PMC4285377  PMID: 23847351
4.  Detectable Clonal Mosaicism in the Human Genome 
Seminars in hematology  2013;50(4):10.1053/j.seminhematol.2013.09.001.
Human genetic mosaicism is the presence of two or more cellular populations with distinct genotypes in an individual who developed from a single fertilized ovum. While initially observed across a spectrum of rare genetic disorders, detailed assessment of data from genome-wide association studies now reveal that detectable clonal mosaicism involving large structural alterations (> 2 Mb) can also be seen in populations of apparently healthy individuals. The first generation of descriptive studies have generated new interest in understanding the molecular basis of the affected genomic regions, percent of the cellular subpopulation involved, and developmental timing of the underlying mutational event, which could reveal new insights into the initiation, clonal expansion and phenotypic manifestations of mosaic events. Early evidence indicates detectable clonal mosaicism increases in frequency with age and could preferentially occur in males. The observed pattern of recurrent events affecting specific chromosomal regions indicates some regions are more susceptible to these events, which could reflect inter-individual differences in genomic stability. Moreover, it is also plausible that the presence of large structural events could be associated with cancer risk. The characterization of detectable genetic mosaicism reveals that there could be important dynamic changes in the human genome associated with the aging process, which could be associated with risk for common disorders, such as cancer, cardiovascular disease, diabetes, and neurological disorders.
doi:10.1053/j.seminhematol.2013.09.001
PMCID: PMC3855860  PMID: 24246702
aneuploidy; clonal expansion; copy-number; genome-wide association study; mutation
5.  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
6.  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
7.  Methodological Considerations in Estimation of Phenotype Heritability Using Genome-Wide SNP Data, Illustrated by an Analysis of the Heritability of Height in a Large Sample of African Ancestry Adults 
PLoS ONE  2015;10(6):e0131106.
Height has an extremely polygenic pattern of inheritance. Genome-wide association studies (GWAS) have revealed hundreds of common variants that are associated with human height at genome-wide levels of significance. However, only a small fraction of phenotypic variation can be explained by the aggregate of these common variants. In a large study of African-American men and women (n = 14,419), we genotyped and analyzed 966,578 autosomal SNPs across the entire genome using a linear mixed model variance components approach implemented in the program GCTA (Yang et al Nat Genet 2010), and estimated an additive heritability of 44.7% (se: 3.7%) for this phenotype in a sample of evidently unrelated individuals. While this estimated value is similar to that given by Yang et al in their analyses, we remain concerned about two related issues: (1) whether in the complete absence of hidden relatedness, variance components methods have adequate power to estimate heritability when a very large number of SNPs are used in the analysis; and (2) whether estimation of heritability may be biased, in real studies, by low levels of residual hidden relatedness. We addressed the first question in a semi-analytic fashion by directly simulating the distribution of the score statistic for a test of zero heritability with and without low levels of relatedness. The second question was addressed by a very careful comparison of the behavior of estimated heritability for both observed (self-reported) height and simulated phenotypes compared to imputation R2 as a function of the number of SNPs used in the analysis. These simulations help to address the important question about whether today's GWAS SNPs will remain useful for imputing causal variants that are discovered using very large sample sizes in future studies of height, or whether the causal variants themselves will need to be genotyped de novo in order to build a prediction model that ultimately captures a large fraction of the variability of height, and by implication other complex phenotypes. Our overall conclusions are that when study sizes are quite large (5,000 or so) the additive heritability estimate for height is not apparently biased upwards using the linear mixed model; however there is evidence in our simulation that a very large number of causal variants (many thousands) each with very small effect on phenotypic variance will need to be discovered to fill the gap between the heritability explained by known versus unknown causal variants. We conclude that today's GWAS data will remain useful in the future for causal variant prediction, but that finding the causal variants that need to be predicted may be extremely laborious.
doi:10.1371/journal.pone.0131106
PMCID: PMC4488332  PMID: 26125186
8.  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
9.  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
10.  Genome-wide association study of susceptibility loci for breast cancer in Sardinian population 
BMC Cancer  2015;15:383.
Background
Despite progress in identifying genes associated with breast cancer, many more risk loci exist. Genome-wide association analyses in genetically-homogeneous populations, such as that of Sardinia (Italy), could represent an additional approach to detect low penetrance alleles.
Methods
We performed a genome-wide association study comparing 1431 Sardinian patients with non-familial, BRCA1/2-mutation-negative breast cancer to 2171 healthy Sardinian blood donors. DNA was genotyped using GeneChip Human Mapping 500 K Arrays or Genome-Wide Human SNP Arrays 6.0. To increase genomic coverage, genotypes of additional SNPs were imputed using data from HapMap Phase II. After quality control filtering of genotype data, 1367 cases (9 men) and 1658 controls (1156 men) were analyzed on a total of 2,067,645 SNPs.
Results
Overall, 33 genomic regions (67 candidate SNPs) were associated with breast cancer risk at the p < 10−6 level. Twenty of these regions contained defined genes, including one already associated with breast cancer risk: TOX3. With a lower threshold for preliminary significance to p < 10−5, we identified 11 additional SNPs in FGFR2, a well-established breast cancer-associated gene. Ten candidate SNPs were selected, excluding those already associated with breast cancer, for technical validation as well as replication in 1668 samples from the same population. Only SNP rs345299, located in intron 1 of VAV3, remained suggestively associated (p-value, 1.16x10−5), but it did not associate with breast cancer risk in pooled data from two large, mixed-population cohorts.
Conclusions
This study indicated the role of TOX3 and FGFR2 as breast cancer susceptibility genes in BRCA1/2-wild-type breast cancer patients from Sardinian population.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1392-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-015-1392-9
PMCID: PMC4434540  PMID: 25956309
Breast cancer risk; BRCA1/2 mutation analysis; Genome-wide association study; Sardinian population
11.  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
12.  A genome-wide association study of prostate cancer in West African men 
Human genetics  2013;133(5):509-521.
Background
Age-adjusted mortality rates for prostate cancer are higher for African American men compared with those of European ancestry. Recent data suggest that West African men also have elevated risk for prostate cancer relative to European men. Genetic susceptibility to prostate cancer could account for part of this difference.
Methods
We conducted a genome-wide association study (GWAS) of prostate cancer in West African men in the Ghana Prostate Study. Association testing was performed using multivariable logistic regression adjusted for age and genetic ancestry for 474 prostate cancer cases and 458 population-based controls on the Illumina HumanOmni-5 Quad BeadChip.
Results
The most promising association was at 10p14 within an intron of a long non-coding RNA (lncRNA RP11-543F8.2) 360 kb centromeric of GATA3 (p=1.29E−7). In sub-analyses, SNPs at 5q31.3 were associated with high Gleason score (≥7) cancers, the strongest of which was a missense SNP in PCDHA1 (rs34575154, p=3.66E−8), and SNPs at Xq28 (rs985081, p=8.66E−9) and 6q21 (rs2185710, p=5.95E−8) were associated with low Gleason score (<7) cancers. We sought to validate our findings in silico in the African Ancestry Prostate Cancer GWAS Consortium, but only one SNP, at 10p14, replicated at p<0.05. Of the 90 prostate cancer loci reported from studies of men of European, Asian or African American ancestry, we were able to test 81 in the Ghana Prostate Study, and 10 of these replicated at p<0.05.
Conclusion
Further genetic studies of prostate cancer in West African men are needed to confirm our promising susceptibility loci.
doi:10.1007/s00439-013-1387-z
PMCID: PMC3988225  PMID: 24185611
prostate cancer; Africa; GWAS; case-control
13.  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
14.  A Comprehensive Resequence-Analysis of 250kb Region of 8q24.21 in Men of African Ancestry 
The Prostate  2014;74(6):579-589.
Summary
Background
Genome-wide association studies (GWAS) have identified that a ∼1M region centromeric to the MYC oncogene on chromosome 8q24.21 harbors at least 5 independent loci associated with prostate cancer risk and additional loci associated with cancers of breast, colon, bladder, and chronic lymphocytic leukemia (CLL). Because GWAS identify genetic markers that may be indirectly associated with disease, fine-mapping based on sequence analysis provides important insights into patterns of linkage disequilibrium (LD) and is critical in defining the optimal variants to nominate for biological follow-up.
Methods
To catalog variation in individuals of African ancestry, we resequenced a region (250kb; chr8:128,050,768-128,300,801, hg19) containing several prostate cancer susceptibility loci as well as a locus associated with CLL. Our samples set included 78 individuals from Ghana and 47 of African-Americans from Johns Hopkins University.
Results
After quality control metrics were applied to next-generation sequence data, 1,838 SNPs were identified. Of these, 285 were novel and not yet reported in any public database. Using genotypes derived from sequencing, we refined the LD and recombination hotspots within the region and determined a set of tag SNPs to be used in future fine-mapping studies. Based on LD, we annotated putative risk loci and their surrogates using ENCODE data, which should help guide laboratory studies.
Conclusions
In comparison to the 1000 Genome Project data, we have identified additional variants that could be important in establishing priorities for future functional work designed to explain the biological basis of associations between SNPs and both prostate cancer and chronic lymphocytic leukemia.
PMCID: PMC4199861  PMID: 24783269
15.  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
16.  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
17.  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
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.  A large-scale assessment of two-way SNP interactions in breast cancer susceptibility using 46 450 cases and 42 461 controls from the breast cancer association consortium 
Milne, Roger L. | Herranz, Jesús | Michailidou, Kyriaki | Dennis, Joe | Tyrer, Jonathan P. | Zamora, M. Pilar | Arias-Perez, José Ignacio | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Wang, Qin | Bolla, Manjeet K. | Czene, Kamila | Eriksson, Mikael | Humphreys, Keith | Darabi, Hatef | Li, Jingmei | Anton-Culver, Hoda | Neuhausen, Susan L. | Ziogas, Argyrios | Clarke, Christina A. | Hopper, John L. | Dite, Gillian S. | Apicella, Carmel | Southey, Melissa C. | Chenevix-Trench, Georgia | Swerdlow, Anthony | Ashworth, Alan | Orr, Nicholas | Schoemaker, Minouk | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Mulligan, Anna Marie | Bojesen, Stig E. | Nordestgaard, Børge G. | Flyger, Henrik | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Wang, Xianshu | Olson, Janet E. | Vachon, Celine | Purrington, Kristen | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Dunning, Alison M. | Shah, Mitul | Guénel, Pascal | Truong, Thérèse | Sanchez, Marie | Mulot, Claire | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Lindblom, Annika | Margolin, Sara | Hooning, Maartje J. | Hollestelle, Antoinette | Collée, J. Margriet | Jager, Agnes | Cox, Angela | Brock, Ian W. | Reed, Malcolm W.R. | Devilee, Peter | Tollenaar, Robert A.E.M. | Seynaeve, Caroline | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Simard, Jacques | Dumont, Martine | Soucy, Penny | Dörk, Thilo | Bogdanova, Natalia V. | Hamann, Ute | Försti, Asta | Rüdiger, Thomas | Ulmer, Hans-Ulrich | Fasching, Peter A. | Häberle, Lothar | Ekici, Arif B. | Beckmann, Matthias W. | Fletcher, Olivia | Johnson, Nichola | dos Santos Silva, Isabel | Peto, Julian | Radice, Paolo | Peterlongo, Paolo | Peissel, Bernard | Mariani, Paolo | Giles, Graham G. | Severi, Gianluca | Baglietto, Laura | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael | Miller, Nicola | Marme, Federik | Burwinkel, Barbara | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Lambrechts, Diether | Yesilyurt, Betul T. | Floris, Giuseppe | Leunen, Karin | Alnæs, Grethe Grenaker | Kristensen, Vessela | Børresen-Dale, Anne-Lise | García-Closas, Montserrat | Chanock, Stephen J. | Lissowska, Jolanta | Figueroa, Jonine D. | Schmidt, Marjanka K. | Broeks, Annegien | Verhoef, Senno | Rutgers, Emiel J. | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Couch, Fergus J. | Toland, Amanda E. | Yannoukakos, Drakoulis | Pharoah, Paul D.P. | Hall, Per | Benítez, Javier | Malats, Núria | Easton, Douglas F.
Human Molecular Genetics  2013;23(7):1934-1946.
Part of the substantial unexplained familial aggregation of breast cancer may be due to interactions between common variants, but few studies have had adequate statistical power to detect interactions of realistic magnitude. We aimed to assess all two-way interactions in breast cancer susceptibility between 70 917 single nucleotide polymorphisms (SNPs) selected primarily based on prior evidence of a marginal effect. Thirty-eight international studies contributed data for 46 450 breast cancer cases and 42 461 controls of European origin as part of a multi-consortium project (COGS). First, SNPs were preselected based on evidence (P < 0.01) of a per-allele main effect, and all two-way combinations of those were evaluated by a per-allele (1 d.f.) test for interaction using logistic regression. Second, all 2.5 billion possible two-SNP combinations were evaluated using Boolean operation-based screening and testing, and SNP pairs with the strongest evidence of interaction (P < 10−4) were selected for more careful assessment by logistic regression. Under the first approach, 3277 SNPs were preselected, but an evaluation of all possible two-SNP combinations (1 d.f.) identified no interactions at P < 10−8. Results from the second analytic approach were consistent with those from the first (P > 10−10). In summary, we observed little evidence of two-way SNP interactions in breast cancer susceptibility, despite the large number of SNPs with potential marginal effects considered and the very large sample size. This finding may have important implications for risk prediction, simplifying the modelling required. Further comprehensive, large-scale genome-wide interaction studies may identify novel interacting loci if the inherent logistic and computational challenges can be overcome.
doi:10.1093/hmg/ddt581
PMCID: PMC3943524  PMID: 24242184
20.  A Genome-wide Association Study of Early-onset Breast Cancer Identifies PFKM as a Novel Breast Cancer Gene and Supports a Common Genetic Spectrum for Breast Cancer at Any Age 
Ahsan, Habibul | Halpern, Jerry | Kibriya, Muhammad G | Pierce, Brandon L | Tong, Lin | Gamazon, Eric | McGuire, Valerie | Felberg, Anna | Shi, Jianxin | Jasmine, Farzana | Roy, Shantanu | Brutus, Rachelle | Argos, Maria | Melkonian, Stephanie | Chang-Claude, Jenny | Andrulis, Irene | Hopper, John L | John, Esther M. | Malone, Kathi | Ursin, Giske | Gammon, Marilie D | Thomas, Duncan C | Seminara, Daniela | Casey, Graham | Knight, Julia A | Southey, Melissa C | Giles, Graham G | Santella, Regina M | Lee, Eunjung | Conti, David | Duggan, David | Gallinger, Steve | Haile, Robert | Jenkins, Mark | Lindor, Noralane M | Newcomb, Polly | Michailidou, Kyriaki | Apicella, Carmel | Park, Daniel J | Peto, Julian | Fletcher, Olivia | Silva, Isabel dos Santos | Lathrop, Mark | Hunter, David J | Chanock, Stephen J | Meindl, Alfons | Schmutzler, Rita K | Müller-Myhsok, Bertram | Lochmann, Magdalena | Beckmann, Lars | Hein, Rebecca | Makalic, Enes | Schmidt, Daniel F | Bui, Quang Minh | Stone, Jennifer | Flesch-Janys, Dieter | Dahmen, Norbert | Nevanlinna, Heli | Aittomäki, Kristiina | Blomqvist, Carl | Hall, Per | Czene, Kamila | Irwanto, Astrid | Liu, Jianjun | Rahman, Nazneen | Turnbull, Clare | Dunning, Alison M. | Pharoah, Paul | Waisfisz, Quinten | Meijers-Heijboer, Hanne | Uitterlinden, Andre G. | Rivadeneira, Fernando | Nicolae, Dan | Easton, Douglas F | Cox, Nancy J | Whittemore, Alice S
Early-onset breast cancer (EOBC) causes substantial loss of life and productivity, creating a major burden among women worldwide. We analyzed 1,265,548 Hapmap3 SNPs among a discovery set of 3,523 EOBC incident case and 2,702 population control women aged <=51 years. The SNPs with smallest P-values were examined in a replication set of 3,470 EOBC case and 5,475 control women. We also tested EOBC association with 19,684 genes by annotating each gene with putative functional SNPs, and then combining their P-values to obtain a gene-based P-value. We examined the gene with smallest P-value for replication in 1,145 breast cancer case and 1,142 control women. The combined discovery and replication sets identified 72 new SNPs associated with EOBC (P<4×10−8) located in six genomic regions previously reported to contain SNPs associated largely with later-onset breast cancer (LOBC). SNP rs2229882 and 10 other SNPs on chromosome 5q11.2 remained associated (P<6×10−4) after adjustment for the strongest published SNPs in the region. Thirty-two of the 82 currently known LOBC SNPs were associated with EOBC (P<0.05). Low power is likely responsible for the remaining 50 unassociated known LOBC SNPs. The gene-based analysis identified an association between breast cancer and the phosphofructokinase-muscle (PFKM) gene on chromosome 12q13.11 that met the genomewide gene-based threshold of 2.5×10−6. In conclusion, EOBC and LOBC appear to have similar genetic etiologies; the 5q11.2 region may contain multiple distinct breast cancer loci; and the PFKM gene region is worthy of further investigation. These findings should enhance our understanding of the etiology of breast cancer.
doi:10.1158/1055-9965.EPI-13-0340
PMCID: PMC3990360  PMID: 24493630
21.  GWAS is going to the dogs 
Genome Biology  2014;15(3):105.
Genome-wide association studies in canine models may help locate genomic susceptibility regions that are relevant to human disease.
See related Research: http://genomebiology.com/2014/15/3/R25
doi:10.1186/gb4166
PMCID: PMC4014671  PMID: 25002063
22.  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
23.  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
24.  Genetic variants in Fas signaling pathway genes and risk of gastric cancer 
Populations in north central China are at high risk for gastric cancers (GC), and altered FAS-mediated cell signaling and/or apoptosis may contribute to this risk. We examined the association of 554 single nucleotide polymorphisms (SNPs) in 53 Fas signaling-related genes using a pathway-based approach in 1758 GC cases (1126 gastric cardia adenocarcinomas (GCA) and 632 gastric noncardia adenocarcinomas (GNCA)), and 2111 controls from a genome-wide association study (GWAS) of GC in ethnic Chinese. SNP associations with risk of overall GC, GCA and GNCA were evaluated using unconditional logistic regressions controlling for age, sex and study. Gene- and pathway-based associations were tested using the adaptive rank-truncated product (ARTP) method. Statistical significance was evaluated empirically by permutation. Significant pathway-based associations were observed for Fas signaling with risk of overall GC (P = 5.5E-04) and GCA (P = 6.3E-03), but not GNCA (P = 8.1E-02). Among examined genes in the Fas signaling pathway, MAP2K4, FAF1, MAPK8, CASP10, CASP8, CFLAR, MAP2K1, CAP8AP2, PAK2 and IKBKB were associated with risk of GC (nominal P < 0.05), and FAF1 and MAPK8 were significantly associated with risk of both GCA and GNCA (nominal P < 0.05). Our examination of genetic variation in the Fas signaling pathway is consistent with an association of altered Fas signaling and/or apoptosis with risk of GC. As one of the first attempts to investigate a pathway-level association, our results suggest that these genes and the Fas signaling pathway warrant further evaluation in relation to GC risk in other populations.
doi:10.1002/ijc.28415
PMCID: PMC3858487  PMID: 23921907
Gastric cancer; gastric cardia; gastric noncardia; Fas signaling; genetic variants; GWAS; single nucleotide polymorphisms; pathway genes
25.  Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with prognosis of estrogen receptor-negative breast cancer after chemotherapy 
Lei, Jieping | Rudolph, Anja | Moysich, Kirsten B | Rafiq, Sajjad | Behrens, Sabine | Goode, Ellen L | Pharoah, Paul PD | Seibold, Petra | Fasching, Peter A | Andrulis, Irene L | Kristensen, Vessela N | Couch, Fergus J | Hamann, Ute | Hooning, Maartje J | Nevanlinna, Heli | Eilber, Ursula | Bolla, Manjeet K | Dennis, Joe | Wang, Qin | Lindblom, Annika | Mannermaa, Arto | Lambrechts, Diether | García-Closas, Montserrat | Hall, Per | Chenevix-Trench, Georgia | Shah, Mitul | Luben, Robert | Haeberle, Lothar | Ekici, Arif B | Beckmann, Matthias W | Knight, Julia A | Glendon, Gord | Tchatchou, Sandrine | Alnæs, Grethe I Grenaker | Borresen-Dale, Anne-Lise | Nord, Silje | Olson, Janet E | Hallberg, Emily | Vachon, Celine | Torres, Diana | Ulmer, Hans-Ulrich | Rüdiger, Thomas | Jager, Agnes | van Deurzen, Carolien HM | Tilanus-Linthorst, Madeleine MA | Muranen, Taru A | Aittomäki, Kristiina | Blomqvist, Carl | Margolin, Sara | Kosma, Veli-Matti | Hartikainen, Jaana M | Kataja, Vesa | Hatse, Sigrid | Wildiers, Hans | Smeets, Ann | Figueroa, Jonine | Chanock, Stephen J | Lissowska, Jolanta | Li, Jingmei | Humphreys, Keith | Phillips, Kelly-Anne | Linn, Sabine | Cornelissen, Sten | van den Broek, Sandra Alexandra J | Kang, Daehee | Choi, Ji-Yeob | Park, Sue K | Yoo, Keun-Young | Hsiung, Chia-Ni | Wu, Pei-Ei | Hou, Ming-Feng | Shen, Chen-Yang | Teo, Soo Hwang | Taib, Nur Aishah Mohd | Yip, Cheng Har | Ho, Gwo Fuang | Matsuo, Keitaro | Ito, Hidemi | Iwata, Hiroji | Tajima, Kazuo | Dunning, Alison M | Benitez, Javier | Czene, Kamila | Sucheston, Lara E | Maishman, Tom | Tapper, William J | Eccles, Diana | Easton, Douglas F | Schmidt, Marjanka K | Chang-Claude, Jenny
Introduction
Tumor lymphocyte infiltration is associated with clinical response to chemotherapy in estrogen receptor (ER) negative breast cancer. To identify variants in immunosuppressive pathway genes associated with prognosis after adjuvant chemotherapy for ER-negative patients, we studied stage I-III invasive breast cancer patients of European ancestry, including 9,334 ER-positive (3,151 treated with chemotherapy) and 2,334 ER-negative patients (1,499 treated with chemotherapy).
Methods
We pooled data from sixteen studies from the Breast Cancer Association Consortium (BCAC), and employed two independent studies for replications. Overall 3,610 single nucleotide polymorphisms (SNPs) in 133 genes were genotyped as part of the Collaborative Oncological Gene-environment Study, in which phenotype and clinical data were collected and harmonized. Multivariable Cox proportional hazard regression was used to assess genetic associations with overall survival (OS) and breast cancer-specific survival (BCSS). Heterogeneity according to chemotherapy or ER status was evaluated with the log-likelihood ratio test.
Results
Three independent SNPs in TGFBR2 and IL12B were associated with OS (P <10−3) solely in ER-negative patients after chemotherapy (267 events). Poorer OS associated with TGFBR2 rs1367610 (G > C) (per allele hazard ratio (HR) 1.54 (95% confidence interval (CI) 1.22 to 1.95), P = 3.08 × 10−4) was not found in ER-negative patients without chemotherapy or ER-positive patients with chemotherapy (P for interaction <10−3). Two SNPs in IL12B (r2 = 0.20) showed different associations with ER-negative disease after chemotherapy: rs2546892 (G > A) with poorer OS (HR 1.50 (95% CI 1.21 to 1.86), P = 1.81 × 10−4), and rs2853694 (A > C) with improved OS (HR 0.73 (95% CI 0.61 to 0.87), P = 3.67 × 10−4). Similar associations were observed with BCSS. Association with TGFBR2 rs1367610 but not IL12B variants replicated using BCAC Asian samples and the independent Prospective Study of Outcomes in Sporadic versus Hereditary Breast Cancer Study and yielded a combined HR of 1.57 ((95% CI 1.28 to 1.94), P = 2.05 × 10−5) without study heterogeneity.
Conclusions
TGFBR2 variants may have prognostic and predictive value in ER-negative breast cancer patients treated with adjuvant chemotherapy. Our findings provide further insights into the development of immunotherapeutic targets for ER-negative breast cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-015-0522-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-015-0522-2
PMCID: PMC4374346  PMID: 25849327

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