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1.  Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression 
Kote-Jarai, Zsofia | Saunders, Edward J. | Leongamornlert, Daniel A. | Tymrakiewicz, Malgorzata | Dadaev, Tokhir | Jugurnauth-Little, Sarah | Ross-Adams, Helen | Al Olama, Ali Amin | Benlloch, Sara | Halim, Silvia | Russell, Roslin | Dunning, Alison M. | Luccarini, Craig | Dennis, Joe | Neal, David E. | Hamdy, Freddie C. | Donovan, Jenny L. | Muir, Ken | Giles, Graham G. | Severi, Gianluca | Wiklund, Fredrik | Gronberg, Henrik | Haiman, Christopher A. | Schumacher, Fredrick | Henderson, Brian E. | Le Marchand, Loic | Lindstrom, Sara | Kraft, Peter | Hunter, David J. | Gapstur, Susan | Chanock, Stephen | Berndt, Sonja I. | Albanes, Demetrius | Andriole, Gerald | Schleutker, Johanna | Weischer, Maren | Canzian, Federico | Riboli, Elio | Key, Tim J. | Travis, Ruth C. | Campa, Daniele | Ingles, Sue A. | John, Esther M. | Hayes, Richard B. | Pharoah, Paul | Khaw, Kay-Tee | Stanford, Janet L. | Ostrander, Elaine A. | Signorello, Lisa B. | Thibodeau, Stephen N. | Schaid, Dan | Maier, Christiane | Vogel, Walther | Kibel, Adam S. | Cybulski, Cezary | Lubinski, Jan | Cannon-Albright, Lisa | Brenner, Hermann | Park, Jong Y. | Kaneva, Radka | Batra, Jyotsna | Spurdle, Amanda | Clements, Judith A. | Teixeira, Manuel R. | Govindasami, Koveela | Guy, Michelle | Wilkinson, Rosemary A. | Sawyer, Emma J. | Morgan, Angela | Dicks, Ed | Baynes, Caroline | Conroy, Don | Bojensen, Stig E. | Kaaks, Rudolf | Vincent, Daniel | Bacot, François | Tessier, Daniel C. | Easton, Douglas F. | Eeles, Rosalind A.
Human Molecular Genetics  2013;22(20):4239.
PMCID: PMC3871151
3.  HGV2012: Leveraging Next-Generation Technology and Large Datasets to Advance Disease Research 
Human mutation  2013;34(4):657-660.
The 13th International Meeting on Human Genome Variation and Complex Genome Analysis (HGV2012: Shanghai, China, 6th 8th September 2012) was a stimulating workshop where researchers from academia and industry explored the latest progress, challenges, and opportunities in genome variation research. Key themes included advancements in next-generation sequencing (NGS) technology, investigation of common and rare diseases, employing NGS in the clinic, utilizing large datasets that leverage biobanks and population-specific cohorts, and exploration of genomic features.
PMCID: PMC3606662  PMID: 23315969
variation; SNP; GWAS; next generation sequencing; NGS; inherited disease
4.  Genetic Variation in the Vitamin D Pathway in Relation to Risk of Prostate Cancer – Results from Breast and Prostate Cancer Cohort Consortium (BPC3) 
Studies suggest that vitamin D status may be associated with prostate cancer risk, although the direction and strength of this association differs between experimental and observational studies. Genome-wide association studies have identified genetic variants associated with 25-hydroxyvitamin D (25(OH)D) status. We examined prostate cancer risk in relation to SNPs in four genes shown to predict circulating levels of 25(OH)D.
SNP markers localized to each of four genes (GC, CYP24A1, CYP2R1, and DHCR7) previously associated with 25(OH)D were genotyped in 10,018 cases and 11,052 controls from the NCI Breast and Prostate Cancer Cohort Consortium. Logistic regression was used to estimate the individual and cumulative association between genetic variants and risk of overall and aggressive prostate cancer.
We observed a decreased risk of aggressive prostate cancer among men with the allele in rs6013897 near CYP24A1 associated with lower serum 25(OH)D (per A allele, OR=0.86, 95%CI=0.80–0.93, p-trend=0.0002), but an increased risk for non-aggressive disease (per a allele: OR=1.10, 95%CI=1.04–1.17, p-trend=0.002). Examination of a polygenic score of the four SNPs revealed statistically significantly lower risk of aggressive prostate cancer among men with a greater number of low vitamin D alleles (OR for 6–8 vs. 0–1 alleles = 0.66, 95% CI = 0.44 – 0.98; p-trend=0.003).
In this large, pooled analysis, genetic variants related to lower 25(OH)D were associated with a decreased risk of aggressive prostate cancer.
Our genetic findings do not support a protective association between loci known to influence vitamin D levels and prostate cancer risk.
PMCID: PMC3617077  PMID: 23377224
Vitamin D; prostatic neoplasms; data pooling; genes; SNPs
5.  Transforming Epidemiology for 21st Century Medicine and Public Health 
In 2012, the National Cancer Institute (NCI) engaged the scientific community to provide a vision for cancer epidemiology in the 21st century. Eight overarching thematic recommendations, with proposed corresponding actions for consideration by funding agencies, professional societies, and the research community emerged from the collective intellectual discourse. The themes are (i) extending the reach of epidemiology beyond discovery and etiologic research to include multilevel analysis, intervention evaluation, implementation, and outcomes research; (ii) transforming the practice of epidemiology by moving towards more access and sharing of protocols, data, metadata, and specimens to foster collaboration, to ensure reproducibility and replication, and accelerate translation; (iii) expanding cohort studies to collect exposure, clinical and other information across the life course and examining multiple health-related endpoints; (iv) developing and validating reliable methods and technologies to quantify exposures and outcomes on a massive scale, and to assess concomitantly the role of multiple factors in complex diseases; (v) integrating “big data” science into the practice of epidemiology; (vi) expanding knowledge integration to drive research, policy and practice; (vii) transforming training of 21st century epidemiologists to address interdisciplinary and translational research; and (viii) optimizing the use of resources and infrastructure for epidemiologic studies. These recommendations can transform cancer epidemiology and the field of epidemiology in general, by enhancing transparency, interdisciplinary collaboration, and strategic applications of new technologies. They should lay a strong scientific foundation for accelerated translation of scientific discoveries into individual and population health benefits.
PMCID: PMC3625652  PMID: 23462917
big data; clinical trials; cohort studies; epidemiology; genomics; medicine; public health; technologies; training; translational research
6.  Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-wide Meta-analysis 
Peters, Ulrike | Jiao, Shuo | Schumacher, Fredrick R. | Hutter, Carolyn M. | Aragaki, Aaron K. | Baron, John A. | Berndt, Sonja I. | Bézieau, Stéphane | Brenner, Hermann | Butterbach, Katja | Caan, Bette J. | Campbell, Peter T. | Carlson, Christopher S. | Casey, Graham | Chan, Andrew T. | Chang-Claude, Jenny | Chanock, Stephen J. | Chen, Lin S. | Coetzee, Gerhard A. | Coetzee, Simon G. | Conti, David V. | Curtis, Keith R. | Duggan, David | Edwards, Todd | Fuchs, Charles S. | Gallinger, Steven | Giovannucci, Edward L. | Gogarten, Stephanie M. | Gruber, Stephen B. | Haile, Robert W. | Harrison, Tabitha A. | Hayes, Richard B. | Henderson, Brian E. | Hoffmeister, Michael | Hopper, John L. | Hudson, Thomas J. | Hunter, David J. | Jackson, Rebecca D. | Jee, Sun Ha | Jenkins, Mark A. | Jia, Wei-Hua | Kolonel, Laurence N. | Kooperberg, Charles | Küry, Sébastien | Lacroix, Andrea Z. | Laurie, Cathy C. | Laurie, Cecelia A. | Le Marchand, Loic | Lemire, Mathieu | Levine, David | Lindor, Noralane M. | Liu, Yan | Ma, Jing | Makar, Karen W. | Matsuo, Keitaro | Newcomb, Polly A. | Potter, John D. | Prentice, Ross L. | Qu, Conghui | Rohan, Thomas | Rosse, Stephanie A. | Schoen, Robert E. | Seminara, Daniela | Shrubsole, Martha | Shu, Xiao-Ou | Slattery, Martha L. | Taverna, Darin | Thibodeau, Stephen N. | Ulrich, Cornelia M. | White, Emily | Xiang, Yongbing | Zanke, Brent W. | Zeng, Yi-Xin | Zhang, Ben | Zheng, Wei | Hsu, Li
Gastroenterology  2012;144(4):799-807.e24.
Heritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis.
We conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent.
Based on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 × 10−8: an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 × 10−8). We also found evidence for 3 additional loci with P values less than 5.0 × 10−7: a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 × 10−8), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 × 10−8), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 × 10−7).
In a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to β-catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.
PMCID: PMC3636812  PMID: 23266556
Colon Cancer; Genetics; Risk Factors; SNP
7.  Common genetic polymorphisms modify the effect of smoking on absolute risk of bladder cancer 
Cancer research  2013;73(7):2211-2220.
Bladder cancer results from the combined effects of environmental and genetic factors, smoking being the strongest risk factor. Evaluating absolute risks resulting from the joint effects of smoking and genetic factors is critical to evaluate the public health relevance of genetic information. Analyses included up to 3,942 cases and 5,680 controls of European background in seven studies. We tested for multiplicative and additive interactions between smoking and 12 susceptibility loci, individually and combined as a polygenic risk score (PRS). Thirty-year absolute risks and risk differences by levels of the PRS were estimated for US-males aged 50-years. Six out of 12 variants showed significant additive gene-environment interactions, most notably NAT2 (P=7×10-4) and UGT1A6 (P=8×10-4). The 30-year absolute risk of bladder cancer in US males was 6.2% for all current smokers. This risk ranged from 2.9% for current smokers in the lowest quartile of the PRS to 9.9% for current smokers in the upper quartile. Risk difference estimates indicated that 8,200 cases would be prevented if elimination of smoking occurred in 100,000 men in the upper PRS quartile, compared to 2,000 cases prevented by a similar effort in the lowest PRS quartile (P-additive =1×10-4). The impact of eliminating smoking the on number of bladder cancer cases prevented is larger for individuals at higher than lower genetic risk. Our findings could have implications for targeted prevention strategies. However, other smoking-related diseases, as well as practical and ethical considerations, need to be considered before any recommendations could be made.
PMCID: PMC3688270  PMID: 23536561
8.  Promoter variants in the MSMB gene associated with prostate cancer regulate MSMB/NCOA4 fusion transcripts 
Human genetics  2012;131(9):1453-1466.
Beta-microseminoprotein (MSP)/MSMB is an immunoglobulin superfamily protein synthesized by prostate epithelial cells and secreted into seminal plasma. Variants in the promoter of the MSMB gene have been associated with the risk of prostate cancer (PCa) in several independent genome-wide association studies. Both MSMB and an adjacent gene, NCOA4, are subjected to transcriptional control via androgen response elements. The gene product of NCOA4 interacts directly with the androgen receptor as a co-activator to enhance AR transcriptional activity. Here, we provide evidence for the expression of full-length MSMB-NCOA4 fusion transcripts regulated by the MSMB promoter. The predominant MSMB-NCOA4 transcript arises by fusion of the 5′UTR and exons 1–2 of the MSMB pre-mRNA, with exons 2–10 of the NCOA4 premRNA, producing a stable fusion protein, comprising the essential domains of NCOA4. Analysis of the splice sites of this transcript shows an unusually strong splice acceptor at NCOA4 exon 2 and the presence of Alu repeats flanking the exons potentially involved in the splicing event. Transfection experiments using deletion clones of the promoter coupled with luciferase reporter assays define a core MSMB promoter element located between –27 and –236 of the gene, and a negative regulatory element immediately upstream of the start codon. Computational network analysis reveals that the MSMB gene is functionally connected to NCOA4 and the androgen receptor signaling pathway. The data provide an example of how GWAS-associated variants may have multiple genetic and epigenetic effects.
PMCID: PMC3956317  PMID: 22661295
9.  Cytokine signaling pathway polymorphisms and AIDS-related non-Hodgkin lymphoma risk in the Multicenter AIDS Cohort Study 
AIDS (London, England)  2010;24(7):1025-1033.
Cytokine stimulation of B-cell proliferation may be an important etiologic mechanism for acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin lymphoma (NHL). The Epstein-Barr virus may be a co-factor, particularly for primary central nervous system (CNS) tumors, which are uniformly EBV-positive in the setting of AIDS. Thus, we examined associations of genetic variation in IL10 and related cytokine signaling molecules (IL10RA, CXCL12, IL13, IL4, IL4R, CCL5 and BCL6) with AIDS-related NHL risk and evaluated differences between primary CNS and systemic tumors. We compared 160 Multicenter AIDS Cohort Study (MACS) participants with incident lymphomas, of which 90 followed another AIDS diagnosis, to HIV-1-seropositive controls matched on duration of lymphoma-free survival post-HIV-1 infection (N=160) or post-AIDS diagnosis (N=90). We fit conditional logistic regression models to estimate odds ratios (ORs) and 95 percent confidence intervals (95%CIs). Carriage of at least one copy of the T allele for the IL10 rs1800871 (as compared to no copies) was associated with decreased AIDS-NHL risk specific to lymphomas arising from the CNS (CC vs. CT/TT: OR=0.3; 95%CI: 0.1, 0.7) but not systemically (CC vs. CT/TT: OR=1.0; 95%CI: 0.5, 1.9) (Pheterogeneity=0.03). Carriage of two copies of the “low IL10” haplotype rs1800896_A/rs1800871_T/rs1800872_A was associated with decreased lymphoma risk that varied by number of copies (Ptrend=0.02). None of the ORs for the other studied polymorphisms was significantly different from 1.0. Excessive IL10 response to HIV-1 infection may be associated with increased risk of NHL, particularly in the CNS. IL10 dysregulation may be an important etiologic pathway for EBV-related lymphomagenesis.
PMCID: PMC3950937  PMID: 20299965
cytokine; SNPs; AIDS-related lymphoma
10.  Nonsteroidal anti-inflammatory drugs and other analgesic use and bladder cancer in northern New England 
A few epidemiologic studies have found that use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with reduced risk of bladder cancer. However, the effects of specific NSAID use and individual variability in risk have not been well studied. We examined the association between NSAIDs use and bladder cancer risk, and its modification by 39 candidate genes related to NSAID metabolism. A population-based case–control study was conducted in northern New England, enrolling 1,171 newly diagnosed cases and 1,418 controls. Regular use of nonaspirin, nonselective NSAIDs was associated with reduced bladder cancer risk, with a statistically significant inverse trend in risk with duration of use (ORs of 1.0, 0.8, 0.6 and 0.6 for <5, 5–9, 10–19 and 201 years, respectively; ptrend = 0.015). This association was driven mainly by ibuprofen; significant inverse trends in risk with increasing duration and dose of ibuprofen were observed (ptrend = 0.009 and 0.054, respectively). The reduced risk from ibuprofen use was limited to individuals carrying the T allele of a single nucleotide polymorphism (rs4646450) compared to those who did not use ibuprofen and did not carry the T allele in the CYP3A locus, providing new evidence that this association might be modified by polymorphisms in genes that metabolize ibuprofen. Significant positive trends in risk with increasing duration and cumulative dose of selective cyclooxygenase (COX-2) inhibitors were observed. Our results are consistent with those from previous studies linking use of NSAIDs, particularly ibuprofen, with reduced risk. We observed a previously unrecognized risk associated with use of COX-2 inhibitors, which merits further evaluation.
PMCID: PMC3951299  PMID: 22505343
bladder cancer; nonsteroidal anti-inflammatory drugs; gene–drug interaction; CYP3A
11.  A re-sequence analysis of genomic loci on chromosomes 1q32.1, 5p15.33 and 13q22.1 associated with pancreatic cancer risk 
Pancreas  2013;42(2):209-215.
To fine-map common pancreatic cancer susceptibility regions.
We conducted targeted Roche-454 re-sequencing across 428 kb in three genomic regions identified in genome-wide association studies (GWAS) of pancreatic cancer, on chromosomes 1q32.1, 5p15.33 and 13q22.1.
An analytical pipeline for calling genotypes was developed using HapMap samples sequenced on chr5p15.33. Concordance to 1000 Genomes data for chr5p15.33 was >96%. The concordance for chr1q32.1 and chr13q22.1 with pancreatic cancer GWAS data was >99%. Between 9.2–19.0% of variants detected were not present in 1000 Genomes for the respective continental population. The majority of completely novel SNPs were less common (MAF ≤ 5%) or rare (MAF ≤ 2%), illustrating the value of enlarging test sets for discovery of less common variants. Using the dataset, we examined haplotype blocks across each region using a tag SNP analysis (r2 >0.8 for MAF ≥5%) and determined that at least 196, 243 and 63 SNPs are required for fine-mapping chr1q32.1, chr5p15.33, and chr13q22.1, respectively, in European populations.
We have characterized germline variation in three regions associated with pancreatic cancer risk and show that targeted re-sequencing leads to the discovery of novel variants and improves the completeness of germline sequence variants for fine-mapping GWAS susceptibility loci.
PMCID: PMC3618611  PMID: 23295781
pancreatic cancer; targeted re-sequencing; GWAS; susceptibility loci; SNP; 1000G
12.  Common variation at 2q22.3 (ZEB2) influences the risk of renal cancer 
Human Molecular Genetics  2012;22(4):825-831.
Genome-wide association studies (GWASs) of renal cell cancer (RCC) have identified four susceptibility loci thus far. To identify an additional RCC common susceptibility locus, we conducted a GWAS and performed a meta-analysis with published GWASs (totalling 2215 cases and 8566 controls of European background) and followed up the most significant association signals [nine single nucleotide polymorphisms (SNPs) in eight genomic regions] in 3739 cases and 8786 controls. A combined analysis identified a novel susceptibility locus mapping to 2q22.3 marked by rs12105918 (P = 1.80 × 10−8; odds ratio 1.29, 95% CI: 1.18–1.41). The signal localizes to intron 2 of the ZEB2 gene (zinc finger E box-binding homeobox 2). Our findings suggest that genetic variation in ZEB2 influences the risk of RCC. This finding provides further insights into the genetic and biological basis of inherited genetic susceptibility to RCC.
PMCID: PMC3554205  PMID: 23184150
13.  Fine-Mapping the HOXB Region Detects Common Variants Tagging a Rare Coding Allele: Evidence for Synthetic Association in Prostate Cancer 
PLoS Genetics  2014;10(2):e1004129.
The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10−14). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.
Author Summary
Genome-wide association studies (GWAS) have identified numerous low penetrance disease susceptibility variants, yet few causal alleles have been unambiguously identified. The underlying causal variants are expected to be predominantly common; however synthetic associations with rare, higher penetrance variants have been hypothesised though not yet observed. Here, we report detection of a novel common, low penetrance prostate cancer association at the HOXB locus at ch17q and show that this signal can actually be attributed to a previously identified rare, moderate penetrance coding variant (G84E) in HOXB13. This study therefore provides the first experimental evidence for the existence of synthetic associations in cancer and shows that where GWAS signals arise through this phenomenon, risk predictions derived using the tag SNP would substantially underestimate the relative risk conferred and overestimate the number of carriers of the causal variant. Synthetic associations at GWAS signals could therefore account for a proportion of the missing heritability of complex diseases.
PMCID: PMC3923678  PMID: 24550738
14.  A Genome-Wide “Pleiotropy Scan” Does Not Identify New Susceptibility Loci for Estrogen Receptor Negative Breast Cancer 
PLoS ONE  2014;9(2):e85955.
Approximately 15–30% of all breast cancer tumors are estrogen receptor negative (ER−). Compared with ER-positive (ER+) disease they have an earlier age at onset and worse prognosis. Despite the vast number of risk variants identified for numerous cancer types, only seven loci have been unambiguously identified for ER-negative breast cancer. With the aim of identifying new susceptibility SNPs for this disease we performed a pleiotropic genome-wide association study (GWAS). We selected 3079 SNPs associated with a human complex trait or disease at genome-wide significance level (P<5×10−8) to perform a secondary analysis of an ER-negative GWAS from the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3), including 1998 cases and 2305 controls from prospective studies. We then tested the top ten associations (i.e. with the lowest P-values) using three additional populations with a total sample size of 3509 ER+ cases, 2543 ER− cases and 7031 healthy controls. None of the 3079 selected variants in the BPC3 ER-GWAS were significant at the adjusted threshold. 186 variants were associated with ER− breast cancer risk at a conventional threshold of P<0.05, with P-values ranging from 0.049 to 2.3×10−4. None of the variants reached statistical significance in the replication phase. In conclusion, this study did not identify any novel susceptibility loci for ER-breast cancer using a “pleiotropic approach”.
PMCID: PMC3921107  PMID: 24523857
15.  Occupational solvent exposure, genetic variation in immune genes, and the risk for non-Hodgkin lymphoma 
Solvent exposure has been inconsistently linked to the risk for non-Hodgkin lymphoma (NHL). The aim of this study was to determine whether the association is modified by genetic variation in immune genes. A population-based case–control study involving 601 incident cases of NHL and 717 controls was carried out in 1996–2000 among women from Connecticut. Thirty single nucleotide polymorphisms in 17 immune genes were examined in relation to the associations between exposure to various solvents and the risk for NHL. The study found that polymorphism in interleukin 10 (IL10; rs1800890) modified the association between occupational exposure to organic solvents and the risk for diffuse large B-cell lymphoma (Pfor interaction=0.0058). The results remained statistically significant after adjustment for false discovery rate. Compared with women who were never occupationally exposed to any organic solvents, women who were exposed to organic solvents at least once had a significantly increased risk for diffuse large B-cell lymphoma if they carried the IL10 (rs1800890) TT genotype (odds ratio=3.31, 95% confidence interval: 1.80–6.08), but not if they carried the AT/AA genotype (odds ratio=1.14, 95% confidence interval: 0.72–1.79). No significant interactions were observed for other immune gene single nucleotide polymorphisms and various solvents in relation to NHL overall and its major subtypes. The study provided preliminary evidence supporting a role of immune gene variations in modifying the association between occupational solvent exposure and the risk for NHL.
PMCID: PMC3469764  PMID: 22609637
immune genes; non-Hodgkin lymphoma; occupational exposure; single nucleotide polymorphism; solvents
16.  Diabetes and risk of pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium 
Cancer causes & control : CCC  2012;24(1):13-25.
Diabetes is a suspected risk factor for pancreatic cancer, but questions remain about whether it is a risk factor or a result of the disease. This study prospectively examined the association between diabetes and the risk of pancreatic adenocarcinoma in pooled data from the NCI pancreatic cancer cohort consortium (PanScan).
The pooled data included 1,621 pancreatic adenocarcinoma cases and 1,719 matched controls from twelve cohorts using a nested case–control study design. Subjects who were diagnosed with diabetes near the time (<2 years) of pancreatic cancer diagnosis were excluded from all analyses. All analyses were adjusted for age, race, gender, study, alcohol use, smoking, BMI, and family history of pancreatic cancer.
Self-reported diabetes was associated with a forty percent increased risk of pancreatic cancer (OR = 1.40, 95 % CI: 1.07, 1.84). The association differed by duration of diabetes; risk was highest for those with a duration of 2–8 years (OR = 1.79, 95 % CI: 1.25, 2.55); there was no association for those with 9+ years of diabetes (OR = 1.02, 95 % CI: 0.68, 1.52).
These findings provide support for a relationship between diabetes and pancreatic cancer risk. The absence of association in those with the longest duration of diabetes may reflect hypoinsulinemia and warrants further investigation.
PMCID: PMC3529822  PMID: 23112111
Diabetes; Risk factor; Cohort consortium; Pancreatic cancer
17.  A genome-wide association study of breast cancer in women of African ancestry 
Human genetics  2012;132(1):39-48.
Genome-wide association studies (GWAS) in diverse populations are needed to reveal variants that are more common and/or limited to defined populations. We conducted a GWAS of breast cancer in women of African ancestry, with genotyping of > 1,000,000 SNPs in 3,153 African American cases and 2,831 controls, and replication testing of the top 66 associations in an additional 3,607 breast cancer cases and 11,330 controls of African ancestry. Two of the 66 SNPs replicated (p < 0.05) in stage 2, which reached statistical significance levels of 10−6 and 10−5 in the stage 1 and 2 combined analysis (rs4322600 at chromosome 14q31: OR = 1.18, p = 4.3×10−6; rs10510333 at chromosome 3p26: OR = 1.15, p = 1.5×10−5). These suggestive risk loci have not been identified in previous GWAS in other populations and will need to be examined in additional samples. Identification of novel risk variants for breast cancer in women of African ancestry will demand testing of a substantially larger set of markers from stage 1 in a larger replication sample.
PMCID: PMC3749077  PMID: 22923054
GWAS; breast cancer; African ancestry; common genetic variation
18.  Application of Multi-SNP Approaches Bayesian LASSO and AUC-RF to Detect Main Effects of Inflammatory-Gene Variants Associated with Bladder Cancer Risk 
PLoS ONE  2013;8(12):e83745.
The relationship between inflammation and cancer is well established in several tumor types, including bladder cancer. We performed an association study between 886 inflammatory-gene variants and bladder cancer risk in 1,047 cases and 988 controls from the Spanish Bladder Cancer (SBC)/EPICURO Study. A preliminary exploration with the widely used univariate logistic regression approach did not identify any significant SNP after correcting for multiple testing. We further applied two more comprehensive methods to capture the complexity of bladder cancer genetic susceptibility: Bayesian Threshold LASSO (BTL), a regularized regression method, and AUC-Random Forest, a machine-learning algorithm. Both approaches explore the joint effect of markers. BTL analysis identified a signature of 37 SNPs in 34 genes showing an association with bladder cancer. AUC-RF detected an optimal predictive subset of 56 SNPs. 13 SNPs were identified by both methods in the total population. Using resources from the Texas Bladder Cancer study we were able to replicate 30% of the SNPs assessed. The associations between inflammatory SNPs and bladder cancer were reexamined among non-smokers to eliminate the effect of tobacco, one of the strongest and most prevalent environmental risk factor for this tumor. A 9 SNP-signature was detected by BTL. Here we report, for the first time, a set of SNP in inflammatory genes jointly associated with bladder cancer risk. These results highlight the importance of the complex structure of genetic susceptibility associated with cancer risk.
PMCID: PMC3877090  PMID: 24391818
19.  Genomic Variation in a Global Village: Report of the 10th Annual Human Genome Variation Meeting 2008 
Human mutation  2009;30(7):10.1002/humu.21008.
The Centre for Applied Genomics of the Hospital for Sick Children and the University of Toronto hosted the 10th Human Genome Variation (HGV) Meeting in Toronto, Canada, in October 2008, welcoming about 240 registrants from 34 countries. During the 3 days of plenary workshops, keynote address, and poster sessions, a strong cross-disciplinary trend was evident, integrating expertise from technology and computation, through biology and medicine, to ethics and law. Single nucleotide polymorphisms (SNPs) as well as the larger copy number variants (CNVs) are recognized by ever-improving array and next-generation sequencing technologies, and the data are being incorporated into studies that are increasingly genome-wide as well as global in scope. A greater challenge is to convert data to information, through databases, and to use the information for greater understanding of human variation. In the wake of publications of the first individual genome sequences, an inaugural public forum provided the opportunity to debate whether we are ready for personalized medicine through direct-to-consumer testing. The HGV meetings foster collaboration, and fruits of the interactions from 2008 are anticipated for the 11th annual meeting in September 2009.
PMCID: PMC3873344  PMID: 19384970
SNP; CNV; GWAS; personalized medicine
20.  HGV2009 Meeting: Bigger and Better Studies Provide More Answers and More Questions 
Human mutation  2010;31(7):10.1002/humu.21270.
The 11th International Meeting on Human Genome Variation and Complex Genome Analysis (HGV2009: Tallinn, Estonia, 11th–13th September 2009) provided a stimulating workshop environment where diverse academics and industry representatives explored the latest progress, challenges, and opportunities in relating genome variation to evolution, technology, health, and disease. Key themes included Genome-Wide Association Studies (GWAS), progress beyond GWAS, sequencing developments, and bioinformatics approaches to large-scale datasets.
PMCID: PMC3871991  PMID: 20506253
HGV2009; SNP; variation; GWAS; CNV
21.  HGV2011: Personalized Genomic Medicine Meets the Incidentalome 
Human mutation  2012;33(3):10.1002/humu.22008.
The 12th International Meeting on Human Genome Variation and Complex Genome Analysis (HGV2011: Berkeley, California, USA, 8th–10th September 2011) was a stimulating workshop where researchers from academia and industry explored the latest progress, challenges, and opportunities in genome variation research. Key themes included progress beyond GWAS, variation in human populations, use of sequence data in medical settings, large-scale sequencing data analysis, and bioinformatics approaches to large datasets.
PMCID: PMC3867005  PMID: 22170622
human variation; GWAS; SNP; medical genomics
22.  Association of Type 2 Diabetes Susceptibility Variants With Advanced Prostate Cancer Risk in the Breast and Prostate Cancer Cohort Consortium 
American Journal of Epidemiology  2012;176(12):1121-1129.
Observational studies have found an inverse association between type 2 diabetes (T2D) and prostate cancer (PCa), and genome-wide association studies have found common variants near 3 loci associated with both diseases. The authors examined whether a genetic background that favors T2D is associated with risk of advanced PCa. Data from the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium, a genome-wide association study of 2,782 advanced PCa cases and 4,458 controls, were used to evaluate whether individual single nucleotide polymorphisms or aggregations of these 36 T2D susceptibility loci are associated with PCa. Ten T2D markers near 9 loci (NOTCH2, ADCY5, JAZF1, CDKN2A/B, TCF7L2, KCNQ1, MTNR1B, FTO, and HNF1B) were nominally associated with PCa (P < 0.05); the association for single nucleotide polymorphism rs757210 at the HNF1B locus was significant when multiple comparisons were accounted for (adjusted P = 0.001). Genetic risk scores weighted by the T2D log odds ratio and multilocus kernel tests also indicated a significant relation between T2D variants and PCa risk. A mediation analysis of 9,065 PCa cases and 9,526 controls failed to produce evidence that diabetes mediates the association of the HNF1B locus with PCa risk. These data suggest a shared genetic component between T2D and PCa and add to the evidence for an interrelation between these diseases.
PMCID: PMC3571230  PMID: 23193118
carcinoma; diabetes mellitus, type 2; genetic predisposition to disease; genetics; genome-wide association study; humans; polymorphism, single nucleotide; prostatic neoplasms
23.  Meta-analysis identifies four new loci associated with testicular germ cell tumor 
Nature genetics  2013;45(6):10.1038/ng.2634.
We conducted a meta-analysis to identify new loci for testicular germ cell tumor (TGCT) susceptibility. In the discovery phase, 931 affected individuals and 1,975 controls from three genome wide association studies (GWAS) were analyzed. Replication was conducted in six independent sample sets totaling 3,211 affected individuals and 7,591 controls. In the combined analysis, TGCT risk was significantly associated with markers at four novel loci: 4q22.2 in HPGDS (per allele odds ratio (OR) 1.19, 95%CI 1.12–1.26, P = 1.11×10−8); 7p22.3 in MAD1L1 (OR 1.21, 95%CI 1.14–1.29, P = 5.59×10−9); 16q22.3 in RFWD3 (OR 1.26, 95%CI 1.18–1.34, P = 5.15×10−12); and 17q22 (rs9905704; OR 1.27, 95%CI 1.18–1.33; P = 4.32×10−13, and rs7221274; OR 1.20, 95%CI 1.12–1.28 P = 4.04×10−9), a locus which includes TEX14, RAD51C and PPM1E. The new TGCT susceptibility loci contain biologically plausible genes encoding proteins important for male germ cell development, chromosomal segregation and DNA damage response.
PMCID: PMC3723930  PMID: 23666239
24.  Common obesity-related genetic variants and papillary thyroid cancer risk 
Epidemiologic studies have shown consistent associations between obesity and increased thyroid cancer risk, but, to date, no studies have investigated the relationship between thyroid cancer risk and obesity-related single nucleotide polymorphisms (SNPs).
We evaluated 575 tag SNPs in 23 obesity-related gene regions in a case-control study of 341 incident papillary thyroid cancer (PTC) cases and 444 controls of European ancestry. Logistic regression models, adjusted for attained age, year of birth, and sex were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) with SNP genotypes, coded as 0, 1, and 2 and modeled continuously to calculate P-trends.
Nine out of 10 top-ranking SNPs (Ptrend<0.01) were located in the FTO (fat mass and obesity associated) gene region, while the other was located in INSR (insulin receptor). None of the associations were significant after correcting for multiple testing.
Our data do not support an important role of obesity-related genetic polymorphisms in determining the risk of PTC.
Factors other than selected genetic polymorphisms may be responsible for the observed associations between obesity and increased PTC risk.
PMCID: PMC3518668  PMID: 23064004
single nucleotide polymorphisms; case-control study; obesity; body mass index; thyroid neoplasms
25.  Likelihood Ratio Test for Detecting Gene (G)-Environment (E) Interactions Under an Additive Risk Model Exploiting G-E Independence for Case-Control Data 
American Journal of Epidemiology  2012;176(11):1060-1067.
There has been a long-standing controversy in epidemiology with regard to an appropriate risk scale for testing interactions between genes (G) and environmental exposure (E ). Although interaction tests based on the logistic model—which approximates the multiplicative risk for rare diseases—have been more widely applied because of its convenience in statistical modeling, interactions under additive risk models have been regarded as closer to true biologic interactions and more useful in intervention-related decision-making processes in public health. It has been well known that exploiting a natural assumption of G-E independence for the underlying population can dramatically increase statistical power for detecting multiplicative interactions in case-control studies. However, the implication of the independence assumption for tests for additive interaction has not been previously investigated. In this article, the authors develop a likelihood ratio test for detecting additive interactions for case-control studies that incorporates the G-E independence assumption. Numerical investigation of power suggests that incorporation of the independence assumption can enhance the efficiency of the test for additive interaction by 2- to 2.5-fold. The authors illustrate their method by applying it to data from a bladder cancer study.
PMCID: PMC3571244  PMID: 23118105
additive risk model; case-control studies; gene-environment independence; gene-environment interaction; multiplicative risk model

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