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1.  Genome-wide association studies of gastric adenocarcinoma and esophageal squamous cell carcinoma identify a shared susceptibility locus in PLCE1 at 10q23 
Nature genetics  2012;44(10):1090-1097.
We conducted a genome-wide association study of gastric cancer (GC) and esophageal squamous cell carcinoma (ESCC) in ethnic Chinese subjects in which we genotyped 551,152 single nucleotide polymorphisms (SNPs). We report a combined analysis of 2,240 GC cases, 2,115 ESCC cases, and 3,302 controls drawn from five studies. In logistic regression models adjusted for age, sex, and study, multiple variants at 10q23 had genome-wide significance for GC and ESCC independently. A notable signal was rs2274223, a nonsynonymous SNP located in PLCE1, for GC (P=8.40×1010; per allele odds ratio (OR) = 1.31) and ESCC (P=3.85×10−9; OR = 1.34). The association with GC differed by anatomic subsite. For tumors located in the cardia the association was stronger (P=4.19 × 10−15; OR= 1.57) and for those located in the noncardia stomach it was absent (P=0.44; OR=1.05). Our findings at 10q23 could provide insight into the high incidence rates of both cancers in China.
doi:10.1038/ng.2411
PMCID: PMC3513832  PMID: 22960999
2.  Cancer GAMAdb: database of cancer genetic associations from meta-analyses and genome-wide association studies 
In the field of cancer, genetic association studies are among the most active and well-funded research areas, and have produced hundreds of genetic associations, especially in the genome-wide association studies (GWAS) era. Knowledge synthesis of these discoveries is the first critical step in translating the rapidly emerging data from cancer genetic association research into potential applications for clinical practice. To facilitate the effort of translational research on cancer genetics, we have developed a continually updated database named Cancer Genome-wide Association and Meta Analyses database that contains key descriptive characteristics of each genetic association extracted from published GWAS and meta-analyses relevant to cancer risk. Here we describe the design and development of this tool with the aim of aiding the cancer research community to quickly obtain the current updated status in cancer genetic association studies.
doi:10.1038/ejhg.2011.53
PMCID: PMC3172934  PMID: 21487441
cancer; meta-analyses; pooled analyses; GWAS
3.  Genome-wide association studies of gastric adenocarcinoma and esophageal squamous cell carcinoma identify a shared susceptibility locus in PLCE1 at 10q23 
Nature genetics  2010;42(9):764-767.
We conducted a genome-wide association study of gastric cancer (GC) and esophageal squamous cell carcinoma (ESCC) in ethnic Chinese subjects in which we genotyped 551,152 single nucleotide polymorphisms (SNPs). We report a combined analysis of 2,240 GC cases, 2,115 ESCC cases, and 3,302 controls drawn from five studies. In logistic regression models adjusted for age, sex, and study, multiple variants at 10q23 had genome-wide significance for GC and ESCC independently. A notable signal was rs2274223, a nonsynonymous SNP located in PLCE1, for GC (P=8.40×10−9; per allele odds ratio (OR) = 1.31) and ESCC (P=3.85×10−9; OR = 1.34). The association with GC differed by anatomic subsite. For tumors located in the cardia the association was stronger (P=4.19 × 10−15; OR= 1.57) and for those located in the noncardia stomach it was absent (P=0.44; OR=1.05). Our findings at 10q23 could provide insight into the high incidence rates of both cancers in China.
doi:10.1038/ng.649
PMCID: PMC2947317  PMID: 20729852
4.  Epidemiology and risk factors for kidney cancer 
Nature reviews. Urology  2010;7(5):245-257.
After over two decades of increasing rates, kidney cancer incidence trends worldwide show signs of plateauing or decreases in recent years. In the United States, rates for renal cell cancer, the predominant form of kidney cancer in adults, continue to rise but mainly for early stage tumors. Incidence rates for renal pelvis cancer have declined, while kidney cancer mortality rates overall have leveled. These patterns are consistent with reports of incidental diagnosis and downward shift of tumor stage and size in clinical series. The changing prevalence of known risk factors for renal cell cancer, including cigarette smoking, obesity, and hypertension, may also be influencing the incidence trends, although their relative impact may differ in various populations,. Evidence is accumulating to suggest an etiologic role for physical activity, alcohol consumption, occupational exposure to trichloroethylene, and high parity among women, but causal conclusions are not yet supported. Genetic susceptibility and its interaction with environmental exposures are believed to influence renal cell cancer risk, but limited studies based on candidate gene approaches have not produced conclusive results. Large consortium efforts employing genome-wide scanning technology are underway, which hold promise for novel discoveries in renal carcinogenesis.
doi:10.1038/nrurol.2010.46
PMCID: PMC3012455  PMID: 20448658
5.  Telomere Length in Peripheral Leukocyte DNA and Gastric Cancer Risk 
Telomere length reflects lifetime cumulative oxidative stress from environmental exposures, such as cigarette smoking and chronic inflammation. Shortened telomere length is thought to cause genomic instability and has been associated with several cancers. We examined the association of telomere length in peripheral leukocyte DNA with gastric cancer risk as well as potential confounding factors and risk modifiers for telomere length–related risk. In a population-based study of gastric cancer conducted in a high-risk population in Warsaw, Poland, between 1994 and 1996, we measured relative telomere length in 300 cases and 416 age- and gender-matched controls using quantitative real-time PCR. Among controls, telomeres were significantly shorter in association with aging (P < 0.001), increasing pack-years of cigarette smoking (P = 0.02), decreasing fruit intake (P = 0.04), and Helicobacter pylori positivity (P = 0.03). Gastric cancer cases had significantly shorter telomere length (mean ± SD relative telomere length, 1.25 ± 0.34) than controls (1.34 ± 0.35; P = 0.0008). Gastric cancer risk doubled [odds ratio (OR), 2.04; 95% confidence interval (95% CI), 1.33-3.13] among subjects in the shortest compared with the highest quartile of telomere length (Ptrend < 0.001). Telomere length–associated risks were higher among individuals with the lowest risk profile, those H. pylori–negative (OR, 5.45; 95% CI, 2.10-14.1), non-smokers (OR, 3.07; 95% CI, 1.71-5.51), and individuals with high intake of fruits (OR, 2.43; 95% CI, 1.46-4.05) or vegetables (OR, 2.39; 95% CI, 1.51-3.81). Our results suggest that telomere length in peripheral leukocyte DNA was associated with H. pylori positivity, cigarette smoking, and dietary fruit intake. Shortened telomeres increased gastric cancer risk in this high-risk Polish population.
doi:10.1158/1055-9965.EPI-09-0347
PMCID: PMC2938741  PMID: 19861514
6.  Urinary Prostaglandin E2 metabolite and Gastric Cancer Risk in the Shanghai Women’s Health Study 
Chronic inflammation has been implicated in the etiology of gastric cancer. Prostaglandin-E2(PGE2) is one of the major end products of the COX-2 pathway, an enzyme that is an important mediator of inflammation. Using a novel method of quantifying the primary urinary metabolite of PGE2(PGE-M, 11 alpha-hydroxy-9,15-dioxo-2,3,4,5-tetranorprostane-1,20-dioic acid), we evaluated urinary PGE-M concentrations in association with subsequent risk of development of gastric cancer in the Shanghai Women’s Health Study, a large population-based prospective cohort, using a nested case-control study design. Controls were matched(1:1) to 153 gastric cancer cases by menopausal status; age, time and date of sample collection; time interval since last meal and availability of urine sample. Odds ratios(OR) and 95% confidence intervals(95%CI) were calculated using conditional logistic regression adjusted for potential confounders. Baseline urinary PGE-M levels were slightly higher among gastric cancer cases with a median of 6.4 ng/mg creatinine (interquartile range: 3.4–11.2) compared to 5.4 among controls (interquartile range: 2.8–9.0) but this difference was not statistically significant (Wilcoxon p-value=0.34). With increasing quartiles of urinary PGE-M levels, the ORs for risk of gastric cancer increased in quartiles 2, 3, and 4: 1.00 (95%CI:0.48–2.08), 1.40 (95%CI:0.67–2.91) and 1.98 (95%CI:0.95–4.13), with a statistically significant test for trend (p=0.04). The association persisted after additional adjustment for H. pylori status, and was slightly strengthened among non-NSAID users, subjects with positive H. pylori status, and for cases diagnosed within 46 months after study enrollment. Our findings suggest that higher levels of urinary PGE-M, a marker of inflammation, may be associated with gastric cancer risk.
doi:10.1158/1055-9965.EPI-09-0680
PMCID: PMC2783404  PMID: 19861525
gastric cancer; prostaglandins; inflammation; urinary marker
7.  Vitamin D Related Genes, CYP24A1 and CYP27B1, and Colon Cancer Risk 
Genetic association studies investigating the role of vitamin D in colon cancer have primarily focused on the vitamin D receptor(VDR), with limited data available for other genes in the vitamin D pathway, including vitamin D activating enzyme 1-alpha hydroxylase(CYP27B1) and vitamin D deactivating enzyme 24-alpha hydroxylase(CYP24A1). We evaluated whether 12 tagging SNPs in CYP24A1, identified by resequencing the gene in 32 Caucasian samples, and 1 SNP in CYP27B1 were associated with colon cancer risk. In addition, we evaluated whether these two genes modify associations between colon cancer and total vitamin D intake and UV-weighted sun exposure, as well as other variants in VDR. Unconditional logistic regression was used to calculate odds ratios(OR) and 95% confidence intervals(95%CI) for the association between polymorphisms and haplotypes in CYP27B1 and CYP24A1 in a multi-center population-based case-control study of 1,600 cases and 1,949 controls. CYP24A1 polymorphism IVS4-66T>G showed a statistically significant association with risk of colon cancer overall, particularly for proximal colon cancer. When stratified by anatomic site, we also found statistically significant associations for three CYP24A1 polymorphisms with risk of distal colon cancer (IVS4+1653C>T: OR for CT/TT vs. CC 0.81, 95%CI 0.68–0.96; IVS9+198T>C: OR for CC vs. TT 1.33, 95%CI 1.03–1.73; and within Whites only: +4125bp 3′ of STPC>G: OR for GG vs. CC 1.44, 95%CI 1.00–2.05). In addition, a possible interaction between CYP27B1 and UV-weighted sun exposure with proximal colon cancer was observed. As this is the first study to evaluate these genes in relation to colon cancer, additional studies are needed to confirm these results.
doi:10.1158/1055-9965.EPI-09-0228
PMCID: PMC2761078  PMID: 19706847
vitamin D; colon cancer; genetics; CYP24A1; CYP27B1
8.  Genetic Susceptibility to Cancer: the Role of Polymorphisms in Candidate Genes 
Context
Continuing advances in genotyping technologies and the inclusion of DNA collection in observational studies have resulted in an increasing number of genetic association studies.
Objective
To evaluate the overall progress and contribution of candidate gene association studies to current understanding of the genetic susceptibility to cancer.
Data Sources
We systematically examined the results of meta- and pooled analyses for genetic polymorphisms and cancer risk published through March 2008.
Study Selection
We identified 161 meta- and pooled analyses, encompassing 18 cancer sites and 99 genes. Analyses had to meet the following criteria: 1) at least 500 cases, 2) cancer risk as outcome, 3) not focused on HLA genetic markers, and 4) published in English.
Data Extraction
Information on cancer site, gene name, variant, point estimate and 95% confidence interval, allelic frequency, number of studies and cases, tests of study heterogeneity and publication bias were extracted by one investigator and reviewed by other investigators.
Results
These 161 analyses evaluated 344 gene-variant/cancer associations and included on average 7.3 studies and 3,551 cases (range: 508–19,729 cases) per investigated association. The summary OR for 98 (28%) statistically significant associations (p-value <0.05) were further evaluated by estimating the false-positive report probability (FPRP) at a given prior probability and statistical power. At a prior probability level of 0.001 and statistical power to detect an OR of 1.5, thirteen gene-variant/cancer associations remained noteworthy (FPRP<0.2). Assuming a very low prior probability of 0.000001, similar to a probability assumed for a randomly selected SNP in a genome-wide association study, and statistical power to detect an OR of 1.5, four associations were considered noteworthy as denoted by a FPRP value < 0.2: 1) GSTM1 null and bladder cancer (OR:1.5, 95% CI: 1.3–1.6, p-value=1.9×10−14), 2) NAT2 slow acetylator and bladder cancer (OR: 1.46, 95% CI:1.26–1.68, p-value=2.5×10−7), 3) MTHFR C677T and gastric cancer (OR: 1.52, 95% CI: 1.31–1.77, p-value=4.9×10−8), and 4) GSTM1 null and acute leukemia (OR: 1.20, 95% CI: 1.14–1.25, p-value=8.6×10−15). When the OR used to determine statistical power was lowered to 1.2, two of the four noteworthy associations remained so: GSTM1 null with bladder cancer and acute leukemia.
Conclusions
Phase II enzymes, which are key enzymes involved in the detoxification and excretion of carcinogens (and particularly deletion of GSTM1), were among the most consistent and highly significant associations.
doi:10.1001/jama.299.20.2423
PMCID: PMC2772197  PMID: 18505952
9.  Genetic Variation in Calcium Sensing Receptor (CASR) and Risk of Colon Cancer 
Background
Experimental and epidemiologic studies have suggested that high calcium intake is associated with decreased colon cancer risk. Yet very limited data are available for candidate genes in the calcium/vitamin D pathway and colon cancer risk. To address this, we evaluated whether calcium sensing receptor(CASR) single nucleotide polymorphisms(SNP) are associated with colon cancer risk. We also examined interactions between CASR and calcium and vitamin D intake, and previously genotyped vitamin D-related genes.
Methods
We conducted a large multi-center population-based case-control study of 1,600 cases and 1,949 controls. Seventeen tagging SNPs for CASR were selected from common SNPs (minor allele frequency ≥5%) based on resequencing data. Haplotypes were estimated and evaluated using HaploStats.
Results
We did not observe an association between any CASR genotypes or haplotypes and colon cancer risk overall. However, when stratified by anatomic site, statistically significant associations were seen with risk of proximal colon cancer (rs10934578 TT: OR 1.35, 95%CI 1.01-1.81; rs12485716 AG/AA: OR 0.84, 95%CI 0.71-1.00; rs4678174 CT/CC: OR 0.83, 95%CI 0.70-0.98; rs2270916 CC: OR 0.43, 95%CI 0.19-0.97). Concordantly, we observed a suggested association for a CASR haplotype (rs4678174, rs2270916) with risk of proximal colon cancer (global p-value=0.08). We did not observe any meaningful gene-environment (calcium and vitamin D) or gene-gene (CYP24A1, CYP27B1, and VDR) interactions with CASR genotypes and colon cancer risk.
Conclusion
Our study does not provide evidence for an overall association between CASR SNPs and colon cancer; however, results suggest a possible role of CASR on proximal colon cancer and subsite differences are consistent with known calcium biology. Nonetheless, these findings require confirmation.
doi:10.1158/1055-9965.EPI-08-0388
PMCID: PMC2633716  PMID: 18843020
10.  An Analysis of Growth, Differentiation and Apoptosis Genes with Risk of Renal Cancer 
PLoS ONE  2009;4(3):e4895.
We conducted a case-control study of renal cancer (987 cases and 1298 controls) in Central and Eastern Europe and analyzed genomic DNA for 319 tagging single-nucleotide polymorphisms (SNPs) in 21 genes involved in cellular growth, differentiation and apoptosis using an Illumina Oligo Pool All (OPA). A haplotype-based method (sliding window analysis of consecutive SNPs) was used to identify chromosome regions of interest that remained significant at a false discovery rate of 10%. Subsequently, risk estimates were generated for regions with a high level of signal and individual SNPs by unconditional logistic regression adjusting for age, gender and study center. Three regions containing genes associated with renal cancer were identified: caspase 1/5/4/12(CASP 1/5/4/12), epidermal growth factor receptor (EGFR), and insulin-like growth factor binding protein-3 (IGFBP3). We observed that individuals with CASP1/5/4/12 haplotype (spanning area upstream of CASP1 through exon 2 of CASP5) GGGCTCAGT were at higher risk of renal cancer compared to individuals with the most common haplotype (OR:1.40, 95% CI:1.10–1.78, p-value = 0.007). Analysis of EGFR revealed three strong signals within intron 1, particularly a region centered around rs759158 with a global p = 0.006 (GGG: OR:1.26, 95% CI:1.04–1.53 and ATG: OR:1.55, 95% CI:1.14–2.11). A region in IGFBP3 was also associated with increased risk (global p = 0.04). In addition, the number of statistically significant (p-value<0.05) SNP associations observed within these three genes was higher than would be expected by chance on a gene level. To our knowledge, this is the first study to evaluate these genes in relation to renal cancer and there is need to replicate and extend our findings. The specific regions associated with risk may have particular relevance for gene function and/or carcinogenesis. In conclusion, our evaluation has identified common genetic variants in CASP1, CASP5, EGFR, and IGFBP3 that could be associated with renal cancer risk.
doi:10.1371/journal.pone.0004895
PMCID: PMC2656573  PMID: 19603096
11.  Dietary Supplement Use and Risk of Neoplastic Progression in Esophageal Adenocarcinoma 
Nutrition and cancer  2008;60(1):39-48.
The incidence of esophageal adenocarcinoma (EA) and its precursor condition, Barrett’s esophagus, has risen rapidly in the United States for reasons that are not fully understood. Therefore, we evaluated the association between use of supplemental vitamins and minerals and risk of neoplastic progression of Barrett’s esophagus and EA. The Seattle Barrett’s Esophagus Program is a prospective study based on 339 men and women with histologically confirmed Barrett’s esophagus. Participants underwent baseline and periodic follow-up exams, which included endoscopy and self-administered questionnaires on diet, supplement use, and lifestyle characteristics. Use of multivitamins and 4 individual supplements was calculated using time-weighted averages of reported use over the observational period. Cox proportional-hazards models were used to calculate hazard ratios (HR) for each endpoint: EA, tetraploidy, and aneuploidy. During a mean follow-up of 5 yr, there were 37 cases of EA, 42 cases of tetraploidy, and 34 cases of aneuploidy. After controlling for multiple covariates including diet, nonsteroidal anti-inflammatory drug use, obesity, and smoking, participants who took 1 or more multivitamin pills/day had a significantly decreased risk of tetraploidy [HR = 0.19; 95% confidence interval (CI) = 0.08-0.47) and EA (HR = 0.38; 95% CI = 0.15-0.99] compared to those not taking multivitamins. Significant inverse associations were also observed between risk of EA and supplemental vitamin C (≥250 mg vs. none: HR = 0.25; 95% 0.25; 95% CI = 0.11-0.58) and vitamin E (≥ 180 mg vs. none: HR = 0.25; 95% CI = 0.10-0.60). In this cohort study, use of multivitamins and single antioxidant supplements was associated with a significantly reduced risk of EA and markers of neoplastic progression among individuals with Barrett’s esophagus.
doi:10.1080/01635580701586762
PMCID: PMC2366201  PMID: 18444134

Results 1-11 (11)