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1.  Type I and II Endometrial Cancers: Have They Different Risk Factors? 
Journal of Clinical Oncology  2013;31(20):2607-2618.
Purpose
Endometrial cancers have long been divided into estrogen-dependent type I and the less common clinically aggressive estrogen-independent type II. Little is known about risk factors for type II tumors because most studies lack sufficient cases to study these much less common tumors separately. We examined whether so-called classical endometrial cancer risk factors also influence the risk of type II tumors.
Patients and Methods
Individual-level data from 10 cohort and 14 case-control studies from the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 14,069 endometrial cancer cases and 35,312 controls were included. We classified endometrioid (n = 7,246), adenocarcinoma not otherwise specified (n = 4,830), and adenocarcinoma with squamous differentiation (n = 777) as type I tumors and serous (n = 508) and mixed cell (n = 346) as type II tumors.
Results
Parity, oral contraceptive use, cigarette smoking, age at menarche, and diabetes were associated with type I and type II tumors to similar extents. Body mass index, however, had a greater effect on type I tumors than on type II tumors: odds ratio (OR) per 2 kg/m2 increase was 1.20 (95% CI, 1.19 to 1.21) for type I and 1.12 (95% CI, 1.09 to 1.14) for type II tumors (Pheterogeneity < .0001). Risk factor patterns for high-grade endometrioid tumors and type II tumors were similar.
Conclusion
The results of this pooled analysis suggest that the two endometrial cancer types share many common etiologic factors. The etiology of type II tumors may, therefore, not be completely estrogen independent, as previously believed.
doi:10.1200/JCO.2012.48.2596
PMCID: PMC3699726  PMID: 23733771
2.  ABO Blood Group and Risk of Pancreatic Cancer: A Study in Shanghai and Meta-Analysis 
American Journal of Epidemiology  2013;177(12):1326-1337.
Studies over 5 decades have examined ABO blood groups and risk of pancreatic cancer in Western, Asian, and other populations, though no systematic review has been published. We studied data from 908 pancreatic cancer cases and 1,067 population controls collected during December 2006–January 2011 in urban Shanghai, China, and reviewed the literature for all studies of this association. Random-effects meta-analysis provided summary odds ratio estimates according to blood group and by populations endemic versus nonendemic for cytotoxin-associated gene A (CagA)-positive Helicobacter pylori. In our Shanghai study, versus group O, only ABO group A was associated with risk (odds ratio (OR) = 1.60, 95% confidence interval (CI): 1.27, 2.03). In 24 pooled studies, group A showed increased risk in both CagA-nonendemic and -endemic populations (ORpooled = 1.40, 95% CI: 1.32, 1.49). In nonendemic populations, groups B and AB were also associated with higher risk (OR = 1.38, 95% CI: 1.16, 1.64; and OR = 1.52, 95% CI: 1.24, 1.85, respectively). However, in CagA-endemic populations, groups B and AB were not associated with risk (OR = 1.05, 95% CI: 0.92, 1.19; and OR = 1.13, 95% CI: 0.92, 1.38, respectively). These population differences were significant. One explanation for contrasts in associations of blood groups B and AB between CagA-endemic and -nonendemic populations could involve gastric epithelial expression of A versus B antigens on colonization behaviors of CagA-positive and CagA-negative H. pylori strains.
doi:10.1093/aje/kws458
PMCID: PMC3732019  PMID: 23652164
ABO blood group system; Asia; case-control studies; meta-analysis; pancreatic neoplasms
3.  Exome-Wide Association Study of Endometrial Cancer in a Multiethnic Population 
PLoS ONE  2014;9(5):e97045.
Endometrial cancer (EC) contributes substantially to total burden of cancer morbidity and mortality in the United States. Family history is a known risk factor for EC, thus genetic factors may play a role in EC pathogenesis. Three previous genome-wide association studies (GWAS) have found only one locus associated with EC, suggesting that common variants with large effects may not contribute greatly to EC risk. Alternatively, we hypothesize that rare variants may contribute to EC risk. We conducted an exome-wide association study (EXWAS) of EC using the Infinium HumanExome BeadChip in order to identify rare variants associated with EC risk. We successfully genotyped 177,139 variants in a multiethnic population of 1,055 cases and 1,778 controls from four studies that were part of the Epidemiology of Endometrial Cancer Consortium (E2C2). No variants reached global significance in the study, suggesting that more power is needed to detect modest associations between rare genetic variants and risk of EC.
doi:10.1371/journal.pone.0097045
PMCID: PMC4014590  PMID: 24810602
4.  The KRAS-Variant and miRNA Expression in RTOG Endometrial Cancer Clinical Trials 9708 and 9905 
PLoS ONE  2014;9(4):e94167.
Objective
To explore the association of a functional germline variant in the 3′-UTR of KRAS with endometrial cancer risk, as well as the association of microRNA (miRNA) signatures and the KRAS-variant with clinical characteristics and survival outcomes in two prospective RTOG endometrial cancer trials.
Methods/Materials
The association of the KRAS-variant with endometrial cancer risk was evaluated by case-control analysis of 467 women with type 1 or 2 endometrial cancer and 582 age-matched controls. miRNA and DNA were isolated for expression profiling and genotyping from tumor specimens of 46 women with type 1 endometrial cancer enrolled in RTOG trials 9708 and 9905. miRNA expression levels and KRAS-variant genotype were correlated with patient and tumor characteristics, and survival outcomes were evaluated by variant allele type.
Results
The KRAS-variant was not significantly associated with overall endometrial cancer risk (14% controls and 17% type 1 cancers), although was enriched in type 2 endometrial cancers (24%, p = 0.2). In the combined analysis of RTOG 9708/9905, miRNA expression differed by age, presence of lymphovascular invasion and KRAS-variant status. Overall survival rates at 3 years for patients with the variant and wild-type alleles were 100% and 77% (HR 0.3, p = 0.24), respectively, favoring the variant.
Conclusions
The KRAS-variant may be a genetic marker of risk for type 2 endometrial cancers. In addition, tumor miRNA expression appears to be associated with patient age, lymphovascular invasion and the KRAS-variant, supporting the hypothesis that altered tumor biology can be measured by miRNA expression, and that the KRAS-variant likely impacts endometrial tumor biology.
doi:10.1371/journal.pone.0094167
PMCID: PMC3986055  PMID: 24732316
5.  Omega-3 and omega-6 fatty acid intakes and endometrial cancer risk in a population-based case–control study 
European journal of nutrition  2012;52(3):1251-1260.
Purpose
Animal and laboratory studies suggest that long-chain omega-3 (n-3) fatty acids, a type of polyunsaturated fat found in fatty fish, may protect against carcinogenesis, but human studies on dietary intake of polyunsaturated fats and fish with endometrial cancer risk show mixed results.
Methods
We evaluated the associations between endometrial cancer risk and intake of fatty acids and fish in a population-based sample of 556 incident cancer cases and 533 age-matched controls using multivariate unconditional logistic regression methods.
Results
Although total n-3 fatty acid intake was not associated with endometrial cancer risk, higher intakes of eicosapentaenoic (EPA 20:5) and docosahexaenoic (DHA 22:6) fatty acids were significantly associated with lower risks (OR = 0.57, 95 % CI: 0.39–0.84; OR = 0.64, 95 % CI: 0.44–0.94; respectively) comparing extreme quartiles. The ratio of n-3:n-6 fatty acids was inversely associated with risk only on a continuous scale (OR = 0.84, 95 % CI: 0.71–0.99), while total fish intake was not associated with risk. Fish oil supplement use was significantly associated with reduced risk of endometrial cancer: OR = 0.63 (95 % CI: 0.45–0.88).
Conclusions
Our results suggest that dietary intake of the long-chain polyunsaturated fatty acids EPA and DHA in foods and supplements may have protective associations against the development of endometrial cancer.
doi:10.1007/s00394-012-0436-z
PMCID: PMC3548981  PMID: 22915050
Endometrial cancer; Fatty acids; Fish oil; Fish; Case–control study
6.  Re-evaluation of ABO gene polymorphisms detected in a genome-wide association study and risk of pancreatic ductal adenocarcinoma in a Chinese population 
Chinese Journal of Cancer  2014;33(2):68-73.
Pancreatic cancer is a fatal malignancy with an increasing incidence in Shanghai, China. A genome-wide association study (GWAS) and other work have shown that ABO alleles are associated with pancreatic cancer risk. We conducted a population-based case-control study involving 256 patients with pathologically confirmed pancreatic ductal adenocarcinoma (PDAC) and 548 healthy controls in Shanghai, China, to assess the relationships between GWAS-identified ABO alleles and risk of PDAC. Carriers of the C allele of rs505922 had an increased cancer risk [adjusted odds ratio (OR) = 1.42, 95% confidence interval (CI): 1.02-1.98] compared to TT carriers. The T alleles of rs495828 and rs657152 were also significantly associated with an elevated cancer risk (adjusted OR = 1.58, 95% CI: 1.17-2.14; adjusted OR = 1.51, 95% CI: 1.09-2.10). The rs630014 variant was not associated with risk. We did not find any significant gene-environment interaction with cancer risk using a multifactor dimensionality reduction (MDR) method. Haplotype analysis also showed that the haplotype CTTC was associated with an increased risk of PDAC (adjusted OR = 1.46, 95% CI: 1.12-1.91) compared with haplotype TGGT. GWAS-identified ABO variants are thus also associated with risk of PDAC in the Chinese population.
doi:10.5732/cjc.013.10060
PMCID: PMC3884064  PMID: 23816557
Pancreatic ductal adenocarcinoma; ABO gene; genome-wide association study; genetic variation; haplotype
7.  Obesity and risk of ovarian cancer subtypes: evidence from the Ovarian Cancer Association Consortium 
Endocrine-related cancer  2013;20(2):10.1530/ERC-12-0395.
Whilst previous studies have reported that higher body-mass index (BMI) increases a woman’s risk of developing ovarian cancer, associations for the different histological subtypes have not been well defined. As the prevalence of obesity has increased dramatically, and classification of ovarian histology has improved in the last decade, we sought to examine the association in a pooled analysis of recent studies participating in the Ovarian Cancer Association Consortium. We evaluated the association between BMI (recent, maximum, and in young adulthood) and ovarian cancer risk using original data from 15 case-control studies (13,548 cases, 17,913 controls). We combined study-specific adjusted odds ratios (ORs) using a random–effects model. We further examined the associations by histological subtype, menopausal status and post-menopausal hormone use. High BMI (all time-points) was associated with increased risk. This was most pronounced for borderline serous (recent BMI: pooled OR=1.24 per 5kg/m2; 95%CI 1.18–1.30), invasive endometrioid (1.17; 1.11–1.23) and invasive mucinous (1.19; 1.06–1.32) tumours. There was no association with serous invasive cancer overall (0.98; 0.94–1.02), but increased risks for low grade serous invasive tumours (1.13, 1.03–1.25) and in pre-menopausal women (1.11; 1.04–1.18). Among post–menopausal women, the associations did not differ between HRT users and non–users. Whilst obesity appears to increase risk of the less common histological subtypes of ovarian cancer, it does not increase risk of high grade invasive serous cancers, and reducing BMI is therefore unlikely to prevent the majority of ovarian cancer deaths. Other modifiable factors must be identified to control this disease.
doi:10.1530/ERC-12-0395
PMCID: PMC3857135  PMID: 23404857
ovarian cancer; obesity; body mass index
8.  Green tea drinking and risk of pancreatic cancer: a large-scale, population-based case-control study in urban Shanghai 
Cancer epidemiology  2012;36(6):e354-e358.
Background
Little is known about the etiology of pancreatic cancer. Epidemiological studies on tea consumption and pancreatic cancer risk have been inconclusive. The purpose of the present study was to investigate the association between green tea drinking and the risk of pancreatic cancer in urban Shanghai, China.
Methods
In this population-based case-control study conducted in urban Shanghai, 908 cases of pancreatic cancer and 1067 healthy controls were recruited. Information on tea drinking, including type of tea, amount of tea consumption, temperature of tea, and the duration of regular tea drinking, were collected via interview questionnaire.
Results
We examined the association of multiple tea drinking habits with the risk of pancreatic cancer. In women, regular green tea drinking was associated with 32% reduction of pancreatic cancer risk (OR 0.68, 95% CI 0.48–0.96), compared to those who did not drink tea regularly. Increased consumption and longer duration of tea drinking were both associated with reduced pancreatic cancer risk in women. Among regular tea drinkers, lower temperature of tea was associated with reduced risk of pancreatic cancer in both men and women, independent of amount or duration of tea drinking.
Conclusions
Habits of green tea drinking, including regular drinking, amount of consumption, persistence of the habit, and tea temperature, may lower pancreatic cancer risk.
doi:10.1016/j.canep.2012.08.004
PMCID: PMC3490023  PMID: 22944495
pancreatic cancer; tea; case-control study; China
9.  Effect of Exercise on Markers of Inflammation in Breast Cancer Survivors: The Yale Exercise and Survivorship Study 
Cancer prevention research (Philadelphia, Pa.)  2012;6(2):10.1158/1940-6207.CAPR-12-0278.
Physical activity is associated with improved breast cancer survival, but the underlying mechanisms, possibly including modification of the inflammatory state, are not well understood. We analyzed changes in interleukin (IL)-6, C-reactive protein (CRP), and TNF-α in a randomized controlled trial of exercise in postmenopausal breast cancer survivors. Seventy-five women, recruited through the Yale-New Haven Hospital Tumor Registry, were randomized to either a six-month aerobic exercise intervention or usual care. Correlations were calculated between baseline cytokines, adiposity, and physical activity measures. Generalized linear models were used to assess the effect of exercise on IL-6, CRP, and TNF-α. At baseline, IL-6 and CRP were positively correlated with body fat and body mass index (BMI) and were inversely correlated with daily pedometer steps (P < 0.001). We found no significant effect of exercise on changes in inflammatory marker concentrations between women randomized to exercise versus usual care, though secondary analyses revealed a significant reduction in IL-6 among exercisers who reached 80% of the intervention goal compared with those who did not. Future studies should examine the effect of different types and doses of exercise and weight loss on inflammatory markers in large-scale trials of women diagnosed with breast cancer.
doi:10.1158/1940-6207.CAPR-12-0278
PMCID: PMC3839104  PMID: 23213072
10.  Circulating MicroRNAs in Relation to EGFR Status and Survival of Lung Adenocarcinoma in Female Non-Smokers 
PLoS ONE  2013;8(11):e81408.
Objectives
Lung adenocarcinoma is considered a unique disease for Asian female non-smokers. We investigated whether plasma microRNA (miRNA) expression profiles are different by the EGFR status and are associated with survival outcomes of the patients.
Methods
Using real-time RT-PCR, we analyzed the expression of 20 miRNAs in the plasma of 105 female patients with lung adenocarcinoma. Kaplan-Meier survival analysis and Cox proportional hazards regression were performed to determine the association between miRNA expression and overall survival. Time dependent receiver operating characteristic (ROC) analysis was also performed.
Results
In the 20 miRNAs, miR-122 were found differently expressed between wild and mutant EGFR carriers (P=0.018). Advanced disease stage and tumor metastasis were independently associated with poor prognosis of patients with lung adenocarcinoma (P=0.010 and 1.0×10-4). Plasma levels of miR-195 and miR-122 expression were also associated with overall survival in the patients, especially in those with advanced stage (HR=0.23, 95%CI:0.07-0.84; and HR=0.22, 95%CI:0.06-0.77) and EGFR mutation (HR=0.27, 95%CI:0.08-0.96; and HR=0.23, 95%CI=0.06-0.81). Moreover, a model including miR-195, miR-122 may predict survival outcomes of female patients with lung adenocarcinoma (AUC=0.707).
Conclusions
Circulating miR-195 and miR-122 may have prognostic values in predicting the overall survival as well as predicting EGFR mutation status in non-smoking female patients with lung adenocarcinoma. Measuring plasma levels of miR-195 and miR-122 may especially be useful in EGFR mutant patients with lung adenocarcinoma.
doi:10.1371/journal.pone.0081408
PMCID: PMC3839880  PMID: 24282590
11.  Effect of Exercise on Metabolic Syndrome Variables in Breast Cancer Survivors 
Objective. Breast cancer survivors are highly sedentary, overweight, or obese, which puts them at increased risk for comorbid chronic disease. We examined the prevalence of, and changes in, metabolic syndrome following 6 months of an aerobic exercise versus usual care intervention in a sample of sedentary postmenopausal breast cancer survivors. Design and Methods. 65 participants were randomized to an aerobic exercise intervention (EX) (n = 35) mean BMI 30.8 (±5.9) kg/m2 or usual care (UC) (n = 30) mean BMI 29.4 (±7.4) kg/m2. Metabolic syndrome prevalence was determined, as well as change in criteria and overall metabolic syndrome. Results. At baseline, 55.4% of total women met the criteria for metabolic syndrome. There was no statistically significant change in metabolic syndrome when comparing EX and UC. However, adhering to the exercise intervention (at least 120 mins/week of exercise) resulted in a significant (P = .009) decrease in metabolic syndrome z-score from baseline to 6 months (−0.76 ± 0.36) when compared to those who did not adhere (0.80 ± 0.42). Conclusions. Due to a higher prevalence of metabolic syndrome in breast cancer survivors, lifestyle interventions are needed to prevent chronic diseases associated with obesity. Increasing exercise adherence is a necessary target for further research in obese breast cancer survivors.
doi:10.1155/2013/168797
PMCID: PMC3844242  PMID: 24319454
12.  Age at Last Birth in Relation to Risk of Endometrial Cancer: Pooled Analysis in the Epidemiology of Endometrial Cancer Consortium 
American Journal of Epidemiology  2012;176(4):269-278.
Childbearing at an older age has been associated with a lower risk of endometrial cancer, but whether the association is independent of the number of births or other factors remains unclear. Individual-level data from 4 cohort and 13 case-control studies in the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 8,671 cases of endometrial cancer and 16,562 controls were included in the analysis. After adjustment for known risk factors, endometrial cancer risk declined with increasing age at last birth (Ptrend < 0.0001). The pooled odds ratio per 5-year increase in age at last birth was 0.87 (95% confidence interval: 0.85, 0.90). Women who last gave birth at 40 years of age or older had a 44% decreased risk compared with women who had their last birth under the age of 25 years (95% confidence interval: 47, 66). The protective association was similar across the different age-at-diagnosis groups and for the 2 major tumor histologic subtypes (type I and type II). No effect modification was observed by body mass index, parity, or exogenous hormone use. In this large pooled analysis, late age at last birth was independently associated with a reduced risk of endometrial cancer, and the reduced risk persisted for many years.
doi:10.1093/aje/kws129
PMCID: PMC3491967  PMID: 22831825
endometrial neoplasms; parity; reproductive history
13.  Polymorphisms in inflammation pathway genes and endometrial cancer risk 
Background
Experimental and epidemiological evidence have suggested that chronic inflammation may play a critical role in endometrial carcinogenesis.
Methods
To investigate this hypothesis, a two-stage study was carried out to evaluate single nucleotide polymorphisms (SNPs) in inflammatory pathway genes in association with endometrial cancer risk. In stage 1, 64 candidate pathway genes were identified and 4,542 directly genotyped or imputed SNPs were analyzed among 832 endometrial cancer cases and 2,049 controls, using data from the Shanghai Endometrial Cancer Genetics Study. Linkage disequilibrium of stage 1 SNPs significantly associated with endometrial cancer (P<0.05) indicated that the majority of associations could be linked to one of 24 distinct loci. One SNP from each of the 24 loci was then selected for follow-up genotyping. Of these, 21 SNPs were successfully designed and genotyped in stage 2, which consisted of ten additional studies including 6,604 endometrial cancer cases and 8,511 controls.
Results
Five of the 21 SNPs had significant allelic odds ratios and 95% confidence intervals as follows: FABP1, 0.92 (0.85-0.99); CXCL3, 1.16 (1.05-1.29); IL6, 1.08 (1.00-1.17); MSR1, 0.90 (0.82-0.98); and MMP9, 0.91 (0.87-0.97). Two of these polymorphisms were independently significant in the replication sample (rs352038 in CXCL3 and rs3918249 in MMP9). The association for the MMP9 polymorphism remained significant after Bonferroni correction and showed a significant association with endometrial cancer in both Asian- and European-ancestry samples.
Conclusions
These findings lend support to the hypothesis that genetic polymorphisms in genes involved in the inflammatory pathway may contribute to genetic susceptibility to endometrial cancer.
Impact Statement
This study adds to the growing evidence that inflammation plays an important role in endometrial carcinogenesis.
doi:10.1158/1055-9965.EPI-12-0903
PMCID: PMC3677562  PMID: 23221126
endometrial cancer; inflammation; genetic risk variants; meta-analysis
14.  Testing the proportional hazards assumption in case-cohort analysis 
Background
Case-cohort studies have become common in epidemiological studies of rare disease, with Cox regression models the principal method used in their analysis. However, no appropriate procedures to assess the assumption of proportional hazards of case-cohort Cox models have been proposed.
Methods
We extended the correlation test based on Schoenfeld residuals, an approach used to evaluate the proportionality of hazards in standard Cox models. Specifically, pseudolikelihood functions were used to define “case-cohort Schoenfeld residuals”, and then the correlation of these residuals with each of three functions of event time (i.e., the event time itself, rank order, Kaplan-Meier estimates) was determined. The performances of the proposed tests were examined using simulation studies. We then applied these methods to data from a previously published case-cohort investigation of the insulin/IGF-axis and colorectal cancer.
Results
Simulation studies showed that each of the three correlation tests accurately detected non-proportionality. Application of the proposed tests to the example case-cohort investigation dataset showed that the Cox proportional hazards assumption was not satisfied for certain exposure variables in that study, an issue we addressed through use of available, alternative analytical approaches.
Conclusions
The proposed correlation tests provide a simple and accurate approach for testing the proportional hazards assumption of Cox models in case-cohort analysis. Evaluation of the proportional hazards assumption is essential since its violation raises questions regarding the validity of Cox model results which, if unrecognized, could result in the publication of erroneous scientific findings.
doi:10.1186/1471-2288-13-88
PMCID: PMC3710085  PMID: 23834739
Proportional hazards; Schoenfeld residuals; Case-cohort studies; Cox models
15.  A KRAS-variant is a Biomarker of Poor Outcome, Platinum Chemotherapy Resistance and a Potential Target for Therapy in Ovarian Cancer 
Oncogene  2011;31(42):4559-4566.
Germ-line variants in the 3′ untranslated region (3′UTR) of cancer genes disrupting microRNA (miRNA) regulation have recently been associated with cancer risk. A variant in the 3′UTR of the KRAS oncogene, referred to as the KRAS-variant, is associated with both cancer risk and altered tumor biology. Here we test the hypothesis that the KRAS-variant can act as a biomarker of outcome in epithelial ovarian cancer (EOC), and investigate the cause of altered outcome in KRAS-variant positive EOC patients. As this variant appears to be associated with tumor biology, we additionally test the hypothesis that this variant can be directly targeted to impact cell survival.
EOC patients with complete clinical data were genotyped for the KRAS-variant and analyzed for outcome (n=536), response to neoadjuvant chemotherapy (n=125), and platinum resistance (n=306). Outcome was separately analyzed for women with known BRCA mutations (n=79). Gene expression was analyzed on a subset of tumors with available tissue. Cell lines were employed to confirm altered sensitivity to chemotherapy with the KRAS-variant. The KRAS-variant was directly targeted through siRNA/miRNA oligonucleotides in cell lines and survival was measured.
Post-menopausal EOC patients with the KRAS-variant were significantly more likely to die of ovarian cancer by multivariate analysis (HR=1.67, 95% CI=1.09–2.57, p=0.019, n=279). Possibly explaining this finding, EOC patients with the KRAS-variant were significantly more likely to be platinum resistant (OR=3.18, CI=1.31–7.72, p=0.0106, n=291). Additionally, direct targeting of the KRAS-variant led to a significant reduction in EOC cell growth and survival in vitro.
These findings confirm the importance of the KRAS-variant in EOC, and indicate that the KRAS-variant is a biomarker of poor outcome in EOC likely due to platinum resistance. In addition, this work supports the hypothesis that these tumors have continued dependence on such 3′UTR lesions, and that direct targeting may be a viable future treatment approach.
doi:10.1038/onc.2011.539
PMCID: PMC3342446  PMID: 22139083
Platinum resistance; KRAS-variant; ovarian cancer; outcome
16.  Elucidating the Landscape of Aberrant DNA Methylation in Hepatocellular Carcinoma 
PLoS ONE  2013;8(2):e55761.
Background
Hepatocellular carcinoma (HCC) is one of the most common cancers and frequently presents with an advanced disease at diagnosis. There is only limited knowledge of genome-scale methylation changes in HCC.
Methods and Findings
We performed genome-wide methylation profiling in a total of 47 samples including 27 HCC and 20 adjacent normal liver tissues using the Illumina HumanMethylation450 BeadChip. We focused on differential methylation patterns in the promoter CpG islands as well as in various less studied genomic regions such as those surrounding the CpG islands, i.e. shores and shelves. Of the 485,577 loci studied, significant differential methylation (DM) was observed between HCC and adjacent normal tissues at 62,692 loci or 13% (p<1.03e-07). Of them, 61,058 loci (97%) were hypomethylated and most of these loci were located in the intergenic regions (43%) or gene bodies (33%). Our analysis also identified 10,775 differentially methylated (DM) loci (17% out of 62,692 loci) located in or surrounding the gene promoters, 4% of which reside in known Differentially Methylated Regions (DMRs) including reprogramming specific DMRs and cancer specific DMRs, while the rest (10,315) involving 4,106 genes could be potential new HCC DMR loci. Interestingly, the promoter-related DM loci occurred twice as frequently in the shores than in the actual CpG islands. We further characterized 982 DM loci in the promoter CpG islands to evaluate their potential biological function and found that the methylation changes could have effect on the signaling networks of Cellular development, Gene expression and Cell death (p = 1.0e-38), with BMP4, CDKN2A, GSTP1, and NFATC1 on the top of the gene list.
Conclusion
Substantial changes of DNA methylation at a genome-wide level were observed in HCC. Understanding epigenetic changes in HCC will help to elucidate the pathogenesis and may eventually lead to identification of molecular markers for liver cancer diagnosis, treatment and prognosis.
doi:10.1371/journal.pone.0055761
PMCID: PMC3577824  PMID: 23437062
17.  Genotyping of stathmin and its association with clinical factors and survival in patients with ovarian cancer 
Oncology Letters  2013;5(4):1315-1320.
Stathmin is closely correlated with the progression and prognosis of a number of types of human cancer. The present study analyzed the associations between genetic variations in the stathmin gene and clinical outcomes of ovarian cancer. A total of 178 patients with epithelial ovarian cancer were treated with cytoreductive surgery followed by platinum-based chemotherapy. DNA was extracted from fresh tumor samples obtained during surgery. A total of 32 DNA samples were selected randomly for resequencing of the stathmin gene. Tag single nucleotide polymorphisms (SNPs) were identified based on the haplotype model as analyzed by PolyPhred software. Direct sequencing was employed in the genotyping of stathmin in 178 cases. A total of 10 nucleotide variations in stathmin were identified, of which 3 high-frequency variations were known SNPs from databases and 7 were new variations with low frequencies. The tag SNPs rs159531 and rs11376635 were selected from the linkage disequilibrium block of the gene to genotype stathmin in 178 cases. The distribution of the rs159531 genotype in ovarian cancer was 52.8% C/C, 35.4% C/T and 11.2% T/T. The distribution of the rs11376635 genotype in ovarian cancer was 32.0% G/G, 48.3% G/-, 18.5% -/-. The main haplotypes calculated by phase2.0 software were 55.6% CG, 27.8% T-, 15.4% C- and 1.2% TG. However, no associations between the stathmin genotype or haplotype and the outcomes in patients with ovarian cancer were observed. The stathmin genotype and haplotype were not associated with the phenotype of patients with ovarian cancer.
doi:10.3892/ol.2013.1144
PMCID: PMC3629093  PMID: 23599786
stathmin; genetic polymorphisms; ovarian cancer; genotype; haplotype
18.  Genome-wide association study identifies a possible susceptibility locus for endometrial cancer 
BACKGROUND
Genome-wide association studies (GWAS) have identified over 100 genetic loci for various cancers. However, only one is for endometrial cancer.
METHODS
We conducted a three-stage GWAS including 8,492 endometrial cancer cases and 16,596 controls. After analyzing 585,963 SNPs in 832 cases and 2,682 controls (Stage 1) from the Shanghai Endometrial Cancer Genetics Study, we selected the top 106 SNPs for in silico replication among 1,265 cases and 5,190 controls from the Australian/British Endometrial Cancer GWAS (Stage 2). Nine SNPs showed results consistent in direction with Stage 1 with P<0.1. These 9 SNPs were investigated among 459 cases and 558 controls (Stage 3a) and 6 SNPs showed a direction of association consistent with Stages 1 and 2. These 6 SNPs, plus 2 additional SNPs selected based on linkage disequilibrium (LD) and P values in Stage 2, were investigated among 5,936 cases and 8,166 controls from an additional 11 studies (Stage 3b).
RESULTS
SNP rs1202524, near the CAPN9 gene on chromosome 1q42.2, showed a consistent association with endometrial cancer risk across all three stages, with odds ratios (OR) of 1.09 (95% CI: 1.03–1.16) for the A/G genotype and 1.17 (95% CI: 1.05–1.30) for the G/G genotype (P=1.6 × 10−4 in combined analyses of all samples). The association was stronger when limited to the endometrioid subtype, with ORs (95% CI) of 1.11 (1.04–1.18) and 1.21 (1.08–1.35), respectively (P=2.4 × 10−5).
CONCLUSIONS
Chromosome 1q42.2 may host an endometrial cancer susceptibility locus.
IMPACT
This study identified a potential genetic locus for endometrial cancer risk.
doi:10.1158/1055-9965.EPI-11-1160
PMCID: PMC3372671  PMID: 22426144
19.  The insulin-like growth factor axis and risk of liver disease in hepatitis C virus/HIV-co-infected women 
AIDS (London, England)  2008;22(4):527-531.
Objective
Insulin-like growth factor (IGF) I stimulates the proliferation of hepatic stellate cells (HSC), the primary source of extracellular matrix accumulation in liver fibrosis. In contrast, insulin-like growth factor binding protein (IGFBP) 3, the most abundant IGFBP in circulation, negatively modulates HSC mitogenesis. To investigate the role of the IGF axis in hepatitis C virus (HCV)-related liver disease among high-risk patients, we prospectively evaluated HCV-viremic/HIV-positive women.
Design
A cohort investigation.
Methods
Total IGF-I and IGFBP-3 were measured in baseline serum specimens obtained from 472 HCV-viremic/HIV-positive subjects enrolled in the Women's Inter-agency HIV Study, a large multi-institutional cohort. The aspartate aminotransferase to platelet ratio index (APRI), a marker of liver fibrosis, was assessed annually.
Results
Normal APRI levels (< 1.0) at baseline were detected in 374 of the 472 HCV-viremic/HIV-positive subjects tested, of whom 302 had complete liver function test data and were studied. IGF-I was positively associated [adjusted odds ratio comparing the highest and lowest quartiles (AORq4–q1), 5.83; 95% confidence interval (CI) 1.17–29.1; Ptrend = 0.03], and IGFBP-3 was inversely associated (AORq4–q1, 0.13; 95% CI 0.02–0.76; Ptrend = 0.04), with subsequent (incident) detection of an elevated APRI level(> 1.5), after adjustment for the CD4 T-cell count, alcohol consumption, and other risk factors.
Conclusion
High IGF-I may be associated with increased risk and high IGFBP-3 with reduced risk of liver disease among HCV-viremic/HIV-positive women.
doi:10.1097/QAD.0b013e3282f22cdf
PMCID: PMC3507535  PMID: 18301066
aspartate aminotransferase to platelet ratio index; APRI; hepatitis C virus (HCV); HIV; IGFBP-3; IGF; liver disease
20.  Reduced Allergy and Immunoglobulin E among Adults with Intra-cranial Meningioma Compared to Controls 
Meningioma, the most frequent tumor in the central nervous system, has few recognized risk factors. We explored the role of allergies in a population-based case-control consortium study of meningioma in five geographic areas. We also studied serum levels of a marker of atopic allergy (IgE) in a subset of study participants, a first for a study on meningioma. Participants (N = 1,065) with surgically resected, pathologically confirmed meningioma and controls (N = 634) selected via random-digit dialing were recruited and interviewed. Cases were less likely than controls to report history of physician-diagnosed allergy [odds ratio (OR) = 0.64; 95% confidence interval (95% CI): 0.51 – 0.80]. Also, cases (N = 295) had lower total serum IgE than controls [N = 192; OR = 0.85, 95% CI: 0.75–0.98 for each unit of Ln(IgE)]. Similar to glioma and cancers at several other sites, meningioma appears to have an inverse relationship with history of allergies and a biomarker of atopic allergy. Since some common opposing predisposition or developmental processes for allergy and meningioma may exist, further research into immune processes that can affect the incidence and natural history of meningioma is warranted.
doi:10.1002/ijc.25858
PMCID: PMC3337969  PMID: 21520030
Meningioma; epidemiology; risk factors; neurosurgery; brain tumor; genetics; immune factors
21.  Long-term overweight and weight gain in early adulthood in association with risk of endometrial cancer 
Long-term overweight and substantial weight gain over adulthood are known risk factors of endometrial cancer, but the timing of weight gain in relation to risk and the effect of weight change on age at diagnosis remain unclear. A population-based case–control study was conducted to evaluate the long-term effect of body weight on endometrial cancer risk. The study enrolled 668 incident cases and 674 population controls. Anthropometric features in each decade of adult life were ascertained through in-person interview and analyzed for their associations with endometrial cancer using unconditional logistic regression. As expected, high body mass index (BMI) was significantly associated with increased risk. Women who were overweight or obese at the time of interview had adjusted odds ratios of 1.54 (95%CI 1.13–2.10) and 4.76 (95%CI 3.50–6.49), respectively, compared to women of normal weight. Similar associations were observed for BMI assessed at each decade of adult life. More importantly, women who were overweight (BMI ≥ 25) in their 20s or 30s and maintained the overweight throughout life had significantly higher risk than those who became overweight at ages 40s or 50s. Women with substantial weight gain (≥35%) in early adulthood (age 20s) developed the disease 10 years earlier than those without such weight change in early life. These observations further confirm the critical link between body weight and development of endometrial cancer.
doi:10.1002/ijc.26046
PMCID: PMC3125463  PMID: 21387312
endometrial cancer; body mass index; risk factors; epidemiology; case–control study; early adulthood
22.  Genetic Effects and Modifiers of Radiotherapy and Chemotherapy on Survival in Pancreatic Cancer 
Pancreas  2011;40(5):657-663.
Objectives
Germline genetic variation may affect clinical outcomes of cancer patients. We applied a candidate-gene approach to evaluate the effect of putative markers on survival of patients with pancreatic cancer. We also examined gene-radiotherapy and gene-chemotherapy interactions, aiming to explain inter-individual differences in treatment outcomes.
Methods
In total, 211 patients with pancreatic cancer were recruited in a population-based study. Sixty-four candidate genes associated with cancer survival or treatment response were selected from existing publications. Genotype information was obtained from a previous GWAS dataset. The main effect of genetic variation and gene-specific treatment interactions on overall survival were examined by proportional hazards regression models.
Results
Fourteen genes showed evidence of association with pancreatic cancer survival. Among these, rs1760217, located at the DPYD gene, rs17091162 at SERPINA3 and rs2231164 at ABCG2 had the lowest P-values of 10−4.60, 0.0013 and 0.0023, respectively. We also observed that two genes, RRM1 and IQGAP2, had significant interactions with radiotherapy in association with survival, and two others, TYMS and MET, showed evidence of interaction with 5-FU and erlotinib, respectively.
Conclusions
Our study suggested significant associations between germline genetic polymorphisms and overall survival in pancreatic cancer, as well as survival interactions between various genes and radiotherapy and chemotherapy.
doi:10.1097/MPA.0b013e31821268d1
PMCID: PMC3116071  PMID: 21487324
Pancreatic neoplasms; Survival; Genetic heterogeneity; Polymorphism; single nucleotide; Prognosis
23.  Meta-Analysis of the Association between Mir-196a-2 Polymorphism and Cancer Susceptibility 
Cancer Biology & Medicine  2012;9(1):63-72.
Objective
MicroRNA plays a vital role in gene expression, and microRNA dysregulation is involved in carcinogenesis. The miR-196a-2 polymorphism rs11614913 is reportedly associated with cancer susceptibility. This meta-analysis was performed to assess the overall association of miR-196a-2 with cancer risk.
Methods
A total of 27 independent case-control studies involving 10,435 cases and 12,075 controls were analyzed for the rs11614913 polymorphism.
Results
A significant association was found between rs11614913 polymorphism and cancer risk in four genetic models (CT vs. TT, OR=1.15, 95%CI=1.05–1.27; CC vs. TT, OR=1.23, 95%CI=1.08–1.39; Dominant model, OR=1.17, 95%CI=1.06–1.30; Additive model, OR=1.08, 95%CI=1.01–1.14). In the subgroup analysis of different tumor types, the C allele was associated with increased risk of lung, breast, and colorectal cancer, but not with liver, gastric, or esophageal cancer. In the subgroup analysis by ethnicity, a significantly increased risk of cancer was found among Asians in all genetic models, but no associations were found in the Caucasian subgroup.
Conclusions
The meta-analysis demonstrated that the miR-196a-2 polymorphism is associated with cancer susceptibility, especially lung cancer, colorectal cancer, and breast cancer among Asian populations.
doi:10.3969/j.issn.2095-3941.2012.01.012
PMCID: PMC3643645  PMID: 23691458
MIRN196 microRNA; human; polymorphism; neoplasms; meta-analysis
24.  PDCD6 is an independent predictor of progression free survival in epithelial ovarian cancer 
Background
Programmed cell death 6 (PDCD6) beside its known proapoptotic functions may be a player in survival pathways in cancer. The purpose of this study is to further explore the roles of PDCD6 in epithelial ovarian cancer.
Methods
Lentiviral vector with shRNA for PDCD6 was used to investigate the effects of PDCD6 knockdown on cell growth, cell cycle, apoptosis and motility in ovarian cancer cells. Two hundred twelve epithelial ovarian cancer tissues were analyzed for mRNA expression of PDCD6 using RT-PCR. Associations of its expression with clinical pathological factors, progression free and overall survival were evaluated.
Results
PDCD6 is highly expressed in metastatic ovarian cancer cells and positively regulates cell migration and invasion. Significantly, the level of PDCD6 expression in epithelial ovarian cancer correlates with clinical progression. Patients with medium or high levels of PDCD6 mRNA were at higher risk for disease progression, compared to those with low levels (HR, 1.29; P = 0.024 for medium levels; and HR, 1.57; P = 0.045 for high levels) after adjusting for age, disease stage, tumor grade, histologic type and residual tumor size. Kaplan-Meier survival analysis demonstrated similar results. However, no association was found between PDCD6 expression and overall survival.
Conclusions
PDCD6 seems to play an important role in ovarian cancer progression and it may be an independent predictor of progression free survival in epithelial ovarian cancer. Further studies are needed to more completely elucidate the molecular mechanisms of PDCD6 involve in ovarian cancer progression.
doi:10.1186/1479-5876-10-31
PMCID: PMC3305474  PMID: 22369209
25.  Physical activity and endometrial cancer in a population-based case–control study 
Cancer causes & control : CCC  2010;22(2):219-226.
Introduction
Published studies of physical activity, BMI, and endometrial cancer risk show conflicting results and many do not report on reliability or validity of physical activity questionnaires.
Methods
We collected physical activity data on 667 incident cases of endometrial cancer and 662 age-matched controls. Interview-administered questionnaires, collecting demographic and lifestyle information, including a validated questionnaire for physical activity. We performed unconditional logistic regression to examine the relationship between moderate- to vigorous-intensity sports/recreational physical activity (MV PA), sit time, and endometrial cancer risk.
Results
Compared to women reporting 0 metabolic equivalent (MET) hours per week of MV PA, those who reported 7.5 MET h/wk or more had a 34% lower endometrial cancer risk (odds ratio (OR) = 0.66, 95% CI 0.50–0.87) after adjusting for risk factors including BMI. Those women sitting more than 8 h per day had a 52% increased odds (95% CI 1.07–2.16) of endometrial cancer compared to those sitting less than 4 h per day. We created a composite measure of physical activity and BMI and found that women with a BMI<25 and activity levels ≥7.5 MET h/wk had a 73% lower endometrial cancer risk (OR = 0.27, 95% CI 0.18–0.39) compared with the reference group of overweight (BMI ≥25) and sedentary (MET h/wk = 0).
Conclusion
Our data support an inverse, independent association between physical activity and endometrial cancer risk after adjusting for BMI and other risk factors.
doi:10.1007/s10552-010-9689-0
PMCID: PMC3075067  PMID: 21110224
Physical activity; Endometrial cancer; BMI

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