Risk prediction models for endometrial cancer: development and validation in an international consortium.

BACKGROUND: Endometrial cancer risk stratification may help target interventions, screening, or prophylactic hysterectomy to mitigate the rising burden of this cancer. However, existing prediction models have been developed in select cohorts and have not considered genetic factors. METHODS: We developed endometrial cancer risk prediction models using data on postmenopausal White women aged 45-85 years from 19 case-control studies in the Epidemiology of Endometrial Cancer Consortium (E2C2). Relative risk estimates for predictors were combined with age-specific endometrial cancer incidence rates and estimates for the underlying risk factor distribution. We externally validated the models in 3 cohorts: Nurses' Health Study (NHS), NHS II, and the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. RESULTS: Area under the receiver operating characteristic curves for the epidemiologic model ranged from 0.64 (95% confidence interval [CI] = 0.62 to 0.67) to 0.69 (95% CI = 0.66 to 0.72). Improvements in discrimination from the addition of genetic factors were modest (no change in area under the receiver operating characteristic curves in NHS; PLCO = 0.64 to 0.66). The epidemiologic model was well calibrated in NHS II (overall expected-to-observed ratio [E/O] = 1.09, 95% CI = 0.98 to 1.22) and PLCO (overall E/O = 1.04, 95% CI = 0.95 to 1.13) but poorly calibrated in NHS (overall E/O = 0.55, 95% CI = 0.51 to 0.59). CONCLUSIONS: Using data from the largest, most heterogeneous study population to date (to our knowledge), prediction models based on epidemiologic factors alone successfully identified women at high risk of endometrial cancer. Genetic factors offered limited improvements in discrimination. Further work is needed to refine this tool for clinical or public health practice and expand these models to multiethnic populations.

Improved risk scoring systems for colorectal cancer screening in Shanghai, China.

BACKGROUND: An optimal risk-scoring system enables more targeted offers for colonoscopy in colorectal cancer (CRC) screening. This analysis aims to develop and validate scoring systems using parametric and non-parametric methods for average-risk populations. METHODS: Screening data of 807,695 subjects and 2806 detected cases in the first-round CRC screening program in Shanghai were used to develop risk-predictive models and scoring systems using logistic-regression (LR) and artificial-neural-network (ANN) methods. Performance of established scoring systems was evaluated using area under the receiver operating characteristic curve (AUC), calibration, sensitivity, specificity, number of high-risk individuals and potential detection rates of CRC. RESULTS: Age, sex, CRC in first-degree relatives, chronic diarrhoea, mucus or bloody stool, history of any cancer and faecal-immunochemical-test (FIT) results were identified as predictors for the presence of CRC. The AUC of LR-based system was 0.642 when using risk factors only in derivation set, and increased to 0.774 by further incorporating one-sample FIT results, and to 0.808 by including two-sample FIT results, while those for ANN-based systems were 0.639, 0.763 and 0.805, respectively. Better calibrations were observed for the LR-based systems than the ANN-based ones. Compared with the currently used initial tests, parallel use of FIT with LR-based systems resulted in improved specificities, less demands for colonoscopy and higher detection rates of CRC, while parallel use of FIT with ANN-based systems had higher sensitivities; incorporating FIT in the scoring systems further increased specificities, decreased colonoscopy demands and improved detection rates of CRC. CONCLUSIONS: Our results indicate the potentials of LR-based scoring systems incorporating one- or two-sample FIT results for CRC mass screening. External validation is warranted for scaling-up implementation in the Chinese population.

Colorectal Cancer Screening Modalities in Chinese Population: Practice and Lessons in Pudong New Area of Shanghai, China.

Background: Parallel test of risk stratification and two-sample qualitative fecal immunochemical tests (FITs) are used to screen colorectal cancer (CRC) in Shanghai, China. This study was designed to identify an optimal initial screening modality based on available data. Methods: A total of 538,278 eligible residents participated in the program during the period of January 2013 to June 2017. Incident CRC was collected through program reporting system and by record linkage with the Shanghai Cancer Registry up to December 2017. Logistic regression model was applied to identify significant factors to calculate risk score for CRC. Cutoff points of risk score were determined based on Youden index and defined specificity. Sensitivity, specificity, and positive predictive values (PPVs) were computed to evaluate validity of assumed screening modalities. Results: A total of 446 CRC were screen-detected, and 777 interval or missed cases were identified through record linkage. The risk score system had an optimal cutoff point of 19 and performed better in detecting CRC and predicting long-term CRC risk than did the risk stratification. When using a cutoff point of 24, parallel test of risk score, and FIT were expected to avoid 56 interval CRCs with minimal decrease in PPV and increase in colonoscopy. However, the observed detection rates were much lower than those expected due to low compliance to colonoscopy. Conclusions: Risk score is superior to risk stratification used in the program, particularly when combined with FIT. Compliance to colonoscopy should be improved to guarantee the effectiveness of CRC screening in the population.

Cancer risk in Chinese diabetes patients: a retrospective cohort study based on management data.

The excess risk of cancer observed in patients with type 2 diabetes (T2DM) may have been influenced by detection bias. The aim of this study was to examine the real association by evaluating time-varying site-specific cancer risks in newly diagnosed T2DM patients. A total of 51,324 registered cancer-free individuals newly diagnosed with T2DM between 2004 and 2014 were linked with the Shanghai Cancer Registry and the Vital Statistics through September 2015. A total of 2920 primary, invasive cancer cases were identified during 325,354 person-years period. Within 1 year following diabetes onset, participants with T2DM had higher risks of total, lung and rectal cancer in men and total, liver, pancreas, thyroid, breast and uteri cancer in women. Thereafter the incidence for overall cancer decreased and then increased along with follow-up time, with the upward trend varying by cancer, suggesting potential detection bias. After the initial 1-year period, standardized incidence ratios (SIR) and 95% CIs for overall cancer were 0.80 (95% CI 0.76-0.85) in men and 0.93 (95% CI 0.88-0.99) in women, but a higher risk of breast and thyroid cancers were observed in women, with SIR and 95% CI being 1.13 (1.01, 1.28) and 1.37 (1.11, 1.63), respectively. Our results suggest that T2DM patients are at higher risk of certain cancers; this risk particularly increases shortly after diabetes diagnosis, which is likely to be due to detection bias caused by increased ascertainment. Prevention of female breast and thyroid cancers should be paid attention in Chinese individuals with T2DM.

Body mass index and cancer risk among Chinese patients with type 2 diabetes mellitus.

BACKGROUND: Obesity and diabetes are two risk factors for cancer. To evaluate the association of body mass index (BMI) with cancer risk in diabetic patients may improve current understanding of potential mechanisms. METHODS: A retrospective cohort study was conducted in 51,004 newly diagnosed T2DM patients derived from an electronic health record (EHR) database of Minhang district in Shanghai, China. Incident cancer cases and all-cause deaths occurred before September 30, 2015 were identified by linking with the Shanghai Cancer Registry and the Shanghai Vital Statistics. To examine the potential non-linear and linear relationships of BMI and cancer risk, Cox proportional hazard models with and without restricted cubic spline functions were used, respectively. RESULTS: A non-linear association was observed between BMI and overall cancer incidence in men younger than 60 years old (p for non-linearity = 0.009). Compared with those having BMI of 25.0 kg/m2, the cancer risk increased in those with either lower or higher BMI. In women older than 60 years old, linear dose-response relationships were observed between BMI and the risk of both overall cancer and breast cancer. As each unit increase in BMI, the overall cancer risks elevated by 3% (95%CI: 1-5%) and the breast cancer risks increased by 7% (95%CI: 1-13%). No significant association was observed between BMI and other common cancer sites. CONCLUSIONS: Our results show that the effect of BMI on cancer risk in Chinese patients with T2DM may vary by gender, age and cancer subtypes, suggesting different underlying biological mechanisms.

Incidence of breast cancer in Chinese women exposed to the 1959-1961 great Chinese famine.

BACKGROUND: The association of malnutrition in early life with breast cancer risk has been studied in Europe by investigating survivors of the Dutch Hunger Winter Famine, but not in China. We evaluated the effect of exposure to the 1959-1961 Great Leap Forward famine on subsequent breast cancer risk in Chinese women. METHODS: A total of 59,060 women born in 1955~1966 were recruited from Minhang district, Shanghai, China, during the period 2008 to 2012. A baseline survey was conducted to collect demographic characteristics and known risk factors for breast cancer. Incident breast cancers were identified by conducting record linkage with the Shanghai Cancer Registry up to June 30, 2015, and confirmed through medical records. Cumulative probabilities of cancer incidence were evaluated after adjusting for age, educational level and other confounders. Cox regression models were applied to estimate the hazard ratios (HR) and 95% confidence intervals (CI) of breast cancer. RESULTS: The overall crude incidence of in situ and invasive breast cancer were 19.2 and 115.0 per 100,000, respectively, in women conceived or born during the famine (1959-1962), slightly higher than those in women born before (1955-1958) (13.2 and 109.8/100,000) and after (1963-1966) (10.4 and 101.5/100,000). Particularly, at age group of 50-52 years when all participants contributed person-year of observations, the age-specific incidence of invasive breast cancer was higher in pre-natal exposed women (123.7/100,000, 95%CI: 94.5-161.9/100,000) than in post-natal exposed (109.6/100,000, 95%CI: 69.1-174.0/100,000) and unexposed women (82.7/100,000, 95%CI: 46.9-145.7/100,000). However, the incidence of cancer in situ was slightly lower in pre-natal exposed women at the age group. Adjusted cumulative probabilities of breast cancer incidence, both in-situ and invasive, were also observed to be higher in women exposed to the famine, however, the difference was not statistically significant. CONCLUSION: Our results suggest a possible adverse, but limited, impact of exposure to the Great famine on the risk of breast cancer in Chinese women.

Cancer incidence in patients with type 2 diabetes mellitus: a population-based cohort study in Shanghai.

BACKGROUND: Type 2 diabetes mellitus (T2DM) has been suggested to increase the risk of cancers. The aim of this study was to investigate the risk of common cancers in Chinese patients with T2DM. METHODS: A population-based retrospective cohort study including 36,379 T2DM patients was conducted in Minhang District of Shanghai, China, during 2004 to 2010. All T2DM patients were enrolled from the standardized management system based on local electronic information system. Newly-diagnosed cancer cases were identified by record-linkage with the Shanghai Cancer Registry. Standardized incidence ratios (SIR) and 95% confidence interval (CI) were used to estimate the risk of cancers among T2DM patients. RESULTS: Overall crude incidence rate (CIR) of cancers was 955.21 per 105 person-years in men and 829.57 per 105 person-years in women. Increased risk of cancer was found in both gender, with an SIR being 1.28 (95% CI = 1.17-1.38) in men and 1.44 (95% CI =1.32-1.55) in women. Increased risk of colon (SIR = 1.97; 95% CI = 1.49 to 2.46), rectum (1.72; 1.23 to 2.21), prostate (2.87; 2.19 to 3.56), and bladder cancers (1.98, 1.28 to 2.68) were observed in men and elevated risk of colon (1.67; 1.25 to 2.08), breast (1.66; 1.38 to 1.95), and corpus uteri cancers (2.87; 2.03 to 3.71) were observed in women. CONCLUSIONS: Our results indicate that Chinese patients with T2DM may have an increased risk of some cancers, and the increase may vary by sub-sites of cancers.

Association of dietary glycemic index and glycemic load with endometrial cancer risk among Chinese women.

We evaluated the association of dietary glycemic index (GI) and glycemic load (GL) with the risk of endometrial cancer in a population-based, case-control study of 1199 endometrial cancer patients and 1212 age-frequency-matched controls in urban Shanghai, China, where diets are typically high in carbohydrates and have a high GL. Information on dietary habits, physical activity, and other relevant information was collected using a validated questionnaire, and anthropometric measurements were taken. Logistic regression was applied in the analysis. Dietary GI and GL were independently associated with risk for endometrial cancer but carbohydrate intake was unrelated to risk. Multivariable-adjusted odds ratios (ORs) for increasing quartiles of intake were 1.0, 1.3, 1.4, and 2.2 [95% confidence interval (CI): 1.2-4.0] for dietary GL (P(trend) = 0.02) and 1.0, 1.2, 1.4, and 1.4 (95% CI: 1.0-2.0) for dietary GI (P(trend) = 0.02). High intake of staples, especially rice, was positively associated with endometrial cancer. The association with GI was more evident among lean and normal weight women, although the test for interaction was not significant. This study suggests that intake of high GL or GI foods, but not carbohydrates per se, may increase risk for endometrial cancer.

Improved self-management skills in Chinese diabetes patients through a comprehensive health literacy strategy: study protocol of a cluster randomized controlled trial.

BACKGROUND: Diabetes self-management often involves the interpretation and application of oral, written, or quantitative information. Numerous diabetes patients in China have limited health literacy, which likely leads to poorer clinical outcomes. This study is designed to examine the efficacy and cost-effectiveness of addressing health literacy to improve self-management skills and glycemic control in Chinese diabetes patients. METHODS/DESIGN: This is a cluster randomized controlled trial (RCT) conducted in 20 community healthcare sites in Shanghai, China. Overall, 800 diabetes patients will be randomized into intervention and control arms and will have a baseline hemoglobin A1c (HbA1c) assay and undergo a baseline survey which includes measures of health literacy and diabetes numeracy using revised Chinese versions of the Health Literacy Management Scale and Diabetes Numeracy Test Scale. During the 1-year period of intervention, while the control group will receive usual care, the intervention group will be supplemented with a comprehensive health literacy strategy which includes i) training healthcare providers in effective health communication skills that address issues related to low literacy, and ii) use of an interactive Diabetes Education Toolkit to improve patient understanding and behaviors. Assessments will be conducted at both patient and healthcare provider levels, and will take place upon admission and after 3, 6, 12, and 24 months of intervention. The primary outcome will be the improvement in HbA1c between Intervention group and Control group patients. Secondary outcomes at the patient level will include improvement in i) clinical outcomes (blood pressure, fasting lipids, body mass index, weight, smoking status), ii) patient reported self-management behaviors, and iii) patient-reported self-efficacy. Outcomes at the provider level will include: i) provider satisfaction and ii) intensity and type of care provided. The effects of the intervention will be examined in multivariable general linear models. Both cost-effectiveness and cost-utility analyses will be performed. DISCUSSION: The main strengths of this study are its large sample size and RCT design, involvement of both patients and healthcare providers, and the long term follow-up (24-months). This project will help to demonstrate the value of addressing health literacy and health communication to improve self-management and clinical outcomes among Chinese diabetes patients. TRIAL REGISTRATION: ISRCTN76130594, Registration date: Sept 22, 2014.

Performance of breast cancer screening methods and modality among Chinese women: a report from a society-based breast screening program (SBSP) in Shanghai.

To evaluate the screening performance of individual and combined use of clinical breast examination, ultrasonography and mammography in Chinese women, we conducted a biennial breast cancer screening program among 14,464 women aged 35 to 74 years old who lived in Qibao County, Minhang district of Shanghai, China, between May 2008 and Sept 2012. All participants were submitted to clinical breast examination, and then women with positive results and all women at age of 45-69 years old were preformed breast ultrasonography and mammography. The examination results were compared against pathological findings as the gold standard of reference. A total of 66 women were diagnosed with breast cancer in the two rounds of the screening, yielding an incident rate of 194 per 100,000 person-years. The sensitivity of clinical breast examination, ultrasonography and mammography alone were 61.4%, 53.7% and 67.3%, respectively. While mammography performed better in elder age groups and hormone receptor positive disease groups, ultrasonography had a higher sensitivity in younger age group and did not differ in sensitivity by estrogen receptor or progesterone receptor status. Combined use of the two imaging examinations increased the sensitivity in almost all age groups, but had a higher sensitivity in hormone receptor positive cancers than in those negative. Our results suggest that the Qibao modality is an effective strategy for breast cancer screening among Chinese women, especially for early detection of elder and hormone receptor positive breast cancer.

Association of genetic markers in the BCL-2 family of apoptosis-related genes with endometrial cancer risk in a Chinese population.

BACKGROUND: In vitro studies have demonstrated the role of the BCL-2 family of genes in endometrial carcinogenesis. The role of genetic variants in BCL-2 genes and their interactions with non-genetic factors in the development of endometrial cancer has not been investigated in epidemiological studies. PATIENTS AND METHODS: We examined the relationship between BCL-2 gene family variants and endometrial cancer risk among 1,028 patients and 1,922 age-matched community controls from Shanghai, China. We also investigated possible interactions between genetic variants and established risk factors (demographic, lifestyle and clinical). Individuals were genotyped for 86 tagging single nucleotide polymorphisms (SNPs) in the BCL2, BAX, BAD and BAK1 genes. RESULTS: Significant associations with endometrial cancer risk were found for 9 SNPs in the BCL2 gene (P trend<0.05 for all). For SNPs rs17759659 and rs7243091 (minor allele for both: G), the associations were independent. The odds ratio was 1.27 (95% CI: 1.04-1.53) for women with AG genotype for the SNP rs17759659 and 1.82 (95% CI: 1.21-2.73) for women with the GG genotype for the SNP rs7243091. No interaction between these two SNPs and established non-genetic risk factors of endometrial cancer was noticed. CONCLUSION: Genetic polymorphisms in the BCL2 gene may be associated with the risk of endometrial cancer in Chinese women.

ABO blood type is associated with endometrial cancer risk in Chinese women.

ABO blood type has been associated with risk of several malignancies. However, results are not consistent. In this population-based case-control study including 1204 incident endometrial cancer cases and 1212 population controls, we examined the association of self-reported serologic blood type with endometrial cancer risk using a logistic regression model. Women with endometrial cancer were more likely to have blood type A. Compared to women with blood type O, the adjusted odds ratios for endometrial cancer were 1.00 [95% confidence interval (CI), 0.79-1.28] for type B, 1.24 (95% CI, 0.90-1.69) for type AB, and 1.50 (95% CI, 1.19-1.90) for type A. A significant dose-response relationship was observed for cancer risk and level of antigen A (P for trend = 0.0003). The positive association of blood type A with cancer risk was observed regardless of menopausal status, body mass index, oral contraceptive use, or family cancer history. Our results suggest that ABO blood type may be involved in the development of endometrial cancer.

Association of obesity-related genetic variants with endometrial cancer risk: a report from the Shanghai Endometrial Cancer Genetics Study.

Obesity is a well-established risk factor for endometrial cancer, the most common gynecologic malignancy. Recent genome-wide association studies (GWAS) have identified multiple genetic markers for obesity. The authors evaluated the association of obesity-related single nucleotide polymorphisms (SNPs) with endometrial cancer using GWAS data from their recently completed study, the Shanghai Endometrial Cancer Genetics Study, which comprised 832 endometrial cancer cases and 2,049 controls (1996-2005). Thirty-five SNPs previously associated with obesity or body mass index (BMI; weight (kg)/height (m)(2)) at a minimum significance level of ≤5 × 10(-7) in the US National Human Genome Research Institute's GWAS catalog (http://genome.gov/gwastudies) and representing 26 unique loci were evaluated by either direct genotyping or imputation. The authors found that for 22 of the 26 unique loci tested (84.6%), the BMI-associated risk variants were present at a higher frequency in cases than in population controls (P = 0.0003). Multiple regression analysis showed that 9 of 35 BMI-associated variants, representing 7 loci, were significantly associated (P ≤ 0.05) with the risk of endometrial cancer; for all but 1 SNP, the direction of association was consistent with that found for BMI. For consistent SNPs, the allelic odds ratios ranged from 1.15 to 1.29. These 7 loci are in the SEC16B/RASAL, TMEM18, MSRA, SOX6, MTCH2, FTO, and MC4R genes. The associations persisted after adjustment for BMI, suggesting that genetic markers of obesity provide value in addition to BMI in predicting endometrial cancer risk.

Relation of FGFR2 genetic polymorphisms to the association between oral contraceptive use and the risk of breast cancer in Chinese women.

The fibroblast growth factor receptor 2 gene (FGFR2) has been associated with the risk of breast cancer in multiple ethnic populations, and its effect has been suggested to be hormone-dependent. A large, 2-stage, population-based case-control study was conducted in urban Shanghai, China, during the periods of 1996-1998 and 2002-2005. Exposure and genotyping information from 2,073 patients with breast cancer and 2,084 age-matched population controls was available for evaluation of the interactions between FGFR2 polymorphisms and exogenous estrogen exposure in the development of breast cancer. A logistic regression model was used to compute adjusted odds ratios and 95% confidence intervals. Of 20 genotyped and 25 imputed single nucleotide polymorphisms (SNPs), 22 were significantly associated with breast cancer. Three genotyped SNPs in close linkage disequilibrium, rs2303568, rs3135730, and rs1078806, and an imputed SNP of rs755793 in complete linkage disequilibrium with other 8 SNPs were observed to interact significantly with oral contraceptive (OC) use. The SNP-cancer association was evident only among OC users, and the OC use was only associated with the risk of breast cancer among carriers of these minor alleles at these loci. These findings suggest that genetic variants in FGFR2 may modify the role of OC use in causing breast cancer in Chinese women.

Dietary iron intake and risk of endometrial cancer: a population-based case-control study in Shanghai, China.

Dietary red meat and animal fat have been linked to endometrial cancer (EC) risk, but the impact of bioavailable iron in animal-derived foods has been less well studied. Our objective was to investigate the effects of iron and fats on the risk of EC in a large, population-based, case-control study. The Shanghai Endometrial Cancer Study enrolled 1,204 EC cases and 1,212 controls who completed in-person interviews, including a food frequency questionnaire. Animal-derived iron and fat intakes were calculated from dietary intakes and food composition tables. Logistic regression models were used to evaluate independent and joint effects of iron and fat on EC risk. Animal-derived iron intake was positively associated with EC risk [adjusted OR = 1.9; 95% CI = 1.4-2.7, P(trend) < 0.01, highest vs. lowest quartile], predominantly after menopause (OR = 2.2; 95%CI = 1.4-3.4, P(trend) < 0.01) and in women with BMI >or= 25 kg/m(2)(OR = 3.2; 95% CI = 1.4-7.5 in postmenopausal obese women, P(trend) < 0.01). Animal-derived fat was also associated with postmenopausal EC risk (OR = 1.7; 95% CI = 1.2-2.5, P(trend) < 0.01). Multiplicative interactions between animal-derived iron and BMI or animal-derived fat intake were not observed. Animal-derived iron intake is associated with increased risk of EC after menopause and among obese women. Avoidance of animal-derived (heme) iron may reduce the risk of EC in these women.

Biomarkers of the metabolic syndrome and breast cancer prognosis.

In spite of its public health importance, our understanding of the mechanisms of breast carcinogenesis and progress is still evolving. The metabolic syndrome (MS) is a constellation of biochemical abnormalities including visceral adiposity, hyperglycemia, hyperinsulinemia, dyslipidemia and high blood pressure. The components of the MS have all been related to late-stage disease and even to a poor prognosis of breast cancer through multiple interacting mechanisms. In this review, we aim to present a summary of recent advances in the understanding of the contribution of the MS to breast cancer with the emphasis on the role of biomarkers of the MS in the prognosis of breast cancer.

Identification of Serum Biomarkers for Biliary Tract Cancers by a Proteomic Approach Based on Time-of-Flight Mass Spectrometry.

Biliary tract cancers (BTCs) are lethal malignancies currently lacking satisfactory methods for early detection and accurate diagnosis. Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) is a promising diagnostic tool for this disease. In this pilot study, sera samples from 50 BTCs and 30 cholelithiasis patients as well as 30 healthy subjects from a population-based case-control study were randomly grouped into training set (30 BTCs, 20 cholelithiasis and 20 controls), duplicate of training set, and blind set (20 BTCs, 10 cholelithiasis and 10 controls); all sets were analyzed on Immobilized Metal Affinity Capture ProteinChips via SELDI-TOF-MS. A decision tree classifier was built using the training set and applied to all test sets. The classification tree constructed with the 3,400, 4,502, 5,680, 7,598, and 11,242 mass-to-charge ratio (m/z) protein peaks had a sensitivity of 96.7% and a specificity of 85.0% when comparing BTCs with non-cancers. When applied to the duplicate set, sensitivity was 66.7% and specificity was 70.0%, while in the blind set, sensitivity was 95.0% and specificity was 75.0%. Positive predictive values of the training, duplicate, and blind sets were 82.9%, 62.5% and 79.2%, respectively. The agreement of the training and duplicate sets was 71.4% (Kappa = 0.43, u = 3.98, P < 0.01). The coefficient of variations based on 10 replicates of one sample for the five differential peaks were 15.8-68.8% for intensity and 0-0.05% for m/z. These pilot results suggest that serum protein profiling by SELDI-TOF-MS may be a promising approach for identifying BTCs but low assay reproducibility may limit its application in clinical practice.

Polymorphisms and haplotypes in the caspase-3, caspase-7, and caspase-8 genes and risk for endometrial cancer: a population-based, case-control study in a Chinese population.

Caspase-3, caspase-7, and caspase-8 are important caspases in the apoptosis pathway and play an important role in the development and progression of cancer. We examined the association between genetic variants in the caspase-3, caspase-7, and caspase-8 genes and risk for endometrial cancer among Chinese women. Genotypes for 1,028 women with endometrial cancer and 1,003 healthy controls were determined with the Affymetrix MegAllele Targeted Genotyping System and Molecular Inversion Probe method. Of 35 selected single-nucleotide polymorphisms, four in the caspase-7 gene were in high linkage disequilibrium (rs11593766, rs3124740, rs11196445, and rs11196418) and associated with the risk for endometrial cancer. The AA genotype of rs11196418 [odds ratio, 0.36; 95% confidence interval (95% CI), 0.14-0.94] and the G allele of rs11593766 were associated with reduced risk (odds ratio of 0.75 and 95% CI of 0.59-0.96 for carriers of one G allele; odds ratio of 0.70 and 95% CI of 0.24-2.03 for carriers of two G alleles). The AA genotype of rs11196445 (odds ratio, 1.74; 95% CI, 0.99-3.05), the CC genotype of rs3124740 (odds ratio, 1.36; 95% CI, 1.06-1.75), and the GG genotype of rs10787498 in the caspase-7 gene (odds ratio, 1.90; 95% CI, 1.16-3.11) were associated with increased risk compared with homozygotes of the major alleles. The gene-disease association seemed to be more pronounced among premenopausal women, although tests for multiplicative interaction between genes and menopausal status failed to reach statistical significance. The GG genotype of rs2705901 in the caspase-3 gene was significantly associated with increased cancer risk compared with the CC genotype (odds ratio, 2.25; 95% CI, 1.03-4.95). No association was observed between polymorphisms of the caspase-8 gene and risk for endometrial cancer. These findings suggest that genetic variants in caspase-3 and caspase-7 may play a role in endometrial cancer susceptibility.

Association of the progesterone receptor gene with endometrial cancer risk in a Chinese population.

BACKGROUND: Single nucleotide polymorphisms (SNPs) in the progesterone receptor (PGR) gene have been associated with the risk of endometrial cancer. However, to the authors' knowledge, no study to date has systematically evaluated the role of the PGR gene in endometrial carcinogenesis. METHODS: Exposure information and DNA samples collected in the Shanghai Endometrial Cancer Study, a population-based case-control study of 1,204 incident cases and 1,212 age- and frequency-matched population controls, were used in this study. Seven tag SNPs were identified for the PGR gene plus the 5-kilobase (kb) flanking regions using the Han Chinese data from the HapMap project with a pairwise correlation coefficient (r(2)) >or= 0.90. These 7 SNPs captured 92% of SNPs in the region with a pairwise r(2) >or= 0.90 or 100% of SNPs with a pairwise r(2) >or= 0.80. Genotyping of polymorphisms was performed by using the Affymetrix MegAllele Targeted Genotyping System. A logistic regression model was used to compute adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: Of 7 tag SNPs that were assessed, 2 polymorphisms in the 3' flanking region of the PGR gene, reference SNP identification number (rs) 11224561 (rs11224561) and rs471767, were associated with the risk of endometrial cancer. The cytosine/cytosine (CC) genotype of SNP rs11224561 was associated with decreased risk (OR, 0.68; 95% CI, 0.50-0.92) compared with the thymine/thymine (TT) genotype. Carrying the guanine (G) allele of the rs471767 SNP also was associated with decreased risk, although the association was not statistically significant (OR, 0.78, 95%CI, 0.59-1.04 and OR, 0.32, 95%CI, 0.03-3.05 for the adenine [A]G and GG genotypes, respectively, compared with the homozygote AA). CONCLUSIONS: The current findings suggested that polymorphisms in the 3' flanking region of the PGR gene may be associated with the risk of endometrial cancer.