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This prospective cohort study was to assess the association of pre-diagnostic dietary intake and dietary pattern with the survival of esophageal squamous cell carcinoma (ESCC) patients.855 patients were recruited and successfully followed. Information on diet over past five years before diagnosis was collected using a food frequency questionnaire, and dietary patterns were extracted using principal component analysis. Hazard ratio (HR) with 95% confidence interval (95% CI) was calculated using the Cox proportional hazard model.164 (19.18%) ESCC patients survived during the follow-up. Every 25-g increment intake of pickled vegetables was associated with a 6.0% (HR: 1.060, 95% CI: 1.003-1.121) increased risk of death after adjustment for covariates. When comparing the highest with lowest tertiles of energy-adjusted intake, pickled vegetables intake was associated with a 21.9% elevated risk of death (HR: 1.219, 95% CI: 1.014-1.465), while fish and shrimp intake was associated with a 19.4% (HR: 0.816, 95% CI: 0.675-0.986) reduced risk of death. Three dietary patterns were defined and labeled as patterns I, II, and III. Every 10-score increment of dietary pattern II, characterized with a higher loading of preserved vegetables, pickled vegetables, and salted meat, was associated with a 1.7% (HR: 1.017, 95% CI: 1.003-1.032) increased risk of death.A diet characterized with higher loading of preserved vegetables, pickled vegetables, and salted meat, was negatively associated with death risk among ESCC patients. Prospective studies concerning the role of post-diagnosis dietary intake in ESCC prognosis are needed.

PDF file, 199KB, Supplementary Table 1. TGF-β signaling pathway SNPs and breast cancer risk, Stage I. Supplementary Table 2. TGF-β signaling pathway variants showing an association with breast cancer risk (P value ≤0.05) in at least one genetic model, Stage 1. Supplementary Table 3. Results for TGF-β signaling pathway SNPs selected for Stage II evaluation (not presented in Table 3).

Background: The TGF-β signaling pathway plays a significant role in the carcinogenic process of breast cancer.Methods: We systematically evaluated associations of common variants in TGF-β signaling pathway genes with breast cancer risk using a multistage, case–control study among Asian women.Results: In the first stage, 341 single-nucleotide polymorphisms with minor allele frequencies ≥ 0.05 across 11 genes were evaluated among 2,926 cases and 2,380 controls recruited as a part of the Shanghai Breast Cancer Genetics Study (SBCGS). In the second stage, 20 SNPs with promising associations were evaluated among an additional 1,890 cases and 2,000 controls from the SBCGS. One variant, TGFBR2 rs1078985, had highly consistent and significant associations with breast cancer risk among participants in both study stages, as well as promising results from in silico analysis. Additional genotyping was carried out among 2,475 cases and 2,343 controls from the SBCGS, as well as among 5,077 cases and 5,384 controls from six studies in the Asian Breast Cancer Consortium (stage III). Pooled analysis of all data indicated that minor allele homozygotes (GG) of TGFBR2 rs1078985 had a 24% reduced risk of breast cancer compared with major allele carriers (AG or AA; OR, 0.76; 95% CI, 0.65–0.89; P = 8.42 × 10−4).Conclusion: These findings support a role for common genetic variation in TGF-β signaling pathway genes, specifically in TGFBR2, in breast cancer susceptibility.Impact: These findings may provide new insights into the etiology of breast cancer as well as future potential therapeutic targets. Cancer Epidemiol Biomarkers Prev; 21(7); 1176–84. ©2012 AACR.

Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and East Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions, and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Cross-tissue analyses indicated that over a third of effector genes most likely act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis, and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.

Abstract. Background and aims: Experimental studies showed that carotenoids had anti-carcinogenesis properties, but epidemiological studies on the association between dietary carotenoids and esophageal squamous cell carcinoma (ESCC) risk were limited, and the findings were inconsistent. This study aimed to investigate the roles of intake of dietary carotenoids in the development of ESCC among a rural Chinese population. Methods: A population-based case-control study was conducted in Southwest China. A total of 915 incident ESCC cases and 925 community-based controls were included. A validated food frequency questionnaire with 76-item was adopted to collect information about dietary consumption. Intake of dietary calories and each carotenoid was calculated according to the China food composition tables. Odds ratios (OR) with 95% confidence intervals (CI) were calculated by using logistic regression model, with adjustments for age, gender, body mass index, family cancer history, cigarette smoking, alcohol drinking, education, marital status, prudent pattern score, and total calories. Results: In comparison of the highest with lowest intake quartiles, intake of total carotene (OR: 0.70, 95% CI: 0.52–0.96, Ptrend: 0.024), α-carotene (OR: 0.62, 95% CI: 0.46–0.83, Ptrend: 0.014), β-carotene (OR: 0.63, 95% CI: 0.46–0.86, P-trend: 0.005), and the sum of lutein and zeaxanthin (OR: 0.41, 95% CI: 0.29–0.56, Ptrend

The association of dietary phytosterols intake with survival of esophageal squamous cell carcinoma (ESCC) remains unclear. This study was to examine the effect of dietary phytosterols intake on ESCC survival in a Chinese rural population.A total of 942 incident ESCC patients diagnosed between 2011 and 2013 in Yanting area were followed up until March 1When comparing the highest with lowest intake quartiles, intake of five specific and total phytosterols was not significantly associated with risk of death after adjustment for covariates, the adjusted HR (95% CI) for β-sitosterol, campesterol, stigmasterol, β-sitostanol, campestanol and total phytosterols was 0.90 (95% CI: 0.70-1.16), 0.92 (95% CI: 0.71-1.19), 0.86 (95% CI: 0.66-1.12), 0.93 (95% CI: 0.73-1.20), 0.94 (95% CI: 0.72-1.21), 0.89 (95% CI: 0.69-1.15), respectively.This study does not find any association between pre-diagnostic phytosterols intake and risk of all-cause mortality among ESCC patients. Further research is required to determine the effect of post-diagnostic phytosterols intake on ESCC survival.

Background Loss to follow-up (LTFU) during post-operative surveillance of breast cancer patients is detrimental. The pattern of LTFU and its risk factors in Chinese breast cancer patients remains unknown. Method Eligible non-metastatic breast cancer patients who underwent surgery at our institution between 2009 and 2012 were included. The clinicopathological features, as well as the LTFU status, were retrieved from the REDCap database. LTFU was defined as the absence of patients for at least 12 months since her last contact. 5-year LTFU was defined as the LTFU status of each patients at 5 years after surgery. The incidence and potential risk factors of LTFU were analyzed. A LTFU-risk score was developed to quantify the risk of LTFU. Results A total of 1536 patients with breast cancer were included, and 411(26.8%) patients were 5-year LTFU. 198 patients were LTFU in the first year. Univariate and multivariate analysis revealed that age (younger and older), a lack of medical insurance, longer distance from residence to the hospital, pathology (DCIS/Paget’s/Phyllodes), lymph node metastasis, the absence of endocrine therapy and fewer than five contact numbers were significantly and independently associated with the risk of LTFU. A LTFU-risk score was developed and was predictive of LTFU. Conclusions A series of risk factors were significantly associated with post-operative LTFU of breast cancer patients. Patients with different risks of LTFU could possibly be identified, and surveillance plans could be individualized for different patients, so as to effectively reduce the overall LTFU rate, and optimize the allocation of medical resources., Highlights • The first research investigating loss to follow-up in patients with breast cancer in China, its patterns and risk factors. • A LTFU (loss to follow-up)-risk score which could be used to predict the risk of LTFUwas developed. • The LTFU-risk score stratified the risk of LTFU, assisting the development of individualized surveillance plans.

Background: Risk variants identified so far for colorectal cancer explain only a small proportion of familial risk of this cancer, particularly in Asians. Methods: We performed a genome-wide association study (GWAS) of colorectal cancer in East Asians, including 23,572 colorectal cancer cases and 48,700 controls. To identify novel risk loci, we selected 60 promising risk variants for replication using data from 58,131 colorectal cancer cases and 67,347 controls of European descent. To identify additional risk variants in known colorectal cancer loci, we performed conditional analyses in East Asians. Results: An indel variant, rs67052019 at 1p13.3, was found to be associated with colorectal cancer risk at P = 3.9 × 10–8 in Asians (OR per allele deletion = 1.13, 95% confidence interval = 1.08–1.18). This association was replicated in European descendants using a variant (rs2938616) in complete linkage disequilibrium with rs67052019 (P = 7.7 × 10–3). Of the remaining 59 variants, 12 showed an association at P < 0.05 in the European-ancestry study, including rs11108175 and rs9634162 at P < 5 × 10−8 and two variants with an association near the genome-wide significance level (rs60911071, P = 5.8 × 10−8; rs62558833, P = 7.5 × 10−8) in the combined analyses of Asian- and European-ancestry data. In addition, using data from East Asians, we identified 13 new risk variants at 11 loci reported from previous GWAS. Conclusions: In this large GWAS, we identified three novel risk loci and two highly suggestive loci for colorectal cancer risk and provided evidence for potential roles of multiple genes and pathways in the etiology of colorectal cancer. In addition, we showed that additional risk variants exist in many colorectal cancer risk loci identified previously. Impact: Our study provides novel data to improve the understanding of the genetic basis for colorectal cancer risk.

ImportanceSeveral polygenic risk scores (PRSs) have been developed to predict the risk of colorectal cancer (CRC); however, virtually all these PRSs were constructed in European descendants.ObjectiveTo develop and validate PRSs using data from large genome-wide association studies (GWAS) conducted in East Asians.Design, Setting, and ParticipantsPRSs were developed using GWAS data from 22,702 cases and 212,486 controls and validated in two case-control studies (1,454 Korean and 1,736 Chinese). PRSs were derived using three approaches: (1) leading risk variants in GWAS-identified CRC loci; (2) risk variants independently associated with CRC in East Asians that were identified via fine-mapping of known GWAS-identified risk loci; and (3) genome-wide risk prediction algorisms using LDpred2 and PRS-CS.Main Outcomes and MeasuresLogistic regression models were used to examine associations of PRSs with CRC risk by estimating odds ratios (ORs) with 95% confidence intervals (CIs) and area under the receiver operating characteristic curve (AUC).ResultsIn the validation sets, PRS115-EAS, a PRS with 115 GWAS-reported leading risk variants derived from East Asian data performed significantly better in discriminating CRC cases from non-cases than PRS115-EUR, a PRS derived using GWAS data from European descendants. In the Korea validation set, ORs per SD increase of PRS115-EAS were 1.63 (95%CI = 1.46 - 1.82; AUC = 0.63), compared with OR of 1.44 (95%CI = 1.29 - 1.60, AUC = 0.60) for PRS115-EUR. PRS115-EAS/EUR derived using results from meta-analyses of East Asian and European-ancestry data slightly improved the AUC to 0.64 (95% CI = 0.61 - 0.67). Similar, but less strong, associations were found in the China validation set. Individuals in the top 5% of PRS115-EAS/EUR were at a 2.52-folded (95% CI = 2.27 - 2.81) elevated risk of CRC as compared with the average risk group and have a 12% or higher risk of developing CRC by age 85 years.Conclusions and RelevanceOur results indicate that PRSs derived using GWAS-identified CRC risk variants are promising in predicting CRC risk in East Asians. Our study highlights the importance of using population-specific data to build CRC risk prediction models.Key PointsQuestionHow well do polygenetic scores (PRS) developed using data from genome-wide association studies (GWAS) predict colorectal cancer (CRC) risk in East Asians?FindingsUsing GWAS data from more than 230,000 cases and controls in East Asian, 11 PRSs were developed with variants ranging from 115 to 747,643. PRS including 115 variants derived from meta-analyses of East Asian and European-ancestry GWAS data showed the highest performance in discriminating CRC cases and controls in validation sets including 1,490 cases and 1,700 controls.MeaningThese findings support the utility of PRS in identifying high-risk individuals for CRC prevention and highlight the importance of using population-specific data to build CRC risk prediction models.

Early diagnosis of Treponema pallidum infection is helpful for disease management, and conventional PCR is suitable for lesion swabs of patients with probable early syphilis. We thus tested nested and real-time PCR (NR-PCR) in various biosamples from syphilitic patients.Samples were collected from syphilis patients before treatment. Specific primer sequences targeting the T. pallidum gene polA were designed for NR-PCR.Across syphilis types, most samples assayed with NR-PCR returned a positive result, including earlobe blood (92.0%), cerebrospinal fluid (CSF) (90.2%), lesion swabs (74.3%), serum (66.9%), and whole blood (64.2%). No significant differences were observed in positive samples for whole blood, serum, and lesion swabs between primary and secondary syphilis (P0.05 for all comparisons). However, more whole-blood samples from patients with secondary syphilis were positive for NR-PCR than whole blood samples from patients with tertiary and latent syphilis (P0.05 for all comparisons). For neurosyphilis patients, significantly more earlobe blood samples tested positive than did whole-blood samples (P0.05), but there was no difference in positive results for earlobe blood and whole blood in latent syphilis. Significantly more serum samples tested positive in latent syphilis patients with rapid plasma regain (RPR) titers of 1:8 or greater, compared to those with RPR of 1:4 or less.Nested and real-time PCR can be used to identify T. pallidum DNA in biosamples from syphilitic patients, especially earlobe blood.

The aim of this population-based case-control study was to investigate the association between dietary consumption of the total flavonoids, subclasses, and specific flavonoids and the risk of esophageal squamous cell carcinoma (ESCC) among adults in a high-risk area of China.We recruited 820 ESCC participants and 863 control participants from Yanting County. Dietary flavonoids were assessed using a validated 76-item food frequency questionnaire. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using logistic regression after considering potential confounders.Comparing the highest and lowest intake quartiles, we observed a negative association of ESCC risk with consumption of isoflavones (OR = 0.34, 95% CI = 0.23-0.50, P for trend0.001), daidzein (OR = 0.31, 95% CI = 0.21-0.45, P for trend0.001), genistein (OR = 0.34, 95% CI = 0.23-0.50, P for trend0.001), and glycitein (OR = 0.32, 95% CI = 0.22-0.48, P for trend0.001) after adjustment for potential confounders. A more pronounced negative association was observed when comparing the third quartile, rather than the fourth, with the lowest quartile for consumption of anthocyanidins (OR = 0.58, 95% CI = 0.42-0.80, P for trend = 0.004), delphinidin (OR = 0.57, 95% CI = 0.41-0.78, P for trend = 0.004), and cyanidin (OR = 0.48, 95% CI = 0.35-0.66, P for trend = 0.003) after considering potential confounders. Consumption of total flavonoids, flavones, flavonols, and six other specific flavonoids (quercetin, myricetin, kaempferol, luteolin, apigenin, and peonidin) was not associated with ESCC risk.The results suggest that increased dietary intake of isoflavones and moderate consumption of anthocyanidins were associated with a decreased risk of ESCC. Future nutritional guidelines may emphasize foods or supplements rich in specific isoflavones and anthocyanidins for ESCC chemoprevention.

BACKGROUND & AIMS: Genome-wide association studies (GWASs) have associated approximately 50 loci with risk of colorectal cancer (CRC)—nearly one-third of these loci were initially associated with CRC in studies conducted in East Asian populations. We conducted a GWAS of East Asians to identify CRC risk loci and evaluate the generalizability of findings from GWAS of European populations to Asian populations METHODS: We analyzed genetic data from 22,775 patients with CRC (cases) and 47,731 individuals without cancer (controls) from 14 studies in the Asia Colorectal Cancer Consortium. First, we performed a meta-analysis of 7 GWAS (10,625 cases and 34,595 controls) and identified 46,554 promising risk variants for replication by adding them to the Multi-Ethnic Global Array (MEGA) for genotype analysis in 6445 cases and 7175 controls. These data were analyzed, along with data from additional 5705 cases and 5961 controls genotyped using the OncoArray. We also obtained data from 57,976 cases and 67,242 controls of European descent. Variants at identified risk loci were functionally annotated and evaluated in correlation with gene expression levels. RESULTS: A meta-analyses of all samples from people of Asian descent identified 13 loci and 1 new variant at a known locus (10q24.2) associated with risk of CRC at the genome-wide significance level of P

Improvements in stent-graft devices and increasing clinical experience with the technique have improved outcomes and expanded clinical indications in patients with Stanford type B aortic dissection (AD) in China. However, the evolution of and modifications to stent grafts have not been reviewed. The aim of this study was to summarize all available published data on technical success, potential benefits, complications, stent evolution, and survival rates associated with endovascular stent-graft placements in patients with Stanford type B AD in China.We performed comprehensive searches of the Chinese-language medical literature in Chinese Biomedical Database, China National Knowledge Infrastructure, and Wanfang Data and of the English-language medical literature in PubMed, Web of Science, and the Cochrane Library. This systematic review was based on all retrospective studies assessing outcomes of Stanford type B AD treated with endovascular stent-graft placement in China.A total of 153 retrospective studies that included 8,694 cases were analyzed in this study. Procedure success was reported in 99.7 ± 0.1% of patients. Overall complications were reported in 19.1 ± 0.6% of patients. Postoperative endoleaks occurred in 7.2 ± 0.3% of patients. Major complications were reported in 3.2 ± 0.2% of patients, with a neurological complication rate of 1.3 ± 0.1%. Periprocedural stroke occurred more frequently than did paraplegia (0.8 ± 0.1% vs. 0.1 ± 0.04%). Overall complications were significantly greater in patients treated with first-generation stents than in those treated with second-generation stents (25.1 ± 1.2% vs. 9.5 ± 0.9%, P 0.001). The in-hospital mortality rate was 1.6 ± 0.1%. In addition, 1.8 ± 0.2% of patients died during a mean follow-up period of 29.4 ± 13.5 months. The Kaplan-Meier estimates of the overall survival rate were 99.0 ± 0.1% at 30 days, 98.5 ± 0.2% at 6 months, 98.4 ± 0.2% at 1 year, 98.1 ± 0.2% at 2 years, and 97.9 ± 0.2% at 5 years.Endovascular stent-graft placement is feasible and has a high technique success rate as well as favorable neurological complication and survival rates when used to treat Stanford type B AD. The new generation of stent grafts appears to have favorable in-hospital and follow-up outcomes.

Background: There has been growing evidence showing that inflammatory markers play an important role in the development of ovarian cancer. We conducted a meta-analysis on the associations between circulating levels of C-reactive protein (CRP), interleukin 6 (IL6), tumor necrosis factor α (TNFα), and soluble TNFα receptor 2 (TNFR2), and the risk of ovarian cancer. Methods: A systematic search of PubMed and EMBASE up until January 19, 2016 was conducted to retrieve prospective studies. The summary risk estimates were pooled using random-effects models. The dose–response relationship was assessed using generalized least-squares trend estimation. Results: Seven nested case–control studies and one prospective cohort study were included in the review. For circulating CRP, women in the highest category had a significantly increased risk of ovarian cancer than women in the lowest category, with no significant between-study heterogeneity [pooled relative risk (RR) = 1.91; 95% confidence intervals (CI) 1.51–2.40; P < 0.001; I2 = 0.0%]. Influence analyses further supported this positive association. A positive dose–response relationship was also observed (pooled RR = 1.15; 95% CI, 1.03–1.30 per 5 mg/L of CRP). Publication bias was found. However, the association persisted after correction using the trim-and-fill method. No significant association was observed for circulating IL6, TNFα, and soluble TNFR2. Conclusion: This meta-analysis provides evidence that elevated levels of CRP, but not circulating IL6, TNFα, or soluble TNFR2, are significantly associated with an increased risk of ovarian cancer. Impact: These results suggest that circulating CRP may play a role in the etiology of ovarian cancer. Cancer Epidemiol Biomarkers Prev; 25(8); 1231–9. ©2016 AACR.

Genome-wide association studies (GWAS) of colorectal cancer (CRC) have been conducted primarily in European descendants. In a GWAS conducted in East Asians, we first analyzed approximately 1.7 million single-nucleotide polymorphisms (SNPs) in four studies with 1,773 CRC cases and 2,642 controls. We then selected 66 promising SNPs for replication and genotyped them in three independent studies with 3,612 cases and 3,523 controls. Five SNPs were further evaluated using data from four additional studies including up to 3,290 cases and 4,339 controls. SNP rs7229639 in the SMAD7 gene was found to be associated with CRC risk with an odds ratio (95% confidence interval) associated with the minor allele (A) of 1.22 (1.15–1.29) in the combined analysis of all 11 studies (p = 2.93 × 10−11). SNP rs7229639 is 2,487 bp upstream from rs4939827, a risk variant identified previously in a European-ancestry GWAS in relation to CRC risk. However, these two SNPs are not correlated in East Asians (r2 = 0.008) nor in Europeans (r2 = 0.146). The CRC association with rs7229639 remained statistically significant after adjusting for rs4939827 as well as three additional CRC risk variants (rs58920878, rs12953717 and rs4464148) reported previously in this region. SNPs rs7229639 and rs4939827 explained approximately 1% of the familial relative risk of CRC in East Asians. This study identifies a new CRC risk variant in the SMAD7 gene, further highlighting the significant role of this gene in the etiology of CRC.

In a consortium including 23 637 breast cancer patients and 25 579 controls of East Asian ancestry, we investigated 70 single-nucleotide polymorphisms (SNPs) in 67 independent breast cancer susceptibility loci recently identified by genome-wide association studies (GWASs) conducted primarily in European-ancestry populations. SNPs in 31 loci showed an association with breast cancer risk at P < 0.05 in a direction consistent with that reported previously. Twenty-one of them remained statistically significant after adjusting for multiple comparisons with the Bonferroni-corrected significance level of, published_or_final_version

To identify new genetic factors for colorectal cancer (CRC), we conducted a genome-wide association study in east Asians. By analyzing genome-wide data in 2,098 cases and 5,749 controls, we selected 64 promising SNPs for replication in an independent set of samples, including up to 5,358 cases and 5,922 controls. We identified four SNPs with association P values of 8.58 × 10(-7) to 3.77 × 10(-10) in the combined analysis of all east Asian samples. Three of the four were replicated in a study conducted in 26,060 individuals of European descent, with combined P values of 1.22 × 10(-10) for rs647161 (5q31.1), 6.64 × 10(-9) for rs2423279 (20p12.3) and 3.06 × 10(-8) for rs10774214 (12p13.32 near the CCND2 gene), derived from meta-analysis of data from both east Asian and European-ancestry populations. This study identified three new CRC susceptibility loci and provides additional insight into the genetics and biology of CRC.

To investigate whether polycyclic aromatic hydrocarbon (PAH) exposure is associated with specific histone modifications and whether DNA damage triggers epigenetic alterations, we recruited 190 male workers with occupational exposure to PAHs and 100 male control workers from Benxi Steel Plant, Liaoning province, China. Urinary 1-hydroxypyrene (1-OHP), DNA damage, specific histone modification levels and the expression of selected DNA damage response (DDR) genes were measured in peripheral blood lymphocytes (PBLCs) of the subjects. The results showed that trimethylated Lys 27 of histone H3 (H3K27me3) and trimethylated Lys 36 of histone H3 (H3K36me3) were elevated in the PAH-exposed group (both P < 0.001), while trimethylated Lys H3 of histone H3 (H3K4me3) was decreased compared to the unexposed group (P < 0.001). Notably, H3K36me3 was positively associated with the level of internal exposure marker 1-OHP (β = 0.197; P < 0.001) and the degree of DNA damage (β = 0.175; P < 0.001) in all subjects, indicating that the PAH-induced DNA damage response might be mediated by H3K36me3 and/or H3K4me3 modifications. Particularly, the ChIP-qPCR assay revealed that the modifications of H3K36me3 were enriched in the gene body of DDR genes, MGMT and MLH1. The up-regulation of MGMT and MLH1 was correlated with the elevated H3K36me3 in the PAH-exposed workers (P < 0.001). Collectively, we revealed that H3K36me3 could be an indicator of PAH exposure and might be involved in the transcriptional regulation of DNA repair genes in response to DNA damage.

Background: The TGF-β signaling pathway plays a significant role in the carcinogenic process of breast cancer. Methods: We systematically evaluated associations of common variants in TGF-β signaling pathway genes with breast cancer risk using a multistage, case–control study among Asian women. Results: In the first stage, 341 single-nucleotide polymorphisms with minor allele frequencies ≥ 0.05 across 11 genes were evaluated among 2,926 cases and 2,380 controls recruited as a part of the Shanghai Breast Cancer Genetics Study (SBCGS). In the second stage, 20 SNPs with promising associations were evaluated among an additional 1,890 cases and 2,000 controls from the SBCGS. One variant, TGFBR2 rs1078985, had highly consistent and significant associations with breast cancer risk among participants in both study stages, as well as promising results from in silico analysis. Additional genotyping was carried out among 2,475 cases and 2,343 controls from the SBCGS, as well as among 5,077 cases and 5,384 controls from six studies in the Asian Breast Cancer Consortium (stage III). Pooled analysis of all data indicated that minor allele homozygotes (GG) of TGFBR2 rs1078985 had a 24% reduced risk of breast cancer compared with major allele carriers (AG or AA; OR, 0.76; 95% CI, 0.65–0.89; P = 8.42 × 10−4). Conclusion: These findings support a role for common genetic variation in TGF-β signaling pathway genes, specifically in TGFBR2, in breast cancer susceptibility. Impact: These findings may provide new insights into the etiology of breast cancer as well as future potential therapeutic targets. Cancer Epidemiol Biomarkers Prev; 21(7); 1176–84. ©2012 AACR.

Objective Transforming growth factor β1 (TGF-β1) is a multifunctional cytokine that may play an important role in tumor development and progression.

Known genetic factors explain only a small fraction of genetic variation in colorectal cancer (CRC). We conducted a genome-wide association study to identify risk loci for CRC.This discovery stage included 8027 cases and 22,577 controls of East-Asian ancestry. Promising variants were evaluated in studies including as many as 11,044 cases and 12,047 controls. Tumor-adjacent normal tissues from 188 patients were analyzed to evaluate correlations of risk variants with expression levels of nearby genes. Potential functionality of risk variants were evaluated using public genomic and epigenomic databases.We identified 4 loci associated with CRC risk; P values for the most significant variant in each locus ranged from 3.92 × 10(-8) to 1.24 × 10(-12): 6p21.1 (rs4711689), 8q23.3 (rs2450115, rs6469656), 10q24.3 (rs4919687), and 12p13.3 (rs11064437). We also identified 2 risk variants at loci previously associated with CRC: 10q25.2 (rs10506868) and 20q13.3 (rs6061231). These risk variants, conferring an approximate 10%-18% increase in risk per allele, are located either inside or near protein-coding genes that include transcription factor EB (lysosome biogenesis and autophagy), eukaryotic translation initiation factor 3, subunit H (initiation of translation), cytochrome P450, family 17, subfamily A, polypeptide 1 (steroidogenesis), splA/ryanodine receptor domain and SOCS box containing 2 (proteasome degradation), and ribosomal protein S2 (ribosome biogenesis). Gene expression analyses showed a significant association (P.05) for rs4711689 with transcription factor EB, rs6469656 with eukaryotic translation initiation factor 3, subunit H, rs11064437 with splA/ryanodine receptor domain and SOCS box containing 2, and rs6061231 with ribosomal protein S2.We identified susceptibility loci and genes associated with CRC risk, linking CRC predisposition to steroid hormone, protein synthesis and degradation, and autophagy pathways and providing added insight into the mechanism of CRC pathogenesis.

Disruption of the balance of IGF (Insulin like growth factor) pathway constituents has been implicated in the etiology and progression of breast and other cancers. We hypothesized that genetic polymorphisms in IGF system members may be associated with breast cancer survival and evaluated this hypothesis in a cohort of 1,455 women diagnosed with breast cancer between 1996 and 1998 in Shanghai, China. Nineteen functional or potentially functional polymorphisms were evaluated in the IGF-1, IGF-1R, IGFALS, and IGFBP3 genes. Disease recurrence and vital status were obtained with a median follow-up time of 7.1 years. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Overall, no significant association was noted between any of the 19 polymorphisms and survival. However, subgroup analyses demonstrated apparent interactions between menopausal status and survival for several (Single nucleotide polymorphism) SNPs in the IGF-1R and IGFBP3 genes. Carriers of the A/G or G/G genotypes (rs951715) in the IGF-1R gene had an increased risk of death among post-menopausal women (HR = 1.7, 95% CI = 1.1-2.7). Significant associations with breast cancer survival in pre-menopausal women were found for two IGFBP3 polymorphisms (rs2854744 and rs3110697), with an additional polymorphism (rs6413441) reaching borderline significance (P = 0.05). Hazard ratios for overall survival among pre-menopausal women were 1.5 (95% CI = 1.1-2.0) for the C/T-T/T genotypes (rs3110697), 1.4 (95% CI = 1.0-1.9) for the A/C-C/C genotypes (rs2854744), and 1.4 (95% CI = 1.0-1.9) for the N/A-A/A genotypes (rs6413441). Taken together, these data suggest that polymorphisms in the IGF-1R and IGFBP3 genes may be associated with altered survival among subgroups of breast cancer patients defined by menopausal status.

Genome-wide association studies (GWAS) of colorectal cancer (CRC) have been conducted primarily in European descendants. In a GWAS conducted in East Asians, we first analyzed approximately 1.7 million single-nucleotide polymorphisms (SNPs) in four studies with 1,773 CRC cases and 2,642 controls. We then selected 66 promising SNPs for replication and genotyped them in three independent studies with 3,612 cases and 3,523 controls. Five SNPs were further evaluated using data from four additional studies including up to 3,290 cases and 4,339 controls. SNP rs7229639 in the SMAD7 gene was found to be associated with CRC risk with an odds ratio (95% confidence interval) associated with the minor allele (A) of 1.22 (1.15-1.29) in the combined analysis of all 11 studies (p = 2.93 × 10(-11) ). SNP rs7229639 is 2,487 bp upstream from rs4939827, a risk variant identified previously in a European-ancestry GWAS in relation to CRC risk. However, these two SNPs are not correlated in East Asians (r(2) = 0.008) nor in Europeans (r(2) = 0.146). The CRC association with rs7229639 remained statistically significant after adjusting for rs4939827 as well as three additional CRC risk variants (rs58920878, rs12953717 and rs4464148) reported previously in this region. SNPs rs7229639 and rs4939827 explained approximately 1% of the familial relative risk of CRC in East Asians. This study identifies a new CRC risk variant in the SMAD7 gene, further highlighting the significant role of this gene in the etiology of CRC.

Background The Dabaoshan mine in the southeast of Guangdong Province, China, is at high risk of multi-metal pollutant discharge into a local river (Hengshihe) and the surrounding area. Following approximately 30 years of exposure to these metals, little is known regarding the subsequent health effects and risks for the local residents. In our present study, we have estimated the relationships between long-term environmental exposure to multiple heavy metals and the risk of cancer mortality in a Chinese population in the vicinity of Dabaoshan. Methods An ecologic study was performed. Between 2000-2007, a total population of 194,131 lived in the nine agricultural villages that surround the Hengshihe area. Heavy metals concentrations were determined in local environmental samples (water and crops) and whole blood taken from 1152 local residents of both a high-exposure area (HEA) and a low-exposure area (LEA). We calculated the rate ratio and standardized mortality ratios based on age- and gender-specific cancer mortality rates for the different reference populations (based on district, county and province). Simple, multiple linear and ridge regression models were used to evaluate the associations between exposure to multiple heavy metals and cancer mortality in the nine villages, after adjustment for age and sex. Results The geometric mean blood levels of cadmium and lead were measured at 24.10 μg/L and 38.91 μg/dL for subjects (n = 563) in the HEA and 1.87 μg/L and 4.46 μg/dL for subjects (n = 589) from the LEA, respectively (P < 0.001). The rate of mortality from all cancers in the HEA was substantially elevated in comparison with the corresponding mortality rate in the LEA for men (rate ratio = 2.13; 95% confidence intervals = 1.63 - 2.77) and women (2.83; 1.91 - 4.19); rates were also significantly elevated compared with the rate when compared to the entire Wengyuan County area, or the provincial reference population. In addition, mortality rates were significantly increased for stomach, lung and esophageal cancer in the HEA in comparison with the corresponding rates in the LEA, in Wengyuan County and the provincial reference population for men, women and both combined. Further analysis showed that there were significantly positive correlations between exposure to cadmium and lead and the risk of all-cancers and stomach cancer mortality among women and both sexes, whilst zinc exposure showed no association with the risk of site-specific cancer mortality in the nine villages evaluated. Conclusions The findings of this study reveal probable associations between long-term environmental exposure to both cadmium and lead and an increased risk of mortality from all cancer, as well as from stomach, esophageal and lung-cancers.

Insulin-like growth factor (IGF)-I and IGF-II have been implicated in breast tumorigenesis due to their ability to stimulate mitogenesis and promote differentiation and their key role in mammary gland cell proliferation and survival ([1][1]-[3][2]). It has been reported that genetic variations in

Cytochrome P450 1B1 (CYP1B1) and catechol-O-methyltransferase (COMT) are important estrogen-metabolizing enzymes that may affect breast cancer risk. Few studies have directly measured the expression of CYP1B1 and COMT genes in breast tissue samples. The subjects in this study were a subgroup of participants of the Shanghai Breast Cancer Study including 64 patients diagnosed with breast cancer and 68 patients diagnosed with benign breast diseases (BBD) who provided samples of tumor tissue and adjacent nontumor tissue to the study. We compared CYP1B1 and COMT mRNA expression in tumor tissue and adjacent nontumor tissue in both breast cancer patients and BBD patients. High levels of CYP1B1 expression and low levels of COMT expression in adjacent nontumor tissue were associated with a significantly increased breast cancer risk in a nonlinear manner. Odds ratios and 95% confidence intervals (in parentheses) for the midpoints of the first, second, fourth, and fifth quintiles of gene expression levels compared with the overall median levels in BBD subjects were 0.21 (0.07-0.67), 0.81 (0.69-0.95), 1.20 (1.05-1.38), and 1.55 (1.12-2.15) for CYP1B1 and 1.72 (1.17-2.55), 1.19 (1.05-1.35), 0.83 (0.73-0.95), and 0.78 (0.65-0.93) for COMT, respectively. These results support the hypothesis that the formation and accumulation of catechol estrogens in breast tissue through increased CYP1B1 expression and reduced COMT expression may play a significant role in breast cancer risk. (Cancer Epidemiol Biomarkers Prev 2007;16(5):917–20)

Introduction Most previous studies have focused on evaluating the association between circulating insulin-like growth factor binding protein 3 (IGFBP-3) levels and breast cancer risk. Emerging evidence over the past few years suggests that IGFBP-3 may act directly on mammary epithelial cells. Methods To understand the role of IGFBP-3 in breast tumorigenesis, we investigated IGFBP3 mRNA expression levels in benign and malignant breast tumors and their adjacent normal tissues using real-time quantitative PCR. Results Cancer tissues had significantly lower IGFBP3 expression than benign tumor tissues (p < 0.001). IGFBP3 expressions in both tumor and adjacent tissues were higher in patients who had proliferative benign tumors than in those who had non-proliferative benign tumors. Among patients with benign breast disease, IGFBP3 expression in the tumor was significantly higher than that in their adjacent normal tissue. There were no apparent associations of IGFBP3 expression in cancer tissues with either overall survival or disease-free survival in a cohort of 521 patients with breast cancer. Conclusion Our findings suggest that the expression level of IGFBP3 in breast tissues may be involved in breast tumorigenesis.

Objectives The optimal treatment of hepatitis C virus (HCV) genotype 6 is unclear owing to its limited geographic distribution. Because of a high predictive value of rapid virological response (RVR) for sustained virological response (SVR), we conducted an open-label randomized controlled trial to compare 24- and 48-week peginterferon/ribavirin combination therapy for patients with HCV genotype 6 in Southern China who achieved an RVR. Methods and Findings Treatment-naive, non-cirrhotic patients with chronic hepatitis C genotype 6 were treated with pegylated interferon α-2a (180 μg/week) and ribavirin (800–1,200 mg, according to weight) for 4 weeks. Patients who achieved an RVR, which was defined as HCV RNA negativity at week 4 (

The level of circulating insulin-like growth factor 1 (IGF-I) has been shown to be positively associated with breast cancer risk. The expression patterns of the IGF-I and its receptor IGFIR genes in breast tissues and their association with breast cancer survival remain unclear. In the present study, we quantified the mRNA levels of the IGF-I and IGFIR genes in both benign and malignant breast tumor tissues and their adjacent normal tissues. We then evaluated whether the expression patterns of these genes in breast cancer tissues are related to breast cancer survival. Included in the study were samples from 508 patients diagnosed with primary breast cancer, and 206 patients diagnosed with benign breast disease (BBD). Patients with BBD had a significantly higher IGF-I gene expression than patients with breast cancer in both tumor and adjacent non-neoplastic tissues. Among BBD patients, mRNA levels of the IGF-I gene were similar between tumor and tumor adjacent tissues. In cancer patients, however, the expression levels of these genes were substantially higher in tumor adjacent tissues than in tumor tissues. Patients with a high expression of the IGF-I gene in cancer tissues tended to have more favorable overall and disease-free survival. Our findings suggest that the expression of IGF-I and IGFIR genes may undergo substantial change over the course of breast tumorigenesis, and the pattern of changes may be associated with breast cancer prognosis.

BACKGROUND In addition to possessing many physiologic functions, human growth hormone-1 (GH1) has been shown in recent in vitro and in vivo experiments to induce malignant disease, including breast carcinoma. The authors investigated the association of breast carcinoma with genetic polymorphisms in the GH1 gene in the Shanghai Breast Cancer Study. METHODS Included in the current investigation were 1193 women with breast carcinoma (case patients) and 1310 healthy women from the same community (control patients) who completed in-person interviews and provided blood samples. Genetic polymorphisms in the proximal promoter region (nucleotide [nt] −162 to nt +148 relative to the transcription start site of the GH1 gene) were searched and confirmed by resequencing DNA samples from 43 study participants. A novel polymorphism, a transition from adenine to guanine at nt 69 (A69G), was identified. Samples from all participants were genotyped with TaqMan 5′ nuclease assays for five common single-nucleotide polymorphisms (SNPs)—four in the proximal region (A-75G, G-57T, A-6G, and A69G) and one in intron 4 (T1169A). RESULTS The frequencies of occurrence for the minor alleles in these polymorphic sites were 0.04, 0.60, 0.24, 0.03, and 0.34, respectively, in the control group; these frequencies were comparable to those observed in the case group. After adjusting for potential confounding factors, none of the SNPs investigated in this study showed a statistically significant association with breast carcinoma risk. This null association was found for both younger women (age < 45 years) and older women (age ≥ 45 years). GH1 gene haplotypes were assessed using SNP data and were analyzed in relation to breast carcinoma risk. Again, none of the haplotypes were associated with breast carcinoma risk. CONCLUSIONS The results of the current study suggest that genetic polymorphisms in the proximal promoter region and in the fourth intron of the GH1 gene are unrelated to breast carcinoma risk in Chinese women. Cancer 2004. © 2004 American Cancer Society.

To study the distribution of poly(ADP-ribose) polymerase(PARP) pseudogene polymorphism and the association with susceptibility to lung cancer in Chinese people.The subjects of this study included 63 patients with lung cancer and 82 healthy controls matched in gender and age. Genome DNA was extracted from white blood cells. Products from PCR with a pair of specific primer were electrophoresized in agarose including EB. Under ultraviolet, observation and imaging were performed.There was no significant difference in genotype between the cases and controls. The frequencies of B allele in cases and controls were 0.095 and 0.116 respectively. Whether there was B allele or not, smoking was a risk factor of lung cancer (P0.05). As the genotype was AA and AB or BB, smoking OR was 2.28 and 4.83 respectively. Among non-smokers, the risk at lung cancer did not increase in AB or BB genotypes(P=0.202).Frequency of B allele is relatively lower in Chinese people than in other races. In smokers, B allele may be a susceptible marker of lung cancer, and there is synergistic function between B allele and smoking.

Sleep habit is closely related to melatonin which protect against breast cancer (BC). Sleep duration, nap habit, and shift work have been separately investigated to associate with BC risk, but the combination has not been reported. In this study, we collected all the sleep habits data from 712 women with incident invasive BC before their treatments and 742 age-matched female controls between July 2010 and January 2012 in Guangzhou, China. We found that the women with either shorter or longer sleep duration had increased BC risk compared to the women with normal sleep time of 6.1-8.9h/day [OR (95%CI: 1.62 (1.18-2.24) and 1.55 (1.14-2.10), respectively]. Night shift work also increased the risk of BC [1.36 (1.07-1.73)] and nap habits marginally associated a decreased risk [0.83 (0.66-1.04)]. Women with night shift work and longer sleep duration had an increased risk of BC [3.80 (1.99-7.26)] compared to the women with normal sleep time and no night shift work. The interaction on BC risk was significant (P for interaction=0.009). We conclude that abnormal sleep increases BC risk and longer sleep duration may not compensate the effect of night shift work on risk of BC. Table 1.Age-adjusted and multivariate-adjusted odds rations for the associations between sleep habits and breast cancer riskVariablesCases Controls OR#(95%CI)OR* (95%CI)OR^ (95%CI)(n=712) (%)(n=742)(%) Shift worknever443 (67.0)527 (73.8)1.00 (reference)1.00 (reference)1.00 (reference)ever218 (33.0)187 (26.2)1.39 (1.10-1.75)1.36 (1.07-1.73)1.34 (1.04-1.71)Napping statusnever293 (44.5)254 (37.7)1.00 (reference)1.00 (reference)1.00 (reference)ever365 (55.5)420 (62.3)0.75 (0.61-0.94)0.83 (0.66-1.04)0.83 (0.66-1.06)24-hour sleep duration≤6.0116 (17.7)85 (12.8)1.62 (1.18-2.21)1.62 (1.18-2.24)1.52 (1.10-2.11)6.1-8.9409 (62.6)485 (72.7)1.00 (reference)1.00 (reference)1.00 (reference)≥9.0129 (19.7)97 (14.5)1.58 (1.18-2.12)1.55 (1.14-2.10)1.59 (1.17-2.17)P-continuous0.6460.8830.451P-trend0.9090.9960.661OR#: Adjusted for age.OR*: Adjusted for age, education, BMI, marital status, age at menarche, menopausal status, parity, activity, breastfeeding and family history of breast cancer.OR^: Adjusted for age, education, BMI, marital status, age at menarche, menopausal status, parity, activity, breastfeeding, family history of breast cancer, and other sleep factors. Citation Format: Zefang Ren. Association of sleep duration, daytime napping, and night shift work with breast cancer risk. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2181. doi:10.1158/1538-7445.AM2014-2181

Genetic factors play an important role in the etiology of both sporadic and familial breast cancer. We aimed to discover novel genetic susceptibility loci for breast cancer. We conducted a four-stage genome-wide association study (GWAS) in 19,091 cases and 20,606 controls of East-Asian descent including Chinese, Korean, and Japanese women. After analyzing 690,947 SNPs in 2,918 cases and 2,324 controls, we evaluated 5,365 SNPs for replication in 3,972 cases and 3,852 controls. Ninety-four SNPs were further evaluated in 5,203 cases and 5,138 controls, and finally the top 22 SNPs were investigated in up to 17,423 additional subjects (7,489 cases and 9,934 controls). SNP rs9485372, near the TGF-beta activated kinase (TAB2) gene in chromosome 6q25.1, showed a consistent association with breast cancer risk across all four stages, with a P-value of 3.8x10(-12) in the combined analysis of all samples. Adjusted odds ratios (95% confidence intervals) were 0.89 (0.85-0.94) and 0.80 (0.75-0.86) for the A/G and A/A genotypes, respectively, compared with the genotype G/G. SNP rs9383951 (P = 1.9x10(-6) from the combined analysis of all samples), located in intron 5 of the ESR1 gene, and SNP rs7107217 (P = 4.6x10(-7)), located at 11q24.3, also showed a consistent association in each of the four stages. This study provides strong evidence for a novel breast cancer susceptibility locus represented by rs9485372, near the TAB2 gene (6q25.1), and identifies two possible susceptibility loci located in the ESR1 gene and 11q24.3, respectively., published_or_final_version