Xiao-Ou Shu

Gateway-Vanderbilt Cancer Treatment Center, Clarksville, Tennessee, United States

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Publications (372)2391.34 Total impact

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    Dataset: 16.paper
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    ABSTRACT: Coinciding with the increased incidence of non-Hodgkin's lymphoma (NHL) during the past decades, there has been a significant increase in the prevalence of diabetes mellitus in mainland China. We therefore evaluated whether type 2 diabetes (T2D) is associated with the risk of NHL using data from the Shanghai Men's Health Study (SMHS) and the Shanghai Women's Health Study (SWHS). The SMHS and SWHS are two on-going, prospective, population-based cohorts of more than 130 000 Chinese adults in urban Shanghai. Self-reported diabetes was recorded on the baseline questionnaire and updated in follow-up surveys. Cox regression models with T2D as a time-varying exposure were used to estimate hazard ratios and 95% confidence intervals, adjusting for covariates. After a median follow-up of 12.9 years for SWHS and 7.4 years for SMHS, 172 NHL cases were identified. Patients with T2D have a higher risk of incident NHL with a hazard ratio of 2.00 (95% confidence interval: 1.32-3.03) compared with those without diabetes. This positive association remained when the analysis was restricted to untreated diabetes or after excluding NHL cases that occurred within 3 years after the onset of diabetes. No interaction effect was found in the development of NHL between T2D and other potential risk factors. A linear inverse association was found between T2D duration and the risk of NHL in both men and women (Pfor linearity<0.01), with a highest risk of incident NHL in the first 5 years after the diagnosis of diabetes. Our study suggested that T2D might be associated with an increased risk of NHL.
    European journal of cancer prevention: the official journal of the European Cancer Prevention Organisation (ECP) 03/2015; DOI:10.1097/CEJ.0000000000000150 · 2.76 Impact Factor
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    ABSTRACT: Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.
    Nature Genetics 03/2015; DOI:10.1038/ng.3242 · 29.65 Impact Factor
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    ABSTRACT: The association between benzene exposure and non-Hodgkin lymphoma (NHL) has been the subject of debate as a result of inconsistent epidemiologic evidence. An IARC working group evaluated benzene in 2009 and noted evidence for a positive association between benzene exposure and NHL risk. To evaluate the association between occupational benzene exposure and non-Hodgkin lymphoma (NHL) among 73,087 women enrolled in the prospective population-based Shanghai Women's Health Study. Benzene exposure estimates were derived using a previously developed exposure assessment framework that combined ordinal job-exposure matrix intensity ratings with quantitative benzene exposure measurements from an inspection database of Shanghai factories collected between 1954-2000. Associations between benzene exposure metrics and NHL (n = 102 cases) were assessed using Cox proportional hazard models, with study follow-up occurring from December 1996 through December 2009. Women ever exposed to benzene had a significantly higher risk of NHL (Hazard Ratio (HR): 1.87, 95% C.I.: 1.19, 2.96). Compared to unexposed women, significant trends in NHL risk were observed for increasing years of benzene exposure (ptrend = 0.006) and increasing cumulative exposure levels (ptrend = 0.005), with the highest duration and cumulative exposure tertiles having a significantly higher association with NHL (HR: 2.07, 95% C.I.: 1.07, 4.01 and HR: 2.16, 95% C.I.: 1.17, 3.98, respectively). Our findings, using a population-based prospective cohort of women with diverse occupational histories, provide additional evidence that occupational exposure to benzene is associated with NHL risk.
    Environmental Health Perspectives 03/2015; DOI:10.1289/ehp.1408307 · 7.03 Impact Factor
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    ABSTRACT: Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
    The American Journal of Human Genetics 03/2015; 96(3):487-97. DOI:10.1016/j.ajhg.2015.01.011 · 10.99 Impact Factor
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    ABSTRACT: The Shanghai Men's Health Study (SMHS) is a population-based cohort study of 61 480 men aged 40-74 years, launched in 2002 in urban Shanghai to investigate the contribution of lifestyle/environmental factors and genetic susceptibility to cancer and other non-communicable diseases (NCDs). At baseline, trained interviewers collected detailed information on personal and dietary habits, occupational/medical history and physical activity, and took anthropometric measurements (response rate: 74%). Blood, urine and DNA were collected from 75%, 89% and 89% of participants, respectively. The cohort has been followed up through a combination of in-person surveys every 3-4 years and annual record linkage with cancer and vital statistics registries. Response rates for in-person follow-up surveys were over 91% and coverage for mortality nearly 100%. SMHS participants have a high smoking rate (58.6%) and moderate alcohol-drinking rate (29.3%), but low obesity rate (2.6%). They have a low calorie intake from fat (16.2% of total calorie intake) and protein (16.4%), high calorie intake from carbohydrates (67.4%), and high intake of soy food, cruciferous vegetables and fish (156.5, 110.6 and 51.7 g/day, respectively). With its unique exposure pattern and wealth of data and biological samples, the SMHS is well positioned for long-term research into NCD aetiology and prognosis. Information about accessing the SMHS resources can be found at: http://www.mc.vanderbilt.edu/swhs-smhs/. © The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.
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    ABSTRACT: High intake of nuts has been linked to a reduced risk of mortality. Previous studies, however, were primarily conducted among people of European descent, particularly those of high socioeconomic status. To examine the association of nut consumption with total and cause-specific mortality in Americans of African and European descent who were predominantly of low socioeconomic status (SES) and in Chinese individuals in Shanghai, China. Three large cohorts were evaluated in the study. One included 71 764 US residents of African and European descent, primarily of low SES, who were participants in the Southern Community Cohort Study (SCCS) in the southeastern United States (March 2002 to September 2009), and the other 2 cohorts included 134 265 participants in the Shanghai Women's Health Study (SWHS) (December 1996 to May 2000) and the Shanghai Men's Health Study (SMHS) (January 2002 to September 2006) in Shanghai, China. Self-reported nut consumption in the SCCS (approximately 50% were peanuts) and peanut-only consumption in the SMHS/SWHS were assessed using validated food frequency questionnaires. Deaths were ascertained through linkage with the National Death Index and Social Security Administration mortality files in the SCCS and annual linkage with the Shanghai Vital Statistics Registry and by biennial home visits in the SWHS/SMHS. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% CIs. With a median follow-up of 5.4 years in the SCCS, 6.5 years in the SMHS, and 12.2 years in the SWHS, 14 440 deaths were identified. More than half of the women in the SCCS were ever smokers compared with only 2.8% in the SWHS. The ever-smoking rate for men was 77.1% in the SCCS and 69.6% in the SMHS. Nut intake was inversely associated with risk of total mortality in all 3 cohorts (all P < .001 for trend), with adjusted HRs associated with the highest vs lowest quintiles of intake being 0.79 (95% CI, 0.73-0.86) and 0.83 (95% CI, 0.77-0.88), respectively, for the US and Shanghai cohorts. This inverse association was predominantly driven by cardiovascular disease mortality (P < .05 for trend in the US cohort; P < .001 for trend in the Shanghai cohorts). When specific types of cardiovascular disease were examined, a significant inverse association was consistently seen for ischemic heart disease in all ethnic groups (HR, 0.62; 95% CI, 0.45-0.85 in blacks; HR, 0.60; 95% CI, 0.39-0.92 in whites; and HR, 0.70; 95% CI, 0.54-0.89 in Asians for the highest vs lowest quintile of nut intake). The associations for ischemic stroke (HR, 0.77; 95% CI, 0.60-1.00 for the highest vs lowest quintile of nut intake) and hemorrhagic stroke (HR, 0.77; 95% CI, 0.60-0.99 for the highest vs lowest quintile of nut intake) were significant only in Asians. The nut-mortality association was similar for men and women and for blacks, whites, and Asians and was not modified by the presence of metabolic conditions at study enrollment. Nut consumption was associated with decreased overall and cardiovascular disease mortality across different ethnic groups and among individuals from low SES groups. Consumption of nuts, particularly peanuts given their general affordability, may be considered a cost-effective measure to improve cardiovascular health.
    JAMA Internal Medicine 03/2015; DOI:10.1001/jamainternmed.2014.8347 · 13.25 Impact Factor
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    ABSTRACT: Low bone mineral density (BMD) is common among breast cancer survivors due to acute estrogen deprivation. Soy food is a rich source of phytoestrogens, namely isoflavones, known to have both estrogenic and anti-estrogenic effects. The objective of the study was to assess the association between soy consumption and BMD in breast cancer survivors, which has not previously been evaluated. Forearm BMD was evaluated using dual-energy X-ray absorptiometry at 60 months post-diagnosis for 1,587 participants of the Shanghai Breast Cancer Survival Study. Soy intakes collected at 6, 18, and 36 months post-diagnosis were averaged, and the association with BMD, osteopenia, and osteoporosis was evaluated using linear and logistic regression. The mean (standard deviation) intake of isoflavones was 48.1 (28.0) mg/day. Soy intake was inversely associated with BMD and positively associated with osteoporosis. Compared with the lowest quartile, the highest quartile of soy isoflavone intake, ≥ 62.64 mg/day, was associated with a reduction of BMD by 1.95 % [95 % confidence interval (CI) -3.54, -0.36 %] and an increased odds ratio of 1.69 for osteoporosis (95 % CI 1.09, 2.61). The inverse association was predominantly seen among women who recently entered menopause (≤5 years). In contrast to observations from general populations, high soy intake (≥62.64 mg of soy isoflavone/day) was associated with lower proximal forearm BMD among breast cancer survivors, particularly during the early years of menopause. Our finding needs to be replicated, particularly in studies with more comprehensive bone density evaluation.
    Cancer Causes and Control 02/2015; 26(4). DOI:10.1007/s10552-015-0534-3 · 2.96 Impact Factor
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    ABSTRACT: To evaluate whether the genetic susceptibility of T2D was associated with overall survival (OS) and disease-free survival (DFS) outcomes for breast cancer (BC). Included in the study were 6346 BC patients who participated in three population-based epidemiological studies of BC and were genotyped with either GWAS or Exome-chip. We constructed a genetic risk score (GRS) for diabetes using risk variants identified from the GWAS catalog (http://genome.gov/gwastudies) that were associated with T2D risk at a minimum significance level of P ≤ 5.0E-8 among Asian population and evaluated its associations with BC outcomes with Cox proportional hazards models. During a median follow-up of 8.08 years (range, 0.01-16.95 years), 1208 deaths were documented in 6346 BC patients. Overall, the diabetes GRS was not associated with OS and DFS. Analyses stratified by estrogen receptor status (ER) showed that the diabetes GRS was inversely associated with OS among women with ER- but not in women with ER+ breast cancer; the multivariable adjusted HR was 1.38 (95% CI: 1.05-1.82) when comparing the highest to the lowest GRS quartiles. The association of diabetes GRS with OS varied by diabetes status (P for interaction <0.01). In women with history of diabetes, higher diabetes GRS was significantly associated with worse OS, with HR of 2.22 (95% CI: 1.28-3.88) for the highest vs. lowest quartile, particularly among women with an ER- breast cancer, with corresponding HR being 4.59 (95% CI: 1.04-20.28). No significant association between the diabetes GRS and OS was observed across different BMI and PR groups. Our study suggested that genetic susceptibility of T2D was positively associated with total mortality among women with ER- breast cancer, particularly among subjects with a history of diabetes. Additional studies are warranted to verify the associations and elucidate the underlying biological mechanism.
    PLoS ONE 02/2015; 10(2):e0117419. DOI:10.1371/journal.pone.0117419 · 3.53 Impact Factor
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    ABSTRACT: We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43,160 cases and 42,600 controls of European ancestry ascertained from 52 studies and a further 5,795 cases and 6,624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (OR=0.90 [0.88-0.92]; P-value=1.58 x 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans approximately 14.5 Kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR=1.12 [1.08-1.17]; P-value=7.89 x 10(-09)) and rs13294895 (OR=1.09 [1.06-1.12]; P-value=2.97 x 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR=1.12 [1.06-1.18]; P-value=2.77 x 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Human Molecular Genetics 02/2015; DOI:10.1093/hmg/ddv035 · 6.68 Impact Factor
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    ABSTRACT: To evaluate the population attributable risks (PARs) between cigarette smoking and deaths of all causes, all cancers, lung cancer and other chronic diseases in urban Shanghai. In total, 61,480 men aged 40-74 years from 2002 to 2006 and 74,941 women aged 40-70 years from 1997 to 2000 were recruited to undergo baseline surveys in urban Shanghai, with response rates of 74.0% and 92.3%, respectively. A Cox proportional hazards regression model was used to estimate relative risks (RRs) and 95% confidence intervals (95% CIs) of deaths associated with cigarette smoking. PARs and 95% CIs for deaths were estimated from smoking exposure rates and the estimated RRs. Cigarette smoking was responsible for 23.9% (95% CI: 19.4-28.3%) and 2.4% (95% CI: 1.6-3.2%) of all deaths in men and women, respectively, in our study population. Respiratory disease had the highest PAR in men [37.5% (95% CI: 21.5-51.6%)], followed by cancer [31.3% (95% CI: 24.6-37.7%)] and cardiovascular disease (CVD) [24.1% (95% CI: 16.7-31.2%)]. While the top three PARs were 12.7% (95% CI: 6.1-19.3%), 4.0% (95% CI: 2.4-5.6%), and 1.1% (95% CI: 0.0-2.3%), for respiratory disease, CVD, and cancer, respectively in women. For deaths of lung cancer, the PAR of smoking was 68.4% (95% CI: 58.2-76.5%) in men. In urban Shanghai, 23.9% and 2.4% of all deaths in men and women could have been prevented if no people had smoked in the area. Effective control programs against cigarette smoking should be strongly advocated to reduce the increasing smoking-related death burden.
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    ABSTRACT: Epidemiologic and experimental studies have shown that a high intake of individual dietary antioxidants is associated with reduced risk of cancers. Few studies, however, have investigated the influences of a combination of antioxidants. We evaluated the association of two dietary antioxidant indices, the Dietary Antioxidant Quality Score (DAQS) and the Composite Dietary Antioxidant Index (CDAI), with 10 oxidative stress or inflammation biomarkers (urinary F2-isoprostanes-15-F2t-IsoP; urinary 15-F2t-IsoPM; urinary prostaglandin E2 metabolite-PGEM; C-reactive protein-CRP; interleukin-1beta-IL-1β; interleukin-6-IL-6; tumor necrosis factor-alpha-TNF-α; soluble TNF-receptor 1-sTNF-R1; soluble TNF-receptor 2-sTNF-R2; and soluble GP130- sGP130) in 3,853 participants of the Shanghai Women's Health Study (SWHS). We found the DAQS and CDAI to be highly correlated (r=0.72), and both inversely associated with levels of IL-1β (Ptrend=0.02 and 0.03, respectively) and TNF-α (Ptrend=0.005 and 0.003, respectively). Also, IL-6 and sTNF-R2 levels were inversely associated with the DAQS score; β-coefficient (±SE) for average-quality and high-quality group vs. low-quality group were -0.22(±0.13) and -0.30(±0.13) (Ptrend=0.06) for IL-6; -0.06(±0.04) and -0.10(±0.04) (Ptrend=0.01) for sTNF-R2. Neither the DAQS nor CDAI score was significantly associated with oxidative stress or other inflammatory biomarkers. Our observations lead us to hypothesize that these two indices offer a potential aggregate method of measuring dietary anti-inflammation, but not anti-oxidation properties.
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    ABSTRACT: Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.
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    ABSTRACT: We previously carried out a multi-stage genome-wide association study (GWAS) on lung cancer among never smokers in the Female Lung Cancer Consortium in Asia (FLCCA) (6,609 cases, 7,457 controls) that identified novel susceptibility loci at 10q25.2, 6q22.2, and 6p21.32, and confirmed two previously identified loci at 5p15.33 and 3q28. Household air pollution (HAP) attributed to solid fuel burning for heating and cooking, is the leading cause of the overall disease burden in Southeast Asia, and is known to contain lung carcinogens. To evaluate the gene-HAP interactions associated with lung cancer in loci independent of smoking, we analyzed data from studies participating in FLCCA with fuel use information available (n = 3; 1,731 cases; 1,349 controls). Coal use was associated with a 30 % increased risk of lung cancer (OR 1.3, 95 % CI 1.0-1.6). Among the five a priori SNPs identified by our GWAS, two showed a significant interaction with coal use (HLA Class II rs2395185, p = 0.02; TP63 rs4488809 (rs4600802), p = 0.04). The risk of lung cancer associated with coal exposure varied with the respective alleles for these two SNPs. Our observations provide evidence that genetic variation in HLA Class II and TP63 may modify the association between HAP and lung cancer risk. The roles played in the cell cycle and inflammation pathways by the proteins encoded by these two genes provide biological plausibility for these interactions; however, additional replication studies are needed in other non-smoking populations.
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    ABSTRACT: Importance Substantial progress has been made in cancer diagnosis and treatment, resulting in a steady improvement in cancer survival. The degree of improvement by age, race, and sex remains unclear.Objective To quantify the degree of survival improvement over time by age, race, and sex in the United States.Design, Setting, and Participants Longitudinal analyses of cancer follow-up data from 1990 to 2010, from 1.02 million patients who had been diagnosed as having cancer of the colon or rectum, breast, prostate, lung, liver, pancreas, or ovary from 1990 to 2009 and who were included in 1 of 9 population-based registries of the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program.Main Outcomes and Measures Hazard ratios (HRs) and 95% CIs for cancer-specific death were estimated for patients diagnosed as having any of these cancers during 1995 to 1999, 2000 to 2004, and 2005 to 2009, compared with those diagnosed in 1990 to 1994.Results Significant improvements in survival were found for cancers of the colon or rectum, breast, prostate, lung, and liver. Improvements were more pronounced for younger patients. For patients aged 50 to 64 years and diagnosed from 2005 to 2009, adjusted HRs (95% CIs) were 0.57 (95% CI, 0.55-0.60), 0.48 (95% CI, 0.45-0.51), 0.61 (95% CI, 0.57-0.69), and 0.32 (95% CI, 0.30-0.36), for cancer of the colon or rectum, breast, liver, and prostate, respectively, compared with the same age groups of patients diagnosed during 1990 to 1994. However, the corresponding HRs (95% CIs) for elderly patients (those 75-85 years old) were only 0.88 (95% CI, 0.84-0.92), 0.88 (95% CI, 0.82-0.95), 0.76 (95% CI, 0.69-0.84), and 0.65 (95% CI, 0.61-0.70), for the same 4 cancer sites, respectively. A similar, although weaker, age-related period effect was observed for lung and pancreatic cancers. The adjusted HRs (95% CIs) for lung cancer were 0.75 (95% CI, 0.73-0.77) and 0.84 (95% CI, 0.81-0.86), respectively, for patients aged 50 to 64 years and 75 to 85 years diagnosed between 2005 and 2009, compared with the same age groups of patients diagnosed between 1990 and 1994 (0.73 [95% CI, 0.69-0.77] and 0.90 [95% CI, 0.85-0.95], respectively. Compared with whites or Asians, African Americans experienced greater improvement in prostate cancer survival. From 1990 to 2009, ovarian cancer survival declined among African Americans but improved among whites. No apparent sex difference in the degree of improvement for any non-sex-specific cancer was noted.Conclusions and Relevance Younger patients experienced greater benefit from recent oncology advances than elderly patients. African Americans experienced poorer survival than whites for all cancers, and the racial difference decreased for prostate cancer but increased for ovarian cancer. Identifying factors associated with varied improvement in cancer survival can inform future improvements in cancer care for all.
    01/2015; DOI:10.1001/jamaoncol.2014.161
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    ABSTRACT: Background: Between- and within-person variation in DNA methylation levels are important parameters to be considered in epigenome-wide association studies. Temporal change is one source of within-person variation in DNA methylation that has been linked to aging and disease. Methods: We analyzed CpG-site-specific intra-individual variation and short-term temporal trend in leukocyte DNA methylation among 24 healthy Chinese women, with blood samples drawn at study entry and after 9 months. Illumina HumanMethylation450 BeadChip was used to measure methylation. Intraclass correlation coefficients (ICC) and trend estimates were summarized by genomic location and probe type. Results: The median ICC was 0.36 across nonsex chromosomes and 0.80 on the X chromosome. There was little difference in ICC profiles by genomic region and probe type. Among CpG loci with high variability between participants, over 99% had ICC > 0.8. Statistically significant trend was observed in 10.9% CpG loci before adjustment for cell type composition and in 3.4% loci after adjustment. Conclusions: For CpG loci differentially methylated across subjects, methylation levels can be reliably assessed with one blood sample. More samples per subject are needed for low-variability and unmethylated loci. Temporal changes are largely driven by changes in cell type composition of blood samples, but temporal trend unrelated to cell types is detected in a small percentage of CpG sites. Impact: This study shows that one measurement can reliably assess methylation of differentially methylated CpG loci. Copyright © 2014, American Association for Cancer Research.
    Cancer Epidemiology Biomarkers & Prevention 12/2014; DOI:10.1158/1055-9965.EPI-14-0853 · 4.32 Impact Factor
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    ABSTRACT: Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER(+): odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, ptrend = 5.7 × 10(-44)) and estrogen-receptor-negative (ER(-): OR = 1.10, 95% CI = 1.05-1.15, ptrend = 3.0 × 10(-4)) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [pcond = 1.61 × 10(-5)]) and five variants composing iCHAV3 (lead rs11949391; ER(+): OR = 0.90, 95% CI = 0.87-0.93, pcond = 1.4 × 10(-4)). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
    The American Journal of Human Genetics 12/2014; DOI:10.1016/j.ajhg.2014.11.009 · 10.99 Impact Factor
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    ABSTRACT: Recent evidence from several relatively small nested case-control studies in prospective cohorts shows an association between longer telomere length measured phenotypically in peripheral white blood cell (WBC) DNA and increased lung cancer risk. We sought to further explore this relationship by examining a panel of 7 telomere-length associated genetic variants in a large study of 5,457 never-smoking female Asian lung cancer cases and 4,493 never-smoking female Asian controls using data from a previously reported genome-wide association study. Using a group of 1,536 individuals with phenotypically measured telomere length in WBCs in the prospective Shanghai Women's Health study, we demonstrated the utility of a genetic risk score (GRS) of 7 telomere-length associated variants to predict telomere length in an Asian population. We then found that GRSs used as instrumental variables to predict longer telomere length were associated with increased lung cancer risk (OR = 1.51 (95% CI=1.34-1.69) for upper vs. lower quartile of the weighted GRS, P-value=4.54 × 10(-14) ) even after removing rs2736100 (P-value=4.81 × 10(-3) ), a SNP in the TERT locus robustly associated with lung cancer risk in prior association studies. Stratified analyses suggested the effect of the telomere-associated GRS is strongest among younger individuals. We found no difference in GRS effect between adenocarcinoma and squamous cell subtypes. Our results indicate that a genetic background that favors longer telomere length may increase lung cancer risk, which is consistent with earlier prospective studies relating longer telomere length with increased lung cancer risk. This article is protected by copyright. All rights reserved. © 2014 UICC.
    International Journal of Cancer 12/2014; DOI:10.1002/ijc.29393 · 5.01 Impact Factor

Publication Stats

8k Citations
2,391.34 Total Impact Points

Institutions

  • 2009–2015
    • Gateway-Vanderbilt Cancer Treatment Center
      Clarksville, Tennessee, United States
    • National Institutes of Health
      • Division of Cancer Epidemiology and Genetics
      Bethesda, MD, United States
    • Northwestern University
      • Department of Preventive Medicine
      Evanston, Illinois, United States
  • 2002–2015
    • Vanderbilt University
      • • Department of Medicine
      • • Center for Health Services Research
      • • Division of Epidemiology
      • • Vanderbilt Center for Evidence-based Medicine
      Нашвилл, Michigan, United States
  • 2012–2014
    • University of Texas MD Anderson Cancer Center
      • Division of Cancer Prevention & Population Sciences
      Houston, Texas, United States
    • Max Planck Institute for Astronomy
      Heidelburg, Baden-Württemberg, Germany
  • 1998–2014
    • Shanghai Cancer Institute
      Shanghai, Shanghai Shi, China
  • 2013
    • Johns Hopkins Medicine
      • Department of Pathology
      Baltimore, Maryland, United States
    • Imperial College London
      Londinium, England, United Kingdom
    • University of North Carolina at Chapel Hill
      • Department of Genetics
      North Carolina, United States
    • Harvard Medical School
      • Department of Medicine
      Boston, MA, United States
    • Institute of Cancer Research
      Londinium, England, United Kingdom
  • 2011–2013
    • University of Science and Technology of China
      • Department of Astronomy
      Luchow, Anhui Sheng, China
    • Queensland Institute of Medical Research
      Brisbane, Queensland, Australia
    • University of Minnesota Duluth
      Duluth, Minnesota, United States
    • The Chinese University of Hong Kong
      • Department of Clinical Oncology
      Hong Kong, Hong Kong
  • 2010–2012
    • National Cancer Institute (USA)
      • Division of Cancer Epidemiology and Genetics
      Bethesda, MD, United States
    • Mayo Clinic - Rochester
      • Department of Health Science Research
      Rochester, MN, United States
    • American Cancer Society
      • Epidemiology Research Program
      Atlanta, Georgia, United States
  • 2007
    • Fox Chase Cancer Center
      Filadelfia, Pennsylvania, United States
  • 2004
    • Northern Inyo Hospital
      BIH, California, United States
  • 2002–2003
    • Yale University
      New Haven, Connecticut, United States