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1.  Dietary Patterns and Endometrial Cancer Risk in the California Teachers Study Cohort 
Cancer causes & control : CCC  2015;26(4):627-634.
Information on the role of dietary patterns and endometrial cancer risk is limited. We investigated whether dietary patterns are associated with endometrial cancer risk among women in the California Teachers Study cohort.
Among 75,093 eligible women, 937 developed invasive endometrial cancer between 1995 and 2011. Multivariate Cox regression was performed to estimate relative risks (RR) and 95% confidence intervals (CI) associated with five dietary patterns identified by principal components factor analysis: “plant-based”, “high protein/high fat”, “high carbohydrates”, “ethnic”, and “salad and wine”.
These dietary patterns were not associated with endometrial cancer risk overall (RR=0.91, 95% CI: 0.72, 1.15 for the highest vs. lowest quintile of the “plant-based” dietary pattern) or by menopausal status and hormone therapy use.
Dietary patterns do not seem to be associated with endometrial cancer risk.
PMCID: PMC4396622  PMID: 25761409
dietary patterns; endometrial cancer; body mass index; cohort
2.  Anthropometry and head and neck cancer:a pooled analysis of cohort data 
Background: Associations between anthropometry and head and neck cancer (HNC) risk are inconsistent. We aimed to evaluate these associations while minimizing biases found in previous studies.
Methods: We pooled data from 1 941 300 participants, including 3760 cases, in 20 cohort studies and used multivariable-adjusted Cox proportional hazard regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of anthropometric measures with HNC risk overall and stratified by smoking status.
Results: Greater waist circumference (per 5 cm: HR = 1.04, 95% CI 1.03–1.05, P-value for trend = <0.0001) and waist-to-hip ratio (per 0.1 unit: HR = 1.07, 95% CI 1.05–1.09, P-value for trend = <0.0001), adjusted for body mass index (BMI), were associated with higher risk and did not vary by smoking status (P-value for heterogeneity = 0.85 and 0.44, respectively). Associations with BMI (P-value for interaction = <0.0001) varied by smoking status. Larger BMI was associated with higher HNC risk in never smokers (per 5 kg/m2: HR = 1.15, 95% CI 1.06–1.24, P-value for trend = 0.0006), but not in former smokers (per 5 kg/m2: HR = 0.99, 95% CI 0.93–1.06, P-value for trend = 0.79) or current smokers (per 5 kg/m2: HR = 0.76, 95% CI 0.71–0.82, P-value for trend = <0.0001). Larger hip circumference was not associated with a higher HNC risk. Greater height (per 5 cm) was associated with higher risk of HNC in never and former smokers, but not in current smokers.
Conclusions: Waist circumference and waist-to-hip ratio were associated positively with HNC risk regardless of smoking status, whereas a positive association with BMI was only found in never smokers.
PMCID: PMC4481608  PMID: 26050257
Head and neck neoplasms; obesity; smoking; waist-hip ratio; waist circumference
3.  Intrauterine devices and endometrial cancer risk: a pooled analysis of the Epidemiology of Endometrial Cancer Consortium 
Intrauterine devices (IUDs), long-acting and reversible contraceptives, induce a number of immunological and biochemical changes in the uterine environment that could affect endometrial cancer (EC) risk. We addressed this relationship through a pooled analysis of data collected in the Epidemiology of Endometrial Cancer Consortium. We combined individual-level data from 4 cohort and 14 case-control studies, in total 8,801 EC cases and 15,357 controls. Using multivariable logistic regression, we estimated pooled odds ratios (pooled-ORs) and 95% confidence intervals (CIs) for EC risk associated with ever use, type of device, ages at first and last use, duration of use, and time since last use, stratified by study and adjusted for confounders. Ever use of IUDs was inversely related to EC risk (pooled-OR=0.81, 95% CI=0.74–0.90). Compared with never use, reduced risk of EC was observed for inert IUDs (pooled-OR=0.69, 95% CI=0.58–0.82), older age at first use (≥35 years pooled-OR=0.53, 95% CI=0.43–0.67), older age at last use (≥45 years pooled-OR=0.60, 95% CI=0.50–0.72), longer duration of use (≥10 years pooled-OR=0.61, 95% CI=0.52–0.71), and recent use (within 1 year of study entry pooled-OR=0.39, 95% CI=0.30–0.49). Future studies are needed to assess the respective roles of detection biases and biologic effects related to foreign body responses in the endometrium, heavier bleeding (and increased clearance of carcinogenic cells), and localized hormonal changes.
PMCID: PMC4267918  PMID: 25242594
contraception; pooled analysis; endometrial neoplasm; etiology
4.  Risk factors for endometrial cancer in black and white women: A pooled analysis from the Epidemiology of Endometrial Cancer Consortium (E2C2) 
Cancer causes & control : CCC  2014;26(2):287-296.
Endometrial cancer (EC) is the most common gynecologic cancer in the United States. Over the last decade, the incidence rate has been increasing, with a larger increase among blacks. The aim of this study was to compare risk factors for EC in black and white women.
Data from 7 cohort and 4 case-control studies were pooled. Unconditional logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals for each risk factor in blacks and whites separately.
Data were pooled for 2,011 black women (516 cases and 1,495 controls) and 19,297 white women (5,693 cases and 13,604 controls). BMI ≥ 30 was associated with an approximate 3-fold increase in risk of EC in both black and white women (ORblack=2.93, 95% CI: 2.11, 4.07 and ORwhite=2.99, 95% CI: 2.74, 3.26). Diabetes was associated with a 30–40% increase in risk among both groups. Increasing parity was associated with decreasing risk of EC in blacks and whites (p-value=0.02 and <0.001, respectively). Current and former smoking was associated with decreased risk of EC among all women. Both black and white women who used oral contraceptives for 10+ years were also at reduced risk of EC (OR=0.49, 95% CI: 0.27, 0.88 and OR=0.69, 95% CI: 0.58, 0.83, respectively). Previous history of hypertension was not associated with EC risk in either group.
The major known risk factors for EC exert similar effects on black and white women. Differences in the incidence rates between the two populations may be due to differences in the prevalence of risk factors.
PMCID: PMC4528374  PMID: 25534916
endometrial neoplasms; race/ethnicity; obesity; parity; diabetes
5.  Novel polymorphisms in caspase-8 are associated with breast cancer risk in the California Teachers Study 
BMC Cancer  2016;16:14.
The ability of tamoxifen and raloxifene to decrease breast cancer risk varies among different breast cancer subtypes. It is important to determine one’s subtype-specific breast cancer risk when considering chemoprevention. A number of single nucleotide polymorphisms (SNPs), including one in caspase-8 (CASP8), have been previously associated with risk of developing breast cancer. Because caspase-8 is an important protein involved in receptor-mediated apoptosis whose activity is affected by estrogen, we hypothesized that additional SNPs in CASP8 could be associated with breast cancer risk, perhaps in a subtype-specific manner.
Twelve tagging SNPs of CASP8 were analyzed in a nested case control study (1,353 cases and 1,384 controls) of non-Hispanic white women participating in the California Teachers Study. Odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated for each SNP using all, estrogen receptor (ER)-positive, ER-negative, human epidermal growth factor receptor 2 (HER2)-positive, and HER2-negative breast cancers as separate outcomes.
Several SNPs were associated with all, ER-positive, and HER2-positive breast cancers; however, after correcting for multiple comparisons (i.e., p < 0.0008), only rs2293554 was statistically significantly associated with HER2-positive breast cancer (OR = 1.98, 95 % CI 1.34-2.92, uncorrected p = 0.0005).
While our results for CASP8 SNPs should be validated in other cohorts with subtype-specific information, we conclude that some SNPs in CASP8 are associated with subtype-specific breast cancer risk. This study contributes to our understanding of CASP8 SNPs and breast cancer risk by subtype.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-2036-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4711015  PMID: 26758508
Breast cancer; Single nucleotide polymorphism; Caspase-8
6.  Reproductive factors, tumor estrogen receptor status and contralateral breast cancer risk: results from the WECARE study 
SpringerPlus  2015;4:825.
Several reproductive factors are known to be associated with risk of breast cancer; however, relationships between these factors with risk of second primary asynchronous contralateral breast cancer (CBC) have not been widely studied. The Women’s Environmental, Cancer, and Radiation Epidemiology (WECARE) Study is a population-based case-control study of 1521 CBC cases and 2212 individually matched controls with unilateral breast cancer. Using multivariable conditional logistic regression models, we examined associations between reproductive factors and CBC risk, and whether associations differed by estrogen receptor (ER) status and menopausal status of the first breast cancer. Older age at menarche was inversely associated with CBC risk (≥14 vs. ≤11 years risk ratio (RR) = 0.82, 95 % confidence interval (CI) 0.65–1.03, Ptrend = 0.02). Among parous women, an increasing number of full-term pregnancies (FTP) was inversely associated with risk (≥4 vs. 1 FTP RR = 0.60, 95 % CI 0.41–0.88, Ptrend = 0.005). Ever breast-feeding was inversely associated with CBC risk only among women with ER-negative first tumors (ever vs. never breast-fed RR = 0.69, 95 % CI 0.48–1.00, Pheterogeneity = 0.05). Older age at first FTP was inversely associated with CBC risk among women with ER-negative first tumors (≥30 vs. <20 years old RR = 0.66, 95 % CI 0.35–1.27, Ptrend = 0.03), but suggestively positively associated with risk among women with ER-positive first tumors (Pheterogeneity = 0.03). Young age at menarche and low parity, both risk factors for first primary breast cancer, were also associated with overall CBC risk. Reductions in risk associated with breast-feeding were limited to women with ER-negative first tumors, who are at higher CBC risk than women with ER-positive primaries.
PMCID: PMC4695460  PMID: 26751177
Contralateral breast cancer; Reproductive risk factors; Breastfeeding; Parity; Estrogen receptor
7.  Integrative post-genome-wide association analysis of CDKN2A and TP53 SNPs and risk of esophageal adenocarcinoma 
Carcinogenesis  2014;35(12):2740-2747.
Integrating data from a large genome-wide association study, a prospective clinical cohort, and a laboratory-based functional assay, this study provides evidence that germline variants in the tumor suppressor CDKN2A may influence susceptibility for esophageal adenocarcinoma, an increasingly important cancer with poor survival.
Incidence of esophageal adenocarcinoma (EA) in Western countries has increased markedly in recent decades. Although several risk factors have been identified for EA and its precursor, Barrett’s esophagus (BE), including reflux, Caucasian race, male gender, obesity, and smoking, less is known about the role of inherited genetic variation. Frequent somatic mutations in the tumor suppressor genes CDKN2A and TP53 were recently reported in EA tumors, while somatic alterations at 9p (CDKN2A) and 17p (TP53) have been implicated as predictors of progression from BE to EA. Motivated by these findings, we used data from a genome-wide association study of 2515 EA cases and 3207 controls to analyze 37 germline single nucleotide polymorphisms at the CDKN2A and TP53 loci. Three CDKN2A polymorphisms were nominally associated (P < 0.05) with reduced risk of EA: rs2518720 C>T [intronic, odds ratio 0.90, P = 0.0121, q = 0.3059], rs3088440 G>A (3′UTR, odds ratio 0.84, P = 0.0186, q = 0.3059), and rs4074785 C>T (intronic, odds ratio 0.85, P = 0.0248, q = 0.3059). None of the TP53 single nucleotide polymorphisms reached nominal significance. Two of the CDKN2A variants identified were also associated with reduced risk of progression from BE to EA, when assessed in a prospective cohort of 408 BE patients: rs2518720 (hazard ratio 0.57, P = 0.0095, q = 0.0285) and rs3088440 (hazard ratio 0.34, P = 0.0368, q = 0.0552). In vitro functional studies of rs3088440, a single nucleotide polymorphism located in the seed sequence of a predicted miR-663b binding site, suggested a mechanism whereby the G>A substitution may attenuate miR-663b-mediated repression of the CDKN2A transcript. This study provides the first evidence that germline variation at the CDKN2A locus may influence EA susceptibility.
PMCID: PMC4247522  PMID: 25280564
8.  Body Mass Index Genetic Risk Score and Endometrial Cancer Risk 
PLoS ONE  2015;10(11):e0143256.
Genome-wide association studies (GWAS) have identified common variants that predispose individuals to a higher body mass index (BMI), an independent risk factor for endometrial cancer. Composite genotype risk scores (GRS) based on the joint effect of published BMI risk loci were used to explore whether endometrial cancer shares a genetic background with obesity. Genotype and risk factor data were available on 3,376 endometrial cancer case and 3,867 control participants of European ancestry from the Epidemiology of Endometrial Cancer Consortium GWAS. A BMI GRS was calculated by summing the number of BMI risk alleles at 97 independent loci. For exploratory analyses, additional GRSs were based on subsets of risk loci within putative etiologic BMI pathways. The BMI GRS was statistically significantly associated with endometrial cancer risk (P = 0.002). For every 10 BMI risk alleles a woman had a 13% increased endometrial cancer risk (95% CI: 4%, 22%). However, after adjusting for BMI, the BMI GRS was no longer associated with risk (per 10 BMI risk alleles OR = 0.99, 95% CI: 0.91, 1.07; P = 0.78). Heterogeneity by BMI did not reach statistical significance (P = 0.06), and no effect modification was noted by age, GWAS Stage, study design or between studies (P≥0.58). In exploratory analyses, the GRS defined by variants at loci containing monogenic obesity syndrome genes was associated with reduced endometrial cancer risk independent of BMI (per BMI risk allele OR = 0.92, 95% CI: 0.88, 0.96; P = 2.1 x 10−5). Possessing a large number of BMI risk alleles does not increase endometrial cancer risk above that conferred by excess body weight among women of European descent. Thus, the GRS based on all current established BMI loci does not provide added value independent of BMI. Future studies are required to validate the unexpected observed relation between monogenic obesity syndrome genetic variants and endometrial cancer risk.
PMCID: PMC4659592  PMID: 26606540
9.  Obesity and Risk of Esophageal Adenocarcinoma and Barrett’s Esophagus: A Mendelian Randomization Study 
Data from observational studies suggest that body mass index (BMI) is causally related to esophageal adenocarcinoma (EAC) and its precursor, Barrett’s esophagus (BE). However, the relationships may be affected by bias and confounding.
We used data from the Barrett’s and Esophageal Adenocarcinoma Genetic Susceptibility Study: 999 patients with EAC, 2061 patients with BE, and 2169 population controls. We applied the two-stage control function instrumental variable method of the Mendelian randomization approach to estimate the unbiased, unconfounded effect of BMI on risk of EAC and BE. This was performed using a genetic risk score, derived from 29 genetic variants shown to be associated with BMI, as an instrument for lifetime BMI. A higher score indicates propensity to obesity. All tests were two-sided.
The genetic risk score was not associated with potential confounders, including gastroesophageal reflux symptoms and smoking. In the instrumental variable analyses (IV), EAC risk increased by 16% (IV-odds ratio [OR] = 1.16, 95% confidence interval [CI] = 1.01 to 1.33) and BE risk increased by 12% (IV-OR = 1.12, 95% CI = 1.00 to 1.25) per 1kg/m2 increase in BMI. BMI was statistically significantly associated with EAC and BE in conventional epidemiologic analyses.
People with a high genetic propensity to obesity have higher risks of esophageal metaplasia and neoplasia than people with low genetic propensity. These analyses provide the strongest evidence to date that obesity is independently associated with BE and EAC, and is not due to confounding or bias inherent in conventional epidemiologic analyses.
PMCID: PMC4200028  PMID: 25269698
10.  A comprehensive examination of breast cancer risk loci in African American women 
Human Molecular Genetics  2014;23(20):5518-5526.
Genome-wide association studies have identified 73 breast cancer risk variants mainly in European populations. Given considerable differences in linkage disequilibrium structure between populations of European and African ancestry, the known risk variants may not be informative for risk in African ancestry populations. In a previous fine-mapping investigation of 19 breast cancer loci, we were able to identify SNPs in four regions that better captured risk associations in African American women. In this study of breast cancer in African American women (3016 cases, 2745 controls), we tested an additional 54 novel breast cancer risk variants. Thirty-eight variants (70%) were found to have an association with breast cancer in the same direction as previously reported, with eight (15%) replicating at P < 0.05. Through fine-mapping, in three regions (1q32, 3p24, 10q25), we identified variants that better captured associations with overall breast cancer or estrogen receptor positive disease. We also observed suggestive associations with variants (at P < 5 × 10−6) in three separate regions (6q25, 14q13, 22q12) that may represent novel risk variants. Directional consistency of association observed for ∼65–70% of currently known genetic variants for breast cancer in women of African ancestry implies a shared functional common variant at most loci. To validate and enhance the spectrum of alleles that define associations at the known breast cancer risk loci, as well as genome-wide, will require even larger collaborative efforts in women of African ancestry.
PMCID: PMC4168823  PMID: 24852375
11.  Risk of Esophageal Adenocarcinoma Decreases With Height, Based on Consortium Analysis and Confirmed by Mendelian Randomization 
Risks for some cancers increase with height. We investigated the relationship between height and risk of esophageal adenocarcinoma (EAC) and its precursor, Barrett’s esophagus (BE).
We analyzed epidemiologic and genome-wide genomic data from individuals of European ancestry in the Barrett’s and Esophageal Adenocarcinoma Consortium, from 999 cases of EAC, 2061 cases of BE, and 2168 population controls. Multivariable logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for associations between height and risks of EAC and BE. We performed a Mendelian randomization analysis to estimate an unconfounded effect of height on EAC and BE using a genetic risk score derived from 243 genetic variants associated with height as an instrumental variable.
Height was associated inversely with EAC (per 10-cm increase in height: OR, 0.70; 95% CI, 0.62–0.79 for men and OR, 0.57; 95% CI 0.40–0.80 for women) and BE (per 10-cm increase in height: OR, 0.69; 95% CI, 0.62–0.77 for men and OR, 0.61; 95% CI, 0.48–0.77 for women). The risk estimates were consistent across strata of age, education level, smoking, gastroesophageal reflux symptoms, body mass index, and weight. Mendelian randomization analysis yielded results quantitatively similar to those from the conventional epidemiologic analysis.
Height is associated inversely with risks of EAC and BE. Results from the Mendelian randomization study showed that the inverse association observed did not result from confounding factors. Mechanistic studies of the effect of height on EAC and BE are warranted; height could have utility in clinical risk stratification.
PMCID: PMC4130803  PMID: 24530603
Esophageal Cancer; Etiology; Risk Factors; Sex Differences
12.  Polymorphisms in Genes of Relevance for Oestrogen and Oxytocin Pathways and Risk of Barrett’s Oesophagus and Oesophageal Adenocarcinoma: A Pooled Analysis from the BEACON Consortium 
PLoS ONE  2015;10(9):e0138738.
The strong male predominance in oesophageal adenocarcinoma (OAC) and Barrett’s oesophagus (BO) continues to puzzle. Hormonal influence, e.g. oestrogen or oxytocin, might contribute.
This genetic-epidemiological study pooled 14 studies from three continents, Australia, Europe, and North America. Polymorphisms in 3 key genes coding for the oestrogen pathway (receptor alpha (ESR1), receptor beta (ESR2), and aromatase (CYP19A1)), and 3 key genes of the oxytocin pathway (the oxytocin receptor (OXTR), oxytocin protein (OXT), and cyclic ADP ribose hydrolase glycoprotein (CD38)), were analysed using a gene-based approach, versatile gene-based test association study (VEGAS).
Among 1508 OAC patients, 2383 BO patients, and 2170 controls, genetic variants within ESR1 were associated with BO in males (p = 0.0058) and an increased risk of OAC and BO combined in males (p = 0.0023). Genetic variants within OXTR were associated with an increased risk of BO in both sexes combined (p = 0.0035) and in males (p = 0.0012). We followed up these suggestive findings in a further smaller data set, but found no replication. There were no significant associations between the other 4 genes studied and risk of OAC, BO, separately on in combination, in males and females combined or in males only.
Genetic variants in the oestrogen receptor alpha and the oxytocin receptor may be associated with an increased risk of BO or OAC, but replication in other large samples are needed.
PMCID: PMC4583498  PMID: 26406593
13.  Body Size and Multiple Myeloma Mortality: a pooled analysis of 20 prospective studies 
British journal of haematology  2014;166(5):667-676.
Multiple myeloma (MM) is a rare but highly fatal malignancy. High body weight is associated with this cancer, but several questions remain regarding the aetiological relevance of timing and location of body weight. To address these questions, we conducted a pooled analysis of MM mortality using 1.5 million participants (including 1,388 MM deaths) from 20 prospective cohorts in the National Cancer Institute Cohort Consortium. Proportional hazards regression was used to calculate pooled multivariate hazard ratios (HRs) and 95% confidence intervals (CIs). Associations with elevated MM mortality were observed for higher early-adult body mass index (BMI; HR=1.22, 95% CI: 1.09–1.35 per 5 kg/m2) and for higher cohort-entry BMI (HR 1.09, 95% CI: 1.03–1.16 per 5 kg/m2) and waist circumference (HR= 1.06, 95% CI: 1.02–1.10 per 5 cm). Women who were the heaviest, both in early adulthood (BMI 25+) and at cohort entry (BMI 30+) were at greater risk compared to those with BMI 18.5–<25 at both time points (HR=1.95, 95% CI: 1.33–2.86). Waist-to-hip ratio and height were not associated with MM mortality. These observations suggest that overall, and possibly also central, obesity influence myeloma mortality, and women have the highest risk of death from this cancer if they remain heavy throughout adulthood.
PMCID: PMC4134758  PMID: 24861847
multiple myeloma; prospective cohort study; pooled analysis; body mass index; anthropometry
14.  Medication use and multiple myeloma risk in Los Angeles County 
Cancer causes & control : CCC  2014;25(9):1233-1237.
The role of medication use in multiple myeloma (MM) risk remains unclear.
The Los Angeles County Multiple Myeloma Case-Control Study, comprising 278 MM cases and individually-matched neighborhood controls, provided data to assess associations between medication use and MM risk. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression.
Erythromycin (ever) use was associated with increased MM risk (OR=1.85, 95% CI=1.13–3.03). This association was restricted to men (OR=3.77, 95% CI=1.72–8.29) and was especially apparent among men who took two or more courses of erythromycin (OR=4.68, 95% CI = 1.70– 12.87).
Compared to females, males have lower levels of CYP3A4, for which erythromycin is both a substrate and inhibitor. Use of CYP3A4-inhibiting drugs such as erythromycin in men may thus result in even lower levels of CYP3A4 and, consequently, higher levels of CYP3A4-metabolized substances. These results could potentially provide clues to explain discrepancies in MM incidence by sex. Consortial efforts to confirm these associations are warranted.
PMCID: PMC4156901  PMID: 24981100
15.  Light at Night and Breast Cancer Risk Among California Teachers 
Epidemiology (Cambridge, Mass.)  2014;25(5):697-706.
There is convincing evidence that circadian disruption mediated by exposure to light at night promotes mammary carcinogenesis in rodents. The role that light at night plays in human breast cancer etiology remains unknown. We evaluated the relationship between estimates of indoor and outdoor light at night and the risk of breast cancer among members of the California Teachers Study.
Indoor light-at-night estimates were based on questionnaire data regarding sleep habits and use of night time lighting while sleeping. Estimates of outdoor light at night were derived from imagery data obtained from the U.S. Defense Meteorological Satellite Program assigned to geocoded addresses of study participants. Analyses were conducted among 106,731 California Teachers Study members who lived in California, had no prior history of breast cancer, and provided information on lighting while sleeping. 5,095 cases of invasive breast cancer diagnosed 1995–2010 were identified via linkage to the California Cancer Registry. We used age-stratified Cox proportional hazard models to calculate hazard ratios (HRs) with 95% confidence intervals (CIs), adjusting for breast cancer risk factors and neighborhood urbanization and socioeconomic class.
An increased risk was found for women living in areas with the highest quintile of outdoor light at night exposure estimates (HR=1.12 [95% CI=1.00 – 1.26], test for trend, P=0.06). While more pronounced among premenopausal women (HR=1.34 [95% CI=1.07 – 1.69], test for trend, P=0.04), the associations did not differ statistically by menopausal status (test for interaction, P=0.34).
Women living in areas with high levels of ambient light at night may be at an increased risk of breast cancer. Future studies that integrate quantitative measurements of indoor and outdoor light at night are warranted.
PMCID: PMC4130422  PMID: 25061924
16.  Cross-cancer pleiotropic analysis of endometrial cancer: PAGE and E2C2 consortia 
Carcinogenesis  2014;35(9):2068-2073.
In the large-scale analysis of GWAS-identified risk variants for other cancers on endometrial cancer risk, a SNP near TET2 gene, rs7679673, previously associated with prostate and breast cancer risk demonstrated a robust association with endometrial cancer (P = 7.37 × 10− 5).
Genome-wide association studies (GWAS) have identified a large number of cancer-associated single nucleotide polymorphisms (SNPs), several of which have been associated with multiple cancer sites suggesting pleiotropic effects and shared biological mechanisms across some cancers. We hypothesized that SNPs associated with other cancers may be additionally associated with endometrial cancer. We examined 213 SNPs previously associated with 14 other cancers for their associations with endometrial cancer in 3758 endometrial cancer cases and 5966 controls of European ancestry from two consortia: Population Architecture Using Genomics and Epidemiology and the Epidemiology of Endometrial Cancer Consortium. Study-specific logistic regression estimates adjusted for age, body mass index and the most significant principal components of genetic ancestry were combined using fixed-effect meta-analysis to evaluate the association between each SNP and endometrial cancer risk. A Bonferroni-corrected P value of 2.35×10−4 was used to determine statistical significance of the associations. SNP rs7679673, ~6.3kb upstream of TET2 and previously reported to be associated with prostate cancer risk, was associated with endometrial cancer risk in the direction opposite to that for prostate cancer [meta-analysis odds ratio = 0.87 (per copy of the C allele), 95% confidence interval = 0.81, 0.93; P = 7.37×10−5] with no evidence of heterogeneity across studies (P heterogeneity = 0.66). This pleiotropic analysis is the first to suggest TET2 as a susceptibility locus for endometrial cancer.
PMCID: PMC4146418  PMID: 24832084
17.  Diabetes and other comorbidities in breast cancer survival by race/ethnicity: The California Breast Cancer Survivorship Consortium (CBCSC) 
The role of comorbidities in survival of breast cancer patients has not been well studied, particularly in non-white populations.
We investigated the association of specific comorbidities with mortality in a multiethnic cohort of 8,952 breast cancer cases within the California Breast Cancer Survivorship Consortium (CBCSC), which pooled questionnaire and cancer registry data from five California-based studies. In total, 2,187 deaths (1,122 from breast cancer) were observed through December 31, 2010. Using multivariable Cox proportional hazards regression, we estimated hazards ratios (HR) and 95% confidence intervals (CI) for overall and breast cancer-specific mortality associated with previous cancer, diabetes, high blood pressure (HBP), and myocardial infarction (MI).
Risk of breast cancer-specific mortality increased among breast cancer cases with a history of diabetes (HR=1.48, 95% CI=1.18, 1.87) or MI (HR=1.94, 95% CI=1.27–2.97). Risk patterns were similar across race/ethnicity (non-Latina White, Latina, African American and Asian American), body size, menopausal status, and stage at diagnosis. In subgroup analyses, risk of breast cancer-specific mortality was significantly elevated among cases with diabetes who received neither radiation nor chemotherapy (HR=2.11, 95% CI=1.32–3.36); no increased risk was observed among those who received both treatments (HR=1.13, 95% CI= 0.70–1.84) (P interaction= 0.03). A similar pattern was found for MI by radiation and chemotherapy (P interaction=0.09).
These results may inform future treatment guidelines for breast cancer patients with a history of diabetes or MI.
Given the growing number of breast cancer survivors worldwide, we need to better understand how comorbidities may adversely affect treatment decisions and ultimately outcome.
PMCID: PMC4523272  PMID: 25425578
race/ethnicity; diabetes; myocardial infarction; survival; treatment; tumor characteristics; lifestyle factors
18.  Medical History, Lifestyle, Family History, and Occupational Risk Factors for Follicular Lymphoma: The InterLymph Non-Hodgkin Lymphoma Subtypes Project 
Follicular lymphoma (FL) has been linked with cigarette smoking and, inconsistently, with other risk factors.
We assessed associations of medical, hormonal, family history, lifestyle, and occupational factors with FL risk in 3530 cases and 22639 controls from 19 case–control studies in the InterLymph consortium. Age-, race/ethnicity-, sex- and study-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression.
Most risk factors that were evaluated showed no association, except for a few modest or sex-specific relationships. FL risk was increased in persons: with a first-degree relative with non-Hodgkin lymphoma (OR = 1.99; 95% CI = 1.55 to 2.54); with greater body mass index as a young adult (OR = 1.15; 95% CI = 1.04 to 1.27 per 5kg/m2 increase); who worked as spray painters (OR = 2.66; 95% CI = 1.36 to 5.24); and among women with Sjögren syndrome (OR = 3.37; 95% CI = 1.23 to 9.19). Lower FL risks were observed in persons: with asthma, hay fever, and food allergy (ORs = 0.79–0.85); blood transfusions (OR = 0.78; 95% CI = 0.68 to 0.89); high recreational sun exposure (OR = 0.74; 95% CI = 0.65 to 0.86, fourth vs first quartile); who worked as bakers or millers (OR = 0.51; 95% CI = 0.28 to 0.93) or university/higher education teachers (OR = 0.58; 95% CI = 0.41 to 0.83). Elevated risks specific to women included current and longer duration of cigarette use, whereas reduced risks included current alcohol use, hay fever, and food allergies. Other factors, including other autoimmune diseases, eczema, hepatitis C virus seropositivity, hormonal drugs, hair dye use, sun exposure, and farming, were not associated with FL risk.
The few relationships observed provide clues suggesting a multifactorial etiology of FL but are limited in the extent to which they explain FL occurrence.
PMCID: PMC4155461  PMID: 25174024
19.  Medical History, Lifestyle, Family History, and Occupational Risk Factors for Diffuse Large B-Cell Lymphoma: The InterLymph Non-Hodgkin Lymphoma Subtypes Project 
Although risk factors for diffuse large B-cell lymphoma (DLBCL) have been suggested, their independent effects, modification by sex, and association with anatomical sites are largely unknown.
In a pooled analysis of 4667 cases and 22639 controls from 19 studies, we used stepwise logistic regression to identify the most parsimonious multivariate models for DLBCL overall, by sex, and for selected anatomical sites.
DLBCL was associated with B-cell activating autoimmune diseases (odds ratio [OR] = 2.36, 95% confidence interval [CI] = 1.80 to 3.09), hepatitis C virus seropositivity (OR = 2.02, 95% CI = 1.47 to 2.76), family history of non-Hodgkin lymphoma (OR = 1.95, 95% CI = 1.54 to 2.47), higher young adult body mass index (OR = 1.58, 95% CI = 1.12 to 2.23, for 35+ vs 18.5 to 22.4 kg/m2), higher recreational sun exposure (OR = 0.78, 95% CI = 0.69 to 0.89), any atopic disorder (OR = 0.82, 95% CI = 0.76 to 0.89), and higher socioeconomic status (OR = 0.86, 95% CI = 0.79 to 0.94). Additional risk factors for women were occupation as field crop/vegetable farm worker (OR = 1.78, 95% CI = 1.22 to 2.60), hairdresser (OR = 1.65, 95% CI = 1.12 to 2.41), and seamstress/embroider (OR = 1.49, 95% CI = 1.13 to 1.97), low adult body mass index (OR = 0.46, 95% CI = 0.29 to 0.74, for <18.5 vs 18.5 to 22.4 kg/m2), hormone replacement therapy started age at least 50 years (OR = 0.68, 95% CI = 0.52 to 0.88), and oral contraceptive use before 1970 (OR = 0.78, 95% CI = 0.62 to 1.00); and for men were occupation as material handling equipment operator (OR = 1.58, 95% CI = 1.02 to 2.44), lifetime alcohol consumption (OR = 0.57, 95% CI = 0.44 to 0.75, for >400kg vs nondrinker), and previous blood transfusion (OR = 0.69, 95% CI = 0.57 to 0.83). Autoimmune disease, atopy, and family history of non-Hodgkin lymphoma showed similar associations across selected anatomical sites, whereas smoking was associated with central nervous system, testicular and cutaneous DLBCLs; inflammatory bowel disease was associated with gastrointestinal DLBCL; and farming and hair dye use were associated with mediastinal DLBCL.
Our results support a complex and multifactorial etiology for DLBCL with some variation in risk observed by sex and anatomical site.
PMCID: PMC4155465  PMID: 25174023
20.  Etiologic Heterogeneity Among Non-Hodgkin Lymphoma Subtypes: The InterLymph Non-Hodgkin Lymphoma Subtypes Project 
Morton, Lindsay M. | Slager, Susan L. | Cerhan, James R. | Wang, Sophia S. | Vajdic, Claire M. | Skibola, Christine F. | Bracci, Paige M. | de Sanjosé, Silvia | Smedby, Karin E. | Chiu, Brian C. H. | Zhang, Yawei | Mbulaiteye, Sam M. | Monnereau, Alain | Turner, Jennifer J. | Clavel, Jacqueline | Adami, Hans-Olov | Chang, Ellen T. | Glimelius, Bengt | Hjalgrim, Henrik | Melbye, Mads | Crosignani, Paolo | di Lollo, Simonetta | Miligi, Lucia | Nanni, Oriana | Ramazzotti, Valerio | Rodella, Stefania | Costantini, Adele Seniori | Stagnaro, Emanuele | Tumino, Rosario | Vindigni, Carla | Vineis, Paolo | Becker, Nikolaus | Benavente, Yolanda | Boffetta, Paolo | Brennan, Paul | Cocco, Pierluigi | Foretova, Lenka | Maynadié, Marc | Nieters, Alexandra | Staines, Anthony | Colt, Joanne S. | Cozen, Wendy | Davis, Scott | de Roos, Anneclaire J. | Hartge, Patricia | Rothman, Nathaniel | Severson, Richard K. | Holly, Elizabeth A. | Call, Timothy G. | Feldman, Andrew L. | Habermann, Thomas M. | Liebow, Mark | Blair, Aaron | Cantor, Kenneth P. | Kane, Eleanor V. | Lightfoot, Tracy | Roman, Eve | Smith, Alex | Brooks-Wilson, Angela | Connors, Joseph M. | Gascoyne, Randy D. | Spinelli, John J. | Armstrong, Bruce K. | Kricker, Anne | Holford, Theodore R. | Lan, Qing | Zheng, Tongzhang | Orsi, Laurent | Dal Maso, Luigino | Franceschi, Silvia | La Vecchia, Carlo | Negri, Eva | Serraino, Diego | Bernstein, Leslie | Levine, Alexandra | Friedberg, Jonathan W. | Kelly, Jennifer L. | Berndt, Sonja I. | Birmann, Brenda M. | Clarke, Christina A. | Flowers, Christopher R. | Foran, James M. | Kadin, Marshall E. | Paltiel, Ora | Weisenburger, Dennis D. | Linet, Martha S. | Sampson, Joshua N.
Non-Hodgkin lymphoma (NHL) comprises biologically and clinically heterogeneous subtypes. Previously, study size has limited the ability to compare and contrast the risk factor profiles among these heterogeneous subtypes.
We pooled individual-level data from 17 471 NHL cases and 23 096 controls in 20 case–control studies from the International Lymphoma Epidemiology Consortium (InterLymph). We estimated the associations, measured as odds ratios, between each of 11 NHL subtypes and self-reported medical history, family history of hematologic malignancy, lifestyle factors, and occupation. We then assessed the heterogeneity of associations by evaluating the variability (Q value) of the estimated odds ratios for a given exposure among subtypes. Finally, we organized the subtypes into a hierarchical tree to identify groups that had similar risk factor profiles. Statistical significance of tree partitions was estimated by permutation-based P values (P NODE).
Risks differed statistically significantly among NHL subtypes for medical history factors (autoimmune diseases, hepatitis C virus seropositivity, eczema, and blood transfusion), family history of leukemia and multiple myeloma, alcohol consumption, cigarette smoking, and certain occupations, whereas generally homogeneous risks among subtypes were observed for family history of NHL, recreational sun exposure, hay fever, allergy, and socioeconomic status. Overall, the greatest difference in risk factors occurred between T-cell and B-cell lymphomas (P NODE < 1.0×10−4), with increased risks generally restricted to T-cell lymphomas for eczema, T-cell-activating autoimmune diseases, family history of multiple myeloma, and occupation as a painter. We further observed substantial heterogeneity among B-cell lymphomas (P NODE < 1.0×10−4). Increased risks for B-cell-activating autoimmune disease and hepatitis C virus seropositivity and decreased risks for alcohol consumption and occupation as a teacher generally were restricted to marginal zone lymphoma, Burkitt/Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma, and/or lymphoplasmacytic lymphoma/Waldenström macroglobulinemia.
Using a novel approach to investigate etiologic heterogeneity among NHL subtypes, we identified risk factors that were common among subtypes as well as risk factors that appeared to be distinct among individual or a few subtypes, suggesting both subtype-specific and shared underlying mechanisms. Further research is needed to test putative mechanisms, investigate other risk factors (eg, other infections, environmental exposures, and diet), and evaluate potential joint effects with genetic susceptibility.
PMCID: PMC4155467  PMID: 25174034
21.  Human Nail Clippings as a Source of DNA for Genetic Studies 
Open journal of epidemiology  2015;5(1):41-50.
Blood samples have traditionally been used as the main source of DNA for genetic analysis. However, this source can be difficult in terms of collection, transportation, and long-term storage. In this study, we investigated whether human nail clippings could be used as a source of DNA for SNP genotyping, null-allele detection, and whole-genome amplification. From extracted nail DNA, we achieved amplicons up to a length of ~400 bp and >96% concordance for SNP genotyping and 100% concordance for null-allele detection compared to DNA derived from matched blood samples. For whole-genome amplification, OmniPlex performed better than Multiple Displacement Amplification with a success rate of 89.3% and 76.8% for SNP genotyping and null-allele detection, respectively. Concordance was ~98% for both methods. When combined with OmniPlex whole-genome amplification, human nail clippings could potentially be used as an alternative to whole blood as a less invasive and more convenient source of DNA for genotyping studies.
PMCID: PMC4499506  PMID: 26180661
Single Nucleotide Polymorphism (SNP); Nail Clippings; Genotyping; Whole Genome Amplification (WGA)
22.  Reduced risk of breast cancer associated with recreational physical activity varies by HER2 status 
Cancer Medicine  2015;4(7):1122-1135.
Convincing epidemiologic evidence indicates that physical activity is inversely associated with breast cancer risk. Whether this association varies by the tumor protein expression status of the estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), or p53 is unclear. We evaluated the effects of recreational physical activity on risk of invasive breast cancer classified by the four biomarkers, fitting multivariable unconditional logistic regression models to data from 1195 case and 2012 control participants in the population-based Women’s Contraceptive and Reproductive Experiences Study. Self-reported recreational physical activity at different life periods was measured as average annual metabolic equivalents of energy expenditure [MET]-hours per week. Our biomarker-specific analyses showed that lifetime recreational physical activity was negatively associated with the risks of ER-positive (ER+) and of HER2-negative (HER2−) subtypes (both Ptrend ≤ 0.04), but not with other subtypes (all Ptrend > 0.10). Analyses using combinations of biomarkers indicated that risk of invasive breast cancer varied only by HER2 status. Risk of HER2–breast cancer decreased with increasing number of MET-hours of recreational physical activity in each specific life period examined, although some trend tests were only marginally statistically significant (all Ptrend ≤ 0.06). The test for homogeneity of trends (HER2– vs. HER2+ ) reached statistical significance only when evaluating physical activity during the first 10 years after menarche (Phomogeneity = 0.03). Our data suggest that physical activity reduces risk of invasive breast cancers that lack HER2 overexpression, increasing our understanding of the biological mechanisms by which physical activity acts.
PMCID: PMC4529350  PMID: 25924995
Breast cancer; ER; HER2; luminal A breast cancer; p53; physical activity; PR; Triple-negative breast cancer
23.  Methodological Considerations in Estimation of Phenotype Heritability Using Genome-Wide SNP Data, Illustrated by an Analysis of the Heritability of Height in a Large Sample of African Ancestry Adults 
PLoS ONE  2015;10(6):e0131106.
Height has an extremely polygenic pattern of inheritance. Genome-wide association studies (GWAS) have revealed hundreds of common variants that are associated with human height at genome-wide levels of significance. However, only a small fraction of phenotypic variation can be explained by the aggregate of these common variants. In a large study of African-American men and women (n = 14,419), we genotyped and analyzed 966,578 autosomal SNPs across the entire genome using a linear mixed model variance components approach implemented in the program GCTA (Yang et al Nat Genet 2010), and estimated an additive heritability of 44.7% (se: 3.7%) for this phenotype in a sample of evidently unrelated individuals. While this estimated value is similar to that given by Yang et al in their analyses, we remain concerned about two related issues: (1) whether in the complete absence of hidden relatedness, variance components methods have adequate power to estimate heritability when a very large number of SNPs are used in the analysis; and (2) whether estimation of heritability may be biased, in real studies, by low levels of residual hidden relatedness. We addressed the first question in a semi-analytic fashion by directly simulating the distribution of the score statistic for a test of zero heritability with and without low levels of relatedness. The second question was addressed by a very careful comparison of the behavior of estimated heritability for both observed (self-reported) height and simulated phenotypes compared to imputation R2 as a function of the number of SNPs used in the analysis. These simulations help to address the important question about whether today's GWAS SNPs will remain useful for imputing causal variants that are discovered using very large sample sizes in future studies of height, or whether the causal variants themselves will need to be genotyped de novo in order to build a prediction model that ultimately captures a large fraction of the variability of height, and by implication other complex phenotypes. Our overall conclusions are that when study sizes are quite large (5,000 or so) the additive heritability estimate for height is not apparently biased upwards using the linear mixed model; however there is evidence in our simulation that a very large number of causal variants (many thousands) each with very small effect on phenotypic variance will need to be discovered to fill the gap between the heritability explained by known versus unknown causal variants. We conclude that today's GWAS data will remain useful in the future for causal variant prediction, but that finding the causal variants that need to be predicted may be extremely laborious.
PMCID: PMC4488332  PMID: 26125186
24.  Meta-analysis of loci associated with age at natural menopause in African-American women 
Human Molecular Genetics  2014;23(12):3327-3342.
Age at menopause marks the end of a woman's reproductive life and its timing associates with risks for cancer, cardiovascular and bone disorders. GWAS and candidate gene studies conducted in women of European ancestry have identified 27 loci associated with age at menopause. The relevance of these loci to women of African ancestry has not been previously studied. We therefore sought to uncover additional menopause loci and investigate the relevance of European menopause loci by performing a GWAS meta-analysis in 6510 women with African ancestry derived from 11 studies across the USA. We did not identify any additional loci significantly associated with age at menopause in African Americans. We replicated the associations between six loci and age at menopause (P-value < 0.05): AMHR2, RHBLD2, PRIM1, HK3/UMC1, BRSK1/TMEM150B and MCM8. In addition, associations of 14 loci are directionally consistent with previous reports. We provide evidence that genetic variants influencing reproductive traits identified in European populations are also important in women of African ancestry residing in USA.
PMCID: PMC4030781  PMID: 24493794
25.  MiRNA-Related SNPs and Risk of Esophageal Adenocarcinoma and Barrett’s Esophagus: Post Genome-Wide Association Analysis in the BEACON Consortium 
PLoS ONE  2015;10(6):e0128617.
Incidence of esophageal adenocarcinoma (EA) has increased substantially in recent decades. Multiple risk factors have been identified for EA and its precursor, Barrett’s esophagus (BE), such as reflux, European ancestry, male sex, obesity, and tobacco smoking, and several germline genetic variants were recently associated with disease risk. Using data from the Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON) genome-wide association study (GWAS) of 2,515 EA cases, 3,295 BE cases, and 3,207 controls, we examined single nucleotide polymorphisms (SNPs) that potentially affect the biogenesis or biological activity of microRNAs (miRNAs), small non-coding RNAs implicated in post-transcriptional gene regulation, and deregulated in many cancers, including EA. Polymorphisms in three classes of genes were examined for association with risk of EA or BE: miRNA biogenesis genes (157 SNPs, 21 genes); miRNA gene loci (234 SNPs, 210 genes); and miRNA-targeted mRNAs (177 SNPs, 158 genes). Nominal associations (P<0.05) of 29 SNPs with EA risk, and 25 SNPs with BE risk, were observed. None remained significant after correction for multiple comparisons (FDR q>0.50), and we did not find evidence for interactions between variants analyzed and two risk factors for EA/BE (smoking and obesity). This analysis provides the most extensive assessment to date of miRNA-related SNPs in relation to risk of EA and BE. While common genetic variants within components of the miRNA biogenesis core pathway appear unlikely to modulate susceptibility to EA or BE, further studies may be warranted to examine potential associations between unassessed variants in miRNA genes and targets with disease risk.
PMCID: PMC4454432  PMID: 26039359

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