Faculty Bibliography
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333
Sustained weight loss and risk of breast cancer in women ≥50 years: a pooled analysis of prospective data
BACKGROUND:Excess body weight is an established cause of postmenopausal breast cancer, but it is unknown if weight loss reduces risk. METHODS:Associations between weight change and risk of breast cancer were examined among women aged ≥50 years in the Pooling Project of Prospective Studies of Diet and Cancer. In 10 cohorts, weight assessed on three surveys was used to examine weight change patterns over approximately 10 years (Interval 1 median= 5.2 years; Interval 2 median = 4.0 years). Sustained weight loss was defined as ≥ 2kg lost in Interval 1 that was not regained in Interval 2. Among 180,885 women, 6,930 invasive breast cancers were identified during follow-up. RESULTS:Compared with women with stable weight (± 2kg), women with sustained weight loss had a lower risk of breast cancer. This risk reduction was linear and specific to women not using postmenopausal hormones (>2-4.5kg lost: Hazard Ratio (HR)= 0.82, 95% confidence interval (CI): 0.70-0.96; >4.5-<9kg lost: HR = 0.75, 95% CI: 0.63-0.90; ≥9kg lost: HR = 0.68, 95% CI: 0.50-0.93). Women who lost ≥9kg and gained some (but not all) of it back were also at a lower risk of breast cancer. Other patterns of weight loss and gain over the two intervals had a similar risk of breast cancer to women with stable weight. CONCLUSIONS:These results suggest that sustained weight loss, even modest amounts, is associated with lower breast cancer risk for women aged ≥50 years. Breast cancer prevention may be a strong weight loss motivator for the two-thirds of American women who are overweight or obese.
PMID: 31845728
ISSN: 1460-2105
CID: 4242382
Circulating unmetabolized folic acid and 5-methyltetrahydrofolate and risk of breast cancer: a nested case-control study
BACKGROUND/OBJECTIVES/OBJECTIVE:Folates found in natural foods are thought to protect against cancer. However, folic acid (FA), a synthetic form of folate used in supplements and fortified foods, may increase breast cancer risk if present in unmetabolized form (UMFA) in the circulation. This study examined the associations of serum UMFA and 5-methyltetrahydrofolate (5-mTHF), the predominant form of circulating folate, with breast cancer risk. SUBJECTS/METHODS/METHODS:We conducted a nested case-control study in a prospective cohort. In total, 553 cases of invasive breast cancer, diagnosed before mandatory FA fortification of grain in the US in 1998, were individually-matched to 1059 controls. Serum UMFA and 5-mTHF were measured using liquid chromatography-tandem mass spectrometry in stored serum samples, and 5-mTHF was corrected for storage degradation. RESULTS: = 0.08). CONCLUSIONS:Circulating UMFA was not associated with breast cancer risk. These results apply to countries without mandatory FA food fortification. Studies are needed in countries with mandatory fortification, where levels of UMFA are much higher than in our study.
PMID: 32317749
ISSN: 1476-5640
CID: 4397082
Cancer epidemiology biomarkers & prevention. 2020:29(9):1784-1791.DOI: 10.1158/1055-9965.EPI-20-0275
Genome-wide gene-diabetes and gene-obesity interaction scan in 8,255 cases and 11,900 controls from the PanScan and PanC4 Consortia
BACKGROUND:Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level. METHODS:We conducted a gene-environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer GWAS datasets (PanScan I-III and PanC4). Obesity (BMI=30 kg/m2) and diabetes (duration = 3 years) were the environmental variables of interest. Approximately 870,000 SNPs were analyzed. Case-control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual-GWAS summary statistics. RESULTS:No genome-wide significant interactions with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the FAM63A (family with sequence similarity 63 member A) gene (significance threshold P<1.25E-6) was observed in the meta-analysis (PGxE= 1.2E-6, PJoint= 4.2E-7). CONCLUSIONS:Our current analyses did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans. IMPACT/CONCLUSIONS:This study may contribute to discovering the mechanism of diabetes-associated pancreatic cancer.
PMID: 32546605
ISSN: 1538-7755
CID: 4484782
Abdominal and Gluteofemoral Size and Risk of Liver Cancer: The Liver Cancer Pooling Project
Obesity is known to be associated with primary liver cancer (PLC), but the separate effects of excess abdominal and gluteofemoral size are unclear. Thus, we examined the association between waist and hip circumference with risk of PLC overall and by histologic type - hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). The Liver Cancer Pooling Project is a consortium of prospective cohort studies that includes data from 1,167,244 individuals (PLC n=2,208, HCC n=1,154, ICC n=335). Multivariable-adjusted hazards ratios (HRs) and 95% confidence intervals (CI) were estimated using proportional hazards regression. Waist circumference, per 5 cm increase, was associated with an 11% increased PLC risk (HR=1.11, 95%CI: 1.09-1.14), including when adjusted for hip circumference (HR=1.12, 95%CI: 1.08-1.17) and also when restricted to individuals in a normal body mass index (BMI) range (18.5-<25 kg/m2 ; HR=1.14, 95%CI: 1.07-1.21). Hip circumference, per 5 cm increase, was associated with a 9% increased PLC risk (HR=1.09, 95%CI: 1.06-1.12), but no association remained after adjustment for waist circumference (HR=0.99, 95%CI: 0.94-1.03). HCC and ICC results were similar. These findings suggest that excess abdominal size is associated with an increased risk of liver cancer, even among individuals considered to have a normal BMI. However, excess gluteofemoral size alone confers no increased risk. Our findings extend prior analyses, which found an association between excess adiposity and risk of liver cancer, by disentangling the separate effects of excess abdominal and gluteofemoral size through utilization of both waist and hip circumference measurements. This article is protected by copyright. All rights reserved.
PMID: 31677159
ISSN: 1097-0215
CID: 4171862
Associations between Prediagnostic Concentrations of Circulating Sex Steroid Hormones and Liver Cancer Among Post-Menopausal Women
BACKGROUND:In almost all countries, incidence rates of liver cancer are 100-200% higher in males than in females. However, this difference is predominantly driven by hepatocellular carcinoma (HCC), which accounts for 75% of liver cancer cases. Intrahepatic cholangiocarcinoma (ICC) accounts for 12% of cases and has rates only 30% higher in males. Hormones are hypothesized to underlie observed sex differences. We investigated whether prediagnostic circulating hormone and sex hormone binding globulin (SHBG) levels were associated with liver cancer risk, overall and by histology, by leveraging resources from five prospective cohorts. METHODS:hormone value (approximate doubling of circulating concentration) and liver cancer were calculated using multivariable-adjusted conditional logistic regression. RESULTS:A doubling in the concentration of 4-androstenedione was associated with a 50% decreased liver cancer risk (OR=0.50,95%CI=0.30-0.82), while SHBG was associated with a 31% increased risk (OR=1.31,95%CI=1.05-1.63). Examining histology, a doubling of estradiol was associated with a 40% increased risk of ICC (OR=1.40,95%CI=1.05-1.89), but not HCC (OR=1.12,95%CI=0.81-1.54). CONCLUSIONS:This study provides the first evidence that higher levels of 4-androstenedione may be associated with lower, and SHBG with higher, liver cancer risk in women. However, this study does not support the hypothesis that higher estrogen levels decrease liver cancer risk. Indeed, estradiol may be associated with an increased ICC risk.
PMID: 31808181
ISSN: 1527-3350
CID: 4218962
International journal of environmental research & public health. 2020:17(15).DOI: 10.3390/ijerph17155493
Genome-Wide DNA Methylation Profiles in Community Members Exposed to the World Trade Center Disaster
The primary goal of this pilot study was to assess feasibility of studies among local community members to address the hypothesis that complex exposures to the World Trade Center (WTC) dust and fumes resulted in long-term epigenetic changes. We enrolled 18 WTC-exposed cancer-free women from the WTC Environmental Health Center (WTC EHC) who agreed to donate blood samples during their standard clinical visits. As a reference WTC unexposed group, we randomly selected 24 age-matched cancer-free women from an existing prospective cohort who donated blood samples before 11 September 2001. The global DNA methylation analyses were performed using Illumina Infinium MethylationEpic arrays. Statistical analyses were performed using R Bioconductor package. Functional genomic analyses were done by mapping the top 5000 differentially expressed CpG sites to the Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway database. Among cancer-free subjects, we observed substantial methylation differences between WTC-exposed and unexposed women. The top 15 differentially methylated gene probes included BCAS2, OSGIN1, BMI1, EEF1A2, SPTBN5, CHD8, CDCA7L, AIDA, DDN, SNORD45C, ZFAND6, ARHGEF7, UBXN8, USF1, and USP12. Several cancer-related pathways were enriched in the WTC-exposed subjects, including endocytosis, mitogen-activated protein kinase (MAPK), viral carcinogenesis, as well as Ras-associated protein-1 (Rap1) and mammalian target of rapamycin (mTOR) signaling. The study provides preliminary data on substantial differences in DNA methylation between WTC-exposed and unexposed populations that require validation in further studies.
PMID: 32751422
ISSN: 1660-4601
CID: 4553982
Exogenous hormone use, reproductive factors and risk of intrahepatic cholangiocarcinoma among women: results from cohort studies in the Liver Cancer Pooling Project and the UK Biobank
BACKGROUND:Intrahepatic cholangiocarcinoma (ICC) arises from cholangiocytes in the intrahepatic bile duct and is the second most common type of liver cancer. Cholangiocytes express both oestrogen receptor-α and -β, and oestrogens positively modulate cholangiocyte proliferation. Studies in women and men have reported higher circulating oestradiol is associated with increased ICC risk, further supporting a hormonal aetiology. However, no observational studies have examined the associations between exogenous hormone use and reproductive factors, as proxies of endogenous hormone levels, and risk of ICC. METHODS:We harmonised data from 1,107,498 women who enroled in 12 North American-based cohort studies (in the Liver Cancer Pooling Project, LCPP) and the UK Biobank between 1980-1998 and 2006-2010, respectively. Cox proportional hazards regression models were used to generate hazard ratios (HR) and 95% confidence internals (CI). Then, meta-analytic techniques were used to combine the estimates from the LCPP (n = 180 cases) and the UK Biobank (n = 57 cases). RESULTS:Hysterectomy was associated with a doubling of ICC risk (HR = 1.98, 95% CI: 1.27-3.09), compared to women aged 50-54 at natural menopause. Long-term oral contraceptive use (9+ years) was associated with a 62% increased ICC risk (HR = 1.62, 95% CI: 1.03-2.55). There was no association between ICC risk and other exogenous hormone use or reproductive factors. CONCLUSIONS:This study suggests that hysterectomy and long-term oral contraceptive use may be associated with an increased ICC risk.
PMID: 32376888
ISSN: 1532-1827
CID: 4430382
Circulating markers of cellular immune activation in pre-diagnostic blood sample and lung cancer risk in the Lung Cancer Cohort Consortium (LC3)
Cell-mediated immune suppression may play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), quinolinic acid (QA), and neopterin as markers of immune regulation and inflammation with lung cancer risk in 5,364 smoking-matched case-control pairs from 20 prospective cohorts included in the international Lung Cancer Cohort Consortium. All biomarkers were quantified by mass spectrometry-based methods in serum/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with individual biomarkers were calculated using conditional logistic regression with adjustment for circulating cotinine. Compared with the lowest quintile, the highest quintiles of kynurenine, KTR, QA and neopterin were associated with a 20-30% higher risk, and tryptophan with a 15% lower risk of lung cancer (all Ptrend <0.05). The strongest associations were seen for current smokers, where the adjusted ORs (95% CIs) of lung cancer for the highest quintile of KTR, QA and neopterin were 1.42 (1.15-1.75), 1.42 (1.14-1.76) and 1.45 (1.13-1.86), respectively. A stronger association was also seen for KTR and QA with risk of lung squamous cell carcinoma followed by adenocarcinoma, and for lung cancer diagnosed within the first 2 years after blood draw. This study demonstrated that components of the tryptophan-kynurenine pathway with immunomodulatory effects are associated with risk of lung cancer overall, especially for current smokers. Further research is needed to evaluate the role of these biomarkers in lung carcinogenesis and progression. This article is protected by copyright. All rights reserved.
PMID: 31276202
ISSN: 1097-0215
CID: 3967432
Cancer epidemiology biomarkers & prevention. 2020:29(5):1074-1078.DOI: 10.1158/1055-9965.EPI-19-0803
Lipid trait variants and the risk of non-Hodgkin lymphoma subtypes: A Mendelian Randomization Study
BACKGROUND:Lipid traits have been inconsistently linked to risk of non-Hodgkin lymphoma (NHL). We examined the association of genetically predicted lipid traits with risk of diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), follicular (FL) and marginal zone (MZL) lymphoma using Mendelian randomization (MR) analysis. METHODS:GWAS data from the InterLymph Consortium were available for 2661 DLBCLs, 2179 CLLs, 2142 FLs, 824 MZLs, and 6221 controls. SNPs associated (P<5x10-8) with high-density lipoprotein (HDL, N=164), low-density lipoprotein (LDL, N=137), total cholesterol (TC, N=161), and triglycerides (TG, N=123) were used as instrumental variables (IV), explaining 14.6%, 27.7%, 16.8% and 12.8% of phenotypic variation, respectively. Associations between each lipid trait and NHL subtype were calculated using the MR inverse variance-weighted method, estimating odds ratios (OR) per standard deviation, and 95% confidence intervals (CI). RESULTS:HDL was positively associated with DLBCL (OR=1.14, CI:1.00-1.30) and MZL (OR=1.09, CI:1.01-1.18), while TG was inversely associated with MZL risk (OR=0.90, CI:0.83-0.99) all at nominal significance (P<0.05). A positive trend was observed for HDL with FL risk (OR=1.08, CI:0.99-1.19; P=0.087). No associations were noteworthy after adjusting for multiple testing. CONCLUSIONS:We did not find evidence of a clear or strong association of these lipid traits with the most common NHL subtypes. While these IVs have been previously linked to other cancers, our findings do not support any causal associations with these NHL subtypes. IMPACT/CONCLUSIONS:Our results suggest that prior reported inverse associations of lipid traits are not likely to be causal and could represent reverse causality or confounding.
PMID: 32108027
ISSN: 1538-7755
CID: 4323682
Cumulative Burden of Colorectal Cancer-Associated Genetic Variants is More Strongly Associated With Early-onset vs Late-onset Cancer
BACKGROUND & AIMS/OBJECTIVE:Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC. METHODS:We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single-nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants. RESULTS:). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI, 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI, 2.70-3.00). Sensitivity analyses were consistent with these findings. CONCLUSIONS:In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer-particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventative measures.
PMID: 31866242
ISSN: 1528-0012
CID: 4243992
