Faculty Bibliography
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334
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
The risk of ovarian cancer increases with an increase in the lifetime number of ovulatory cycles: an analysis from the Ovarian Cancer Cohort Consortium (OC3)
Repeated exposure to the acute pro-inflammatory environment that follows ovulation at the ovarian surface and distal fallopian tube over a woman's reproductive years may increase ovarian cancer risk. To address this, analyses included individual-level data from 558,709 naturally menopausal women across 20 prospective cohorts, among whom 3,246 developed invasive epithelial ovarian cancer (2045 serous, 319 endometrioid, 184 mucinous, 121 clear cell, 577 other/unknown). Cox models were used to estimate multivariable-adjusted hazard ratios (HR) between lifetime ovulatory cycles (LOC) and its components and ovarian cancer risk overall and by histotype. Women in the 90th percentile of LOC (>514 cycles) were almost twice as likely to be diagnosed with ovarian cancer than women in the 10th percentile (<294) [HR (95% confidence interval): 1.92 (1.60-2.30)]. Risk increased 14% per five-year increase in LOC (60 cycles) [(1.10-1.17)]; this association remained after adjustment for LOC components: number of pregnancies and oral contraceptive use [1.08 (1.04-1.12)]. The association varied by histotype, with increased risk of serous [1.13 (1.09-1.17)], endometrioid [1.20 (1.10-1.32)], and clear cell [1.37 (1.18-1.58)], but not mucinous [0.99 (0.88-1.10), P-heterogeneity=0.01] tumors. Heterogeneity across histotypes was reduced [P-heterogeneity=0.15] with adjustment for LOC components [1.08 serous, 1.11 endometrioid, 1.26 clear cell, 0.94 mucinous]. Although the 10-year absolute risk of ovarian cancer is small, it roughly doubles as the number of LOC rises from ~300 to 500. The consistency and linearity of effects strongly support the hypothesis that each ovulation leads to small increases in the risk of most ovarian cancers, a risk which cumulates through life, suggesting this as an important area for identifying intervention strategies.
PMID: 31932455
ISSN: 1538-7445
CID: 4263142
Inherited variants at 3q13.33 and 3p24.1 are associated with risk of diffuse large B-cell lymphoma and implicate immune pathways
We previously identified five SNPs at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (GWAS). To further elucidate genetic susceptibility to DLBCL, we sought to validate 2 loci at 3q13.33 and 3p24.1 that were suggestive in the original GWAS with additional genotyping. In the meta-analysis (5,662 cases and 9,237 controls) of the four original GWAS discovery scans and three replication studies, the 3q13.33 locus (rs9831894; minor allele frequency [MAF]=0.40) was associated with DLBCL risk (OR=0.83, P=3.62x10-13). rs9831894 is in linkage disequilibrium (LD) with additional variants that are part of a super-enhancer that physically interacts with promoters of CD86 and ILDR1. In the meta-analysis (5,510 cases and 12,817 controls) of the four GWAS discovery scans and four replication studies, the 3p24.1 locus (rs6773363; MAF=0.45) was also associated with DLBCL risk (OR=1.20, P=2.31x10-12). This SNP is 29,426 bp upstream of the nearest gene EOMES and in LD with additional SNPs that are part of a highly lineage-specific and tumor-acquired super-enhancer that shows long-range interaction with AZI2 promoter. These loci provide additional evidence for the role of immune function in the etiology of DLBCL, the most common lymphoma subtype.
PMID: 31600786
ISSN: 1460-2083
CID: 4130032
Reproductive and hormonal factors and risk of ovarian cancer by tumor dominance: results from the Ovarian Cancer Cohort Consortium (OC3)
BACKGROUND:Laterality of epithelial ovarian tumors may reflect the underlying carcinogenic pathways and origins of tumor cells. METHODS:We pooled data from 9 prospective studies participating in the Ovarian Cancer Cohort Consortium. Information on measures of tumor size or tumor dominance was extracted from surgical pathology reports or obtained through cancer registries. We defined dominant tumors as those restricted to one ovary or where the dimension of one ovary was at least twice as large as the other, and non-dominant tumors as those with similar dimensions across the two ovaries or peritoneal tumors. Competing risks Cox models were used to examine whether associations with reproductive and hormonal risk factors differed by ovarian tumor dominance. RESULTS:Of 1,058 ovarian cancer cases with tumor dominance information, 401 were left-dominant, 363 were right-dominant, and 294 were non-dominant. Parity was more strongly inversely associated with risk of dominant than non-dominant ovarian cancer (p-heterogeneity=0.004). Ever use of oral contraceptives (OCs) was associated with lower risk of dominant tumors, but was not associated with non-dominant tumors (p-heterogeneity=0.01). Higher body mass index was associated with higher risk of left-dominant tumors, but not significantly associated with risk of right-dominant or non-dominant tumors (p-heterogeneity=0.08). CONCLUSIONS:These data suggest that reproductive and hormonal risk factors appear to have a stronger impact on dominant tumors, which may have an ovarian or endometriosis origin. IMPACT/CONCLUSIONS:Examining the associations of ovarian cancer risk factors by tumor dominance may help elucidate the mechanisms through which these factors influence ovarian cancer risk.
PMID: 31719062
ISSN: 1538-7755
CID: 4185342
Smoking, Alcohol, and Biliary Tract Cancer Risk: A Pooling Project of 26 Prospective Studies
BACKGROUND:Tobacco and alcohol are well-established risk factors for numerous cancers, yet their relationship to biliary tract cancers remains unclear. METHODS:We pooled data from 26 prospective studies to evaluate associations of cigarette smoking and alcohol consumption with biliary tract cancer risk. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with smoking and alcohol consumption were calculated. Random effects meta-analysis produced summary estimates. All statistical tests were two-sided. RESULTS:Over a period of 38,369,156 person-years of follow-up, 1,391 gallbladder, 758 intrahepatic bile duct, 1,208 extrahepatic bile duct, and 623 ampulla of Vater cancer cases were identified. Ever, former, and current smoking were associated with increased extrahepatic bile duct and ampulla of Vater cancers risk (e.g., current versus never smokers hazard ratio [HR] = 1.69, 95% confidence interval [CI] = 1.34 to 2.13 and 2.22, 95%CI = 1.69 to 2.92, respectively), with dose-response effects for smoking pack-years, duration, and intensity (all P-trend<0.01). Current smoking and smoking intensity were also associated with intrahepatic bile duct cancer (e.g., >40 cigarettes/day versus never smokers HR = 2.15, 95%CI: 1.15 to 4.00; P-trend=0.001). No convincing association was observed between smoking and gallbladder cancer. Alcohol consumption was only associated with intrahepatic bile duct cancer, with increased risk for individuals consuming ≥5 versus 0 drinks/day (HR = 2.35, 95%CI = 1.46 to 3.78; P-trend=0.04). There was evidence of statistical heterogeneity between several cancer sites, particularly between gallbladder cancer and the other biliary tract cancers. CONCLUSIONS:Smoking appears to increase the risk of developing all biliary tract cancers except gallbladder cancer. Alcohol may increase the risk of intrahepatic bile duct cancer. Findings highlight etiologic heterogeneity across the biliary tract.
PMID: 31127946
ISSN: 1460-2105
CID: 3921162
High levels of C-reactive protein are associated with an increased risk of ovarian cancer: Results from the Ovarian Cancer Cohort Consortium
Growing epidemiologic evidence supports chronic inflammation as a mechanism of ovarian carcinogenesis. An association between a circulating marker of inflammation, C-reactive protein (CRP), and ovarian cancer risk has been consistently observed, yet, potential heterogeneity of this association by tumor and patient characteristics has not been adequately explored. In this study, we pooled data from case-control studies nested within six cohorts in the Ovarian Cancer Cohort Consortium (OC3) to examine the association between CRP and epithelial ovarian cancer risk overall, by histologic subtype and by participant characteristics. CRP concentrations were measured from pre-diagnosis serum or plasma in 1,091 cases and 1,951 controls. Multivariable conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). When CRP was evaluated using tertiles, no associations with ovarian cancer risk were observed. A 67% increased ovarian cancer risk was found for women with CRP concentrations >10mg/L compared to <1mg/L (OR=1.67, 95% CI=1.12, 2.48). A CRP concentration >10mg/L was positively associated with risk of mucinous (OR=9.67, 95% CI=1.10, 84.80) and endometrioid carcinoma (OR=3.41, 95% CI=1.07, 10.92), and suggestively positive, though not statistically significant, for serous (OR=1.43, 95% CI=0.82, 2.49) and clear cell carcinoma (OR=2.05, 95% CI=0.36, 11.57; p-heterogeneity=0.20). Heterogeneity was observed with oral contraceptive use (p-interaction=0.03), where the increased risk was present only among ever users (OR=3.24, 95% CI=1.62, 6.47). The present study adds to the existing evidence that CRP plays a role in ovarian carcinogenesis, and suggests that inflammation may be particularly implicated in the etiology of endometrioid and mucinous carcinoma.
PMID: 31462430
ISSN: 1538-7445
CID: 4054522
Is high vitamin B12 status a cause of lung cancer?
Vitamin B supplementation can have side effects for human health, including cancer risk. We aimed to elucidate the role of vitamin B12 in lung cancer aetiology via direct measurements of pre-diagnostic circulating vitamin B12 concentrations in a nested case-control study, complemented with a Mendelian randomization (MR) approach in an independent case-control sample. We used pre-diagnostic biomarker data from 5,183 case-control pairs nested within 20 prospective cohorts, and genetic data from 29,266 cases and 56,450 controls. Exposures included directly measured circulating vitamin B12 in pre-diagnostic blood samples from the nested case-control study, and 8 single nucleotide polymorphisms associated with vitamin B12 concentrations in the MR study. Our main outcome of interest was increased risk for lung cancer, overall and by histological subtype, per increase in circulating vitamin B12 concentrations. We found circulating vitamin B12 to be positively associated with overall lung cancer risk in a dose response fashion (odds ratio for a doubling in B12 [ORlog2B12 ] = 1.15, 95% confidence interval (95%CI) = 1.06-1.25). The MR analysis based on 8 genetic variants also indicated that genetically determined higher vitamin B12 concentrations were positively associated with overall lung cancer risk (OR per 150 pmol/L standard deviation increase in B12 [ORSD ]= 1.08, 95%CI= 1.00-1.16). Considering the consistency of these two independent and complementary analyses, these findings support the hypothesis that high vitamin B12 status increases the risk of lung cancer.
PMID: 30499135
ISSN: 1097-0215
CID: 3500852
Anthropometric Risk Factors for Cancers of the Biliary Tract in the Biliary Tract Cancers Pooling Project
Biliary tract cancers are rare but highly fatal with poorly understood etiology. Identifying potentially modifiable risk factors for these cancers is essential for prevention. Here we estimated the relationship between adiposity and cancer across the biliary tract, including cancers of the gallbladder (GBC), intrahepatic bile ducts (IHBDC), extrahepatic bile ducts (EHBDC), and the ampulla of Vater (AVC). We pooled data from 27 prospective cohorts with over 2.7 million adults. Adiposity was measured using baseline body mass index, waist circumference, hip circumference, waist-to-hip and waist-to-height ratios. Hazard ratios (HR) and 95% confidence intervals (95%CI) were estimated using Cox proportional hazards models adjusted for sex, education, race, smoking, and alcohol consumption with age as the time metric and the baseline hazard stratified by study. During 37,883,648 person-years of follow-up, 1,343 GBC cases, 1,194 EHBDC cases, 784 IHBDC cases, and 623 AVC cases occurred. For each 5 kg/m2 increase in body mass index there were risk increases for GBC (HR: 1.27 [95% CI: 1.19, 1.36]), IHBDC (HR: 1.32 [95% CI: 1.21, 1.45]), and EHBDC (HR: 1.13 [95% CI: 1.03, 1.23]), but not AVC (HR: 0.99 [95% CI: 0.88, 1.11]). Increasing waist circumference, hip circumference, waist-to-hip ratio, and waist-to-height ratio were associated with GBC and IHBDC but not EHBDC or AVC. These results indicate that adult adiposity is associated with an increased risk of biliary tract cancer, particularly GBC and IHBDC. Moreover, they provide evidence for recommending weight maintenance programs to reduce the risk of developing these cancers.
PMID: 31113819
ISSN: 1538-7445
CID: 3920552
Development of a Neighborhood Walkability Index for Studying Neighborhood Physical Activity Contexts in Communities across the U.S. over the Past Three Decades
To examine how urban form shapes physical activity and health over time, a measure of neighborhood walkability is needed that can be linked to cohort studies with participants living across the United States (U.S.) that have been followed over the past decades. The Built Environment and Health-Neighborhood Walkability Index (BEH-NWI), a measure of neighborhood walkability that can be calculated for communities across the United States between 1990 and 2015, was conceptualized, developed, and tested using data from the New York City Tri-State Area. BEH-NWI measures were created for 1990 and 2010 using historical data on population density, street intersection density, density of rail stops, and density of pedestrian trip generating/supporting establishments. BEH-NWI scores were calculated for 1-km buffers around the 1990 residences of NYU Women's Health Study (NYUWHS) participants and NYC Department of Health and Mental Hygiene's Physical Activity and Transit (PAT) survey participants enrolled in 2011. Higher neighborhood BEH-NWI scores were significantly associated with greater self-reported walking per week (+ 0.31 MET-hours/week per unit BEH-NWI, 95% CI 0.23, 0.36) and lower body mass index (- 0.17 BMI units per unit BEH-NWI, 95% - 0.23, - 0.12) among NYUWHS participants. Higher neighborhood BEH-NWI scores were associated with significantly higher accelerometer-measured physical activity among PAT survey participants (39% more minutes of moderate-intensity equivalent activity/week across the interquartile range of BEH-NWI, 95% CI 21%, 60%). The BEH-NWI can be calculated using historical data going back to 1990, and BEH-NWI scores predict BMI, weekly walking, and physical activity in two NYC area datasets.
PMID: 31214976
ISSN: 1468-2869
CID: 3939152
Ovarian cancer risk factors by tumor aggressiveness: an analysis from the Ovarian Cancer Cohort Consortium
Ovarian cancer risk factors differ by histotype; however, within subtype there is substantial variability in outcomes. We hypothesized that risk factor profiles may influence tumor aggressiveness, defined by time between diagnosis and death, independent of histology. Among 1.3 million women from 21 prospective cohorts, 4,584 invasive epithelial ovarian cancers were identified and classified as highly aggressive (death in <1 year, n=864), very aggressive (death in 1-<3 years, n=1,390), moderately aggressive (death in 3-<5 years, n=639), and less aggressive (lived 5+ years, n=1,691). Using competing risks Cox proportional hazards regression, we assessed heterogeneity of associations by tumor aggressiveness for all cases and among serous and endometrioid/clear cell tumors. Associations between parity (phet =0.01), family history of ovarian cancer (phet =0.02), body mass index (BMI; phet ≤0.04) and smoking (phet <0.01) and ovarian cancer risk differed by aggressiveness. A first/single pregnancy, relative to nulliparity, was inversely associated with highly aggressive disease (HR: 0.72; 95% CI [0.58-0.88]), no association was observed for subsequent pregnancies (per pregnancy, 0.97 [0.92-1.02]). In contrast, first and subsequent pregnancies were similarly associated with less aggressive disease (0.87 for both). Family history of ovarian cancer was only associated with risk of less aggressive disease (1.94 [1.47-2.55]). High BMI (≥35 vs. 20-<25 kg/m2 , 1.93 [1.46-2.56] and current smoking (vs. never, 1.30 [1.07-1.57]) were associated with increased risk of highly aggressive disease. Results were similar within histotypes. Ovarian cancer risk factors may be directly associated with subtypes defined by tumor aggressiveness, rather than through differential effects on histology. Studies to assess biological pathways are warranted.
PMID: 30561796
ISSN: 1097-0215
CID: 3557002
