Faculty Bibliography
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543
Metabolic Dysregulation of the Insulin-Glucose Axis and Risk of Obesity-Related Cancers in the Framingham Heart Study-Offspring Cohort (1971-2008)
BACKGROUND: Obesity-related dysregulation of the insulin-glucose axis is hypothesized in carcinogenesis. We studied impaired fasting glucose (IFG) and other markers of insulin-glucose metabolism in the Framingham Heart Study-Offspring Cohort, which uniquely tracks these markers and cancer >37 years. METHODS: Participants were recruited between 1971 and 1975 and followed until 2008 (n = 4,615; mean age 66.8 years in 2008). Serum glucose, insulin, and hemoglobin A1c were determined from fasting blood in quart-annual exams. Lifestyle and demographic information was self-reported. HRs and 95% confidence intervals (CI) of cancer risk were computed using time-dependent survival analysis (SASv9.3), while accounting for temporal changes for relevant variables. RESULTS: We identified 787 obesity-related cancers, including 136 colorectal, 217 breast, and 219 prostate cancers. Absence versus presence of IFG 10 to 20 years and 20+ years before the event or last follow-up was associated with 44% (95% CI, 1.15-1.79) and 57% (95% CI, 1.17-2.11) increased risk of obesity-related cancers, respectively. When time-dependent variables were used, after adjusting for age, sex, smoking, alcohol, and body mass index, IFG was associated with a 27% increased risk of obesity-related cancer (HR = 1.27; CI, 1.1-1.5). Associations were stronger in smokers (HR = 1.41; CI, 1.13-1.76). Increased risk was noted among persons with higher insulin (HR = 1.47; CI, 1.15-1.88) and hemoglobin A1c (HR = 1.54; CI, 1.13-2.10) for the highest (>/=5.73%) versus lowest (2-fold increase in colorectal cancer risk was observed for all blood biomarkers of insulin-glucose metabolism, particularly with earlier IFG exposure. Nonsignificant increased risk of breast and prostate cancer was observed for blood biomarkers. CONCLUSIONS: Earlier IFG exposure (>10 years before) increased obesity-related cancer risk, particularly for colorectal cancer. IMPACT: Our study explicitly recognizes the importance of prolonged IFG exposure in identifying links between glucose dysregulation and obesity-related cancers. Cancer Epidemiol Biomarkers Prev; 22(10); 1-12. (c)2013 AACR.
PMID: 24064521
ISSN: 1055-9965
CID: 551162
Cigarette, cigar, and pipe smoking and the risk of head and neck cancers: pooled analysis in the international head and neck cancer epidemiology consortium
Cigar and pipe smoking are considered risk factors for head and neck cancers, but the magnitude of effect estimates for these products has been imprecisely estimated. By using pooled data from the International Head and Neck Cancer Epidemiology (INHANCE) Consortium (comprising 13,935 cases and 18,691 controls in 19 studies from 1981 to 2007), we applied hierarchical logistic regression to more precisely estimate odds ratios and 95% confidence intervals for cigarette, cigar, and pipe smoking separately, compared with reference groups of those who had never smoked each single product. Odds ratios for cigar and pipe smoking were stratified by ever cigarette smoking. We also considered effect estimates of smoking a single product exclusively versus never having smoked any product (reference group). Among never cigarette smokers, the odds ratio for ever cigar smoking was 2.54 (95% confidence interval (CI): 1.93, 3.34), and the odds ratio for ever pipe smoking was 2.08 (95% CI: 1.55, 2.81). These odds ratios increased with increasing frequency and duration of smoking (Ptrend
PMCID:3755640
PMID: 23817919
ISSN: 0002-9262
CID: 550092
A meta-analysis of genome-wide association studies to identify prostate cancer susceptibility loci associated with aggressive and non-aggressive disease
Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS including 5953 cases of aggressive PrCa and 11 463 controls (men without PrCa). We computed association tests for approximately 2.6 million SNPs and followed up the most significant SNPs by genotyping 49 121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa [odds ratio = 1.12 (95% confidence interval 1.03-1.21), P = 1.4 x 10(-8)]. This report describes a genetic variant which is associated with aggressive PrCa, which is a type of PrCa associated with a poorer prognosis.
PMCID:3526158
PMID: 23065704
ISSN: 0964-6906
CID: 522992
Prospective study of the relationship between coffee and tea with colorectal cancer risk: The PLCO Cancer Screening Trial
Background:Coffee and tea are commonly consumed and carry potential anticancer components that could reduce the risk of colorectal cancer; however, their relationships with colorectal cancer risk remain inconsistent.Methods:A prospective analysis was carried out to examine the relationships of coffee and tea intake with colorectal cancer risk in 57 398 men and women in the intervention arm of the National Cancer Institute-Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, a national screening study that limits differential detection biases. Coffee and tea intakes were assessed by food frequency questionnaire.Results:Six hundred and eighty-one incident colorectal cancer cases were ascertained during a median follow-up of 11.4 years. Greater coffee intake was not associated with risk of colorectal cancer (relative risk (RR)=1.08, 95% confidence interval (CI)=0.79-1.48, Ptrend=0.23). Stratifying by cancer site (Pheterogeneity=0.48) or stage (Pheterogeneity=0.83) did not alter the relationship. Associations remained unchanged in subsets of participants for either caffeinated or decaffeinated coffee or when stratifying by several colorectal cancer risk factors. Similarly, greater tea intake was not associated with colorectal cancer risk overall (RR=0.77, 95% CI=0.55-1.09, Ptrend=0.17) or by cancer site (Pheterogeneity=0.14) or stage (Pheterogeneity=0.60). These associations were not modified by several colorectal cancer risk factors.Conclusion:The findings of this study do not provide evidence to suggest that drinking coffee or tea is beneficial in protecting against colorectal cancer.
PMCID:3778290
PMID: 23907431
ISSN: 0007-0920
CID: 519472
Circulating adipokine levels and endometrial cancer risk in the prostate, lung, colorectal, and ovarian cancer screening trial
BACKGROUND: Circulating adipokine levels may be associated with endometrial cancer risk, yet few studies have evaluated these markers prospectively. METHODS: We conducted a nested case-control study of postmenopausal women in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (n = 78,216), including 167 incident endometrial cancer cases and 327 controls that were matched on age, study center, race, study year of diagnosis, year of blood draw, time of day of blood draw, and menopausal hormone therapy (MHT) use. Adipokine and estradiol levels were categorized into tertiles (T). ORs and 95% confidence intervals (CIs) for the associations of adiponectin, leptin, and visfatin with endometrial cancer risk were estimated by conditional logistic regression, adjusting for known endometrial cancer risk factors, including body mass index (BMI) and circulating estradiol levels. RESULTS: Adiponectin levels were inversely associated with risk of endometrial cancer [ORT3vsT1 = 0.48; 95% CI, 0.29-0.80); Ptrend < 0.01], whereas elevated leptin levels showed a positive association [2.77 (1.60-4.79); Ptrend < 0.01]. These results remained significant after adjustment for estradiol, but not after further adjustment for BMI. When analyses were restricted to non-MHT users, associations of adiponectin and leptin were stronger and remained significant after adjustment for estradiol and BMI [0.25 (0.08-0.75); Ptrend = 0.01 and 4.72 (1.15-19.38); Ptrend = 0.02, respectively]. Nonsignificant positive associations were observed for visfatin. CONCLUSION: Adipokines may influence endometrial cancer risk through pathways other than estrogen-mediated cell growth in postmenopausal women not currently on MHT. IMPACT: Understanding how adipokines influence endometrial cancer risk may help to elucidate biological mechanisms important for the observed obesity-endometrial cancer association. Cancer Epidemiol Biomarkers Prev; 22(7); 1304-12. (c)2013 AACR.
PMCID:3819202
PMID: 23696194
ISSN: 1055-9965
CID: 425342
Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression
Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease.
PMCID:3658165
PMID: 23535824
ISSN: 0964-6906
CID: 394872
Association of obesity with cardiovascular disease mortality in the PLCO trial
OBJECTIVE: Obesity is a risk factor for cardiovascular disease (CVD) mortality, but the association between obesity and specific causes of CVD mortality is still under investigation. METHOD: We prospectively examined body-mass index (BMI) in relation to CVD-specific causes of death in approximately 86,000 US men and women in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, followed for up to 13years. BMI was calculated from self-reported weight and height at baseline. Hazard ratios (HRs) were calculated overall and stratified by sex, smoking status, and educational level. RESULT: Overweight non-obese participants (BMI: 25.0-29.9) were not at excess risk for CVD mortality (HR and CIs are 1.02 [0.92-1.13]), compared to participants of normal BMI (18.5-24.9). Excess CVD mortality was observed for participants of BMI 30.0-34.9 (HR and CIs: 1.29 [1.13-1.48]), BMI 35.0-39.9 (HR and CIs: 1.87 [1.51-2.32]) and BMI 40.0+ (HR and CIs: 2.21 [1.57-3.21]) (p<0.001 for trend). BMI was unrelated to mortality due to stroke. The observed association of BMI with CVD was independent of gender, smoking status and educational level. CONCLUSION: Obesity is associated with increased mortality due to CVD.
PMCID:3674167
PMID: 23632233
ISSN: 0091-7435
CID: 366852
Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array
Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 x 10(-8)). More than 70 prostate cancer susceptibility loci, explaining approximately 30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies.
PMCID:3832790
PMID: 23535732
ISSN: 1061-4036
CID: 306232
Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-Wide Meta-analysis
BACKGROUND & AIMS: Heritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis. METHODS: We conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent. RESULTS: Based on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 x 10(-8): an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 x 10(-8)). We also found evidence for 3 additional loci with P values less than 5.0 x 10(-7): a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 x 10(-8)), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 x 10(-8)), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 x 10(-7)). CONCLUSIONS: In a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to beta-catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.
PMCID:3636812
PMID: 23266556
ISSN: 0016-5085
CID: 287692
Coffee, tea, and fatal oral/pharyngeal cancer in a large prospective US cohort
Epidemiologic studies suggest that coffee intake is associated with reduced risk of oral/pharyngeal cancer. The authors examined associations of caffeinated coffee, decaffeinated coffee, and tea intake with fatal oral/pharyngeal cancer in the Cancer Prevention Study II, a prospective US cohort study begun in 1982 by the American Cancer Society. Among 968,432 men and women who were cancer free at enrollment, 868 deaths due to oral/pharyngeal cancer occurred during 26 years of follow-up. Cox proportional hazards regression was used to estimate multivariable-adjusted relative risk. Intake of >4 cups/day of caffeinated coffee was associated with a 49% lower risk of oral/pharyngeal cancer death relative to no/occasional coffee intake (relative risk = 0.51, 95% confidence interval: 0.40, 0.64) (1 cup/day = 237 ml). A dose-related decline in relative risk was observed with each single cup/day consumed (P(trend) < 0.001). The association was not modified by sex, smoking status, or alcohol use. An inverse association for >2 cups/day of decaffeinated coffee intake was suggested (relative risk = 0.61, 95% confidence interval: 0.37, 1.01). No association was found for tea drinking. In this large prospective study, caffeinated coffee intake was inversely associated with oral/pharyngeal cancer mortality. Research is needed to elucidate biologic mechanisms whereby coffee might help to protect against these often fatal cancers.
PMID: 23230042
ISSN: 0002-9262
CID: 216292
