Faculty Bibliography
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539
Pilot study of oral microbiome and risk of pancreatic cancer [Meeting Abstract]
ISI:000331220600020
ISSN: 0008-5472
CID: 853292
Additive and multiplicative gene-environment interactions for colorectal cancer risk [Meeting Abstract]
ISI:000331220600363
ISSN: 0008-5472
CID: 853342
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
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
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
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
Leukemia-related chromosomal loss detected in hematopoietic progenitor cells of benzene-exposed workers
Benzene exposure causes acute myeloid leukemia and hematotoxicity, shown as suppression of mature blood and myeloid progenitor cell numbers. As the leukemia-related aneuploidies monosomy 7 and trisomy 8 previously had been detected in the mature peripheral blood cells of exposed workers, we hypothesized that benzene could cause leukemia through the induction of these aneuploidies in hematopoietic stem and progenitor cells. We measured loss and gain of chromosomes 7 and 8 by fluorescence in situ hybridization in interphase colony-forming unit-granulocyte-macrophage (CFU-GM) cells cultured from otherwise healthy benzene-exposed (n=28) and unexposed (n=14) workers. CFU-GM monosomy 7 and 8 levels (but not trisomy) were significantly increased in subjects exposed to benzene overall, compared with levels in the control subjects (P=0.0055 and P=0.0034, respectively). Levels of monosomy 7 and 8 were significantly increased in subjects exposed to <10 p.p.m. (20%, P=0.0419 and 28%, P=0.0056, respectively) and >/=10 p.p.m. (48%, P=0.0045 and 32%, 0.0354) benzene, compared with controls, and significant exposure-response trends were detected (P(trend)=0.0033 and 0.0057). These data show that monosomies 7 and 8 are produced in a dose-dependent manner in the blood progenitor cells of workers exposed to benzene, and may be mechanistically relevant biomarkers of early effect for benzene and other leukemogens.
PMCID:3472034
PMID: 22643707
ISSN: 0887-6924
CID: 209712
Models for Admixture Mapping in a Regression Framework [Meeting Abstract]
ISI:000309913200032
ISSN: 0741-0395
CID: 183732
Polygenes and Estimated Heritability of Prostate Cancer in an African American Sample Using GWAS Data [Meeting Abstract]
ISI:000309913200064
ISSN: 0741-0395
CID: 183752
Cancer epidemiology biomarkers & prevention. 2012:21(11):2014-21.DOI: 10.1158/1055-9965.EPI-12-0700-T
Prospective study of genomic hypomethylation of leukocyte DNA and colorectal cancer risk
BACKGROUND: Systematic genome-wide reductions of methylated cytosine (5-mC) levels have been observed in colorectal cancer tissue and are suspected to play a role in carcinogenesis, possibly as a consequence of inadequate folate intake. Reduced 5-mC levels in peripheral blood leukocytes have been associated with increased risk of colorectal cancer and adenoma in cross-sectional studies. METHODS: To minimize disease- and/or treatment-related effects, we studied leukocyte 5-mC levels in prospectively collected blood specimens of 370 cases and 493 controls who were cancer-free at blood collection from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Leukocyte 5-mC level was determined by a high-pressure liquid chromatography (HPLC)/tandem mass spectrometry method and expressed as the relative amount of methyl to total cytosine residues, or %5-mC. We estimated the association between colorectal cancer risk and %5-mC categories by computing ORs and 95% confidence intervals (CI) through logistic regression modeling. RESULTS: We observed no dose-dependent association between colorectal cancer and%5-mC categories (lowest vs. highest tertile: OR, 1.14; 95% CI, 0.80-1.63; P(trend) = 0.51). However, among subjects whose 5-mC levels were at the highest tertile, we observed an inverse association between natural folate intake and colorectal cancer (highest tertile of natural folate vs. lowest: OR, 0.35; 95% CI, 0.17-0.71; P(trend) = 0.003; P(interaction) = 0.003). CONCLUSIONS: This prospective investigation show no clear association between leukocyte 5-mC level and subsequent colorectal cancer risk but a suggestive risk modification between 5-mC level and natural folate intake. Impact: Adequate folate status may protect against colorectal carcinogenesis through mechanisms involving adequate DNA methylation in the genome. Cancer Epidemiol Biomarkers Prev; 21(11); 2014-21. (c)2012 AACR.
PMCID:3493855
PMID: 23001241
ISSN: 1055-9965
CID: 185482
