Association of Cancer Susceptibility Variants with Risk of Multiple Primary Cancers: The Population Architecture using Genomics and Epidemiology Study

Multiple primary cancers account for ~16% of all incident cancers in the U.S.. While genome-wide association studies (GWAS) have identified many common genetic variants associated with various cancer sites, no study has examined the association of these genetic variants with risk of multiple primary cancers (MPC)

Association of the FTO Obesity Risk Variant rs8050136 With Percentage of Energy Intake From Fat in Multiple Racial/Ethnic Populations

Common obesity risk variants have been associated with macronutrient intake; however, these associations' generalizability across populations has not been demonstrated. We investigated the associations between 6 obesity risk variants in (or near) the NEGR1, TMEM18, BDNF, FTO, MC4R, and KCTD15 genes and macronutrient intake (carbohydrate, protein, ethanol, and fat) in 3 Population Architecture using Genomics and Epidemiology (PAGE) studies: the Multiethnic Cohort Study (1993–2006) (n = 19,529), the Atherosclerosis Risk in Communities Study (1987–1989) (n = 11,114), and the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) Study, which accesses data from the Third National Health and Nutrition Examination Survey (1991–1994) (n = 6,347). We used linear regression, with adjustment for age, sex, and ethnicity, to estimate the associations between obesity risk genotypes and macronutrient intake. A fixed-effects meta-analysis model showed that the FTO rs8050136 A allele (n = 36,973) was positively associated with percentage of calories derived from fat (βmeta = 0.2244 (standard error, 0.0548); P = 4 × 10−5) and inversely associated with percentage of calories derived from carbohydrate (βmeta = −0.2796 (standard error, 0.0709); P = 8 × 10−5). In the Multiethnic Cohort Study, percentage of calories from fat assessed at baseline was a partial mediator of the rs8050136 effect on body mass index (weight (kg)/height (m)2) obtained at 10 years of follow-up (mediation of effect = 0.0823 kg/m2, 95% confidence interval: 0.0559, 0.1128). Our data provide additional evidence that the association of FTO with obesity is partially mediated by dietary intake

Pleiotropic Associations of Risk Variants Identified for Other Cancers With Lung Cancer Risk: The PAGE and TRICL Consortia

BackgroundGenome-wide association studies have identified hundreds of genetic variants associated with specific cancers. A few of these risk regions have been associated with more than one cancer site; however, a systematic evaluation of the associations between risk variants for other cancers and lung cancer risk has yet to be performed.MethodsWe included 18023 patients with lung cancer and 60543 control subjects from two consortia, Population Architecture using Genomics and Epidemiology (PAGE) and Transdisciplinary Research in Cancer of the Lung (TRICL). We examined 165 single-nucleotide polymorphisms (SNPs) that were previously associated with at least one of 16 non–lung cancer sites. Study-specific logistic regression results underwent meta-analysis, and associations were also examined by race/ethnicity, histological cell type, sex, and smoking status. A Bonferroni-corrected P value of 2.5×10–5 was used to assign statistical significance.ResultsThe breast cancer SNP LSP1 rs3817198 was associated with an increased risk of lung cancer (odds ratio [OR] = 1.10; 95% confidence interval [CI] = 1.05 to 1.14; P = 2.8×10–6). This association was strongest for women with adenocarcinoma (P = 1.2×10–4) and not statistically significant in men (P = .14) with this cell type (P het by sex = .10). Two glioma risk variants, TERT rs2853676 and CDKN2BAS1 rs4977756, which are located in regions previously associated with lung cancer, were associated with increased risk of adenocarcinoma (OR = 1.16; 95% CI = 1.10 to 1.22; P = 1.1×10–8) and squamous cell carcinoma (OR = 1.13; CI = 1.07 to 1.19; P = 2.5×10–5), respectively.ConclusionsOur findings demonstrate a novel pleiotropic association between the breast cancer LSP1 risk region marked by variant rs3817198 and lung cancer risk

Pleiotropic effects of genetic risk variants for other cancers on colorectal cancer risk: PAGE, GECCO and CCFR consortia

Genome-wide association studies (GWAS) have identified a large number of single nucleotide polymorphisms (SNPs) associated with a wide array of cancer sites. Several of these variants demonstrate associations with multiple cancers, suggesting pleiotropic effects and shared biological mechanisms across some cancers. We hypothesized that SNPs previously associated with other cancers may additionally be associated with colorectal cancer. In a large-scale study, we examined 171 SNPs previously associated with 18 different cancers for their associations with colorectal cancer

Plasma coenzyme Q10 levels and postmenopausal breast cancer risk: the multiethnic cohort study.

Coenzyme Q10 (CoQ10) is a component of the mitochondrial electron transport chain and is considered an important cellular antioxidant. Decreased circulating CoQ10 levels have been reported in women with breast cancer, but evidence is limited. We examined the association of plasma CoQ10 levels with postmenopausal breast cancer risk using prospectively collected blood samples.Prediagnostic plasma levels of total CoQ10 were measured among 160 incident postmenopausal breast cancer cases and 289 controls in the Multiethnic Cohort Study. Cases and controls were individually matched on age, sex, ethnicity, study location (Hawaii or California), hormone replacement therapy use, date and time of specimen collection, and hours of fasting. Logistic regression was used to compute odds ratios and 95% confidence intervals.Plasma CoQ10 levels were positively associated with breast cancer risk, overall (P = 0.04). The association was stronger after women diagnosed within 1 year of blood draw were excluded to eliminate possible preclinical cases (odds ratio for the highest versus the lowest tertile, 2.26; 95% confidence interval, 1.22-4.19; P for trend = 0.01).Higher CoQ10 levels in postmenopausal women may be associated with increased breast cancer risk.A potential role for CoQ10 in the development and progression of breast cancer has been postulated, but epidemiologic evidence is lacking. Findings from this prospective cohort study add to the limited literature, indicating the potential positive association of circulating CoQ10 with postmenopausal breast cancer risk

Plasma coenzyme Q10 levels and prostate cancer risk: the multiethnic cohort study.

Coenzyme Q10 (CoQ10) is considered to be a potential anticancer agent, but epidemiologic evidence regarding CoQ10 and prostate cancer risk is lacking. We examined the association of circulating CoQ10 levels with prostate cancer risk, using prediagnostic blood samples.Each of the 307 cases was individually matched to approximately 2 controls, for a total of 596 controls, on age, ethnicity, geographic location, date/time of specimen collection, and hours of fasting. Logistic regression was used to compute ORs and 95% CIs.There was no overall statistically significant association of plasma CoQ10 levels with prostate cancer risk (P(trend) = 0.50). However, after matched sets in which controls who had possible undiagnosed prostate cancer (prostate specific antigen value >4.0) were excluded, the ORs for quintiles 2 to 5 were all less than 1.0.The results suggest the possibility that moderate levels of circulating CoQ10 may be optimal for the reduction of prostate cancer risk; however, the findings were weak and not statistically significant. Because this is the first epidemiologic study of the association between CoQ10 and prostate cancer, further research on this topic is needed.If a nutritional factor such as CoQ10 were determined to reduce prostate cancer risk, it would have considerable public health significance because of the very high incidence of this cancer

Association of Cancer Susceptibility Variants with Risk of Multiple Primary Cancers: The Population Architecture using Genomics and Epidemiology Study

BACKGROUND: Multiple primary cancers account for ~16% of all incident cancers in the U.S.. While genome-wide association studies (GWAS) have identified many common genetic variants associated with various cancer sites, no study has examined the association of these genetic variants with risk of multiple primary cancers (MPC). METHODS: As part of the NHGRI Population Architecture using Genomics and Epidemiology (PAGE) study, we used data from the Multiethnic Cohort and Women’s Health Initiative. Incident MPC (IMPC) cases (n=1,385) were defined as participants diagnosed with >1 incident cancers after cohort entry. Participants diagnosed with only one incident cancer after cohort entry with follow-up equal to or longer than IMPC cases served as controls (single-index cancer controls; n= 9,626). Fixed-effects meta-analyses of unconditional logistic regression analyses were used to evaluate the association between cancer risk variants and IMPC risk. To account for multiple comparisons, we used the false positive report probability (FPRP) to determine statistical significance. RESULTS: A nicotine dependence-associated and lung cancer variant, CHRNA3 rs578776 (OR=1.16, 95% CI=1.05–1.26; p=0.004) and two breast cancer variants, EMBP1 rs11249433 and TOX3 rs3803662 (OR=1.16, 95% CI=1.04–1.28; p=0.005 and OR=1.13, 95% CI=1.03–1.23; p=0.006) were significantly associated with risk of IMPC. The associations for rs578776 and rs11249433 remained (p<0.05) after removing subjects who had lung or breast cancers, respectively (p-values≤0.046). These associations did not show significant heterogeneity by smoking status (p-heterogeneity≥0.53). CONCLUSIONS: Our study has identified rs578776 and rs11249433 as risk variants for IMPC. IMPACT: These findings may help to identify genetic regions associated with IMPC risk