Christian Caberto

Nicotine Metabolism in Three Ethnic/Racial Groups with Different Risks of Lung Cancer

Previously, we documented that smoking-associated lung cancer risk is greater in Hawaiians and lower in Japanese compared with Whites. Nicotine metabolism by cytochrome P450 2A6 (CYP2A6) varies across ethnicity/race and is hypothesized to affect smoking behavior. We investigated whether higher CYP2A6 activity results in the smoker extracting more nicotine (adjusting for cigarettes per day) and being exposed to higher levels of tobacco-specific nitrosamine [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)] and pyrene, a representative polycyclic aromatic hydrocarbon. We conducted a cross-sectional study of 585 smokers among the three main ethnic/racial groups in Hawaii and examined whether differences in CYP2A6 activity correlate with the ethnic/racial differences in lung cancer risk. We assessed CYP2A6 activity by nicotine metabolite ratio (total trans-3-hydroxycotinine/total cotinine) and caffeine metabolite ratio (1,7-dimethyl uric acid/1,7-dimethylxanthine) in 12 h urine. We also measured urinary nicotine equivalents (sum of nicotine, cotinine, and trans-3-hydroxycotinine and their respective glucuronides), a marker of nicotine dose, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronide, markers of NNK exposure, and 1-hydroxypyrene, a marker of pyrene exposure. The nicotine metabolite ratio was higher in Whites than in Japanese and intermediate in Hawaiians (P values < 0.05). Cigarettes per day-adjusted nicotine equivalents were lower in Japanese compared with Hawaiians or Whites (P = 0.005 and P < 0.0001, respectively) and greater in men than women (P < 0.0001). Nicotine equivalents and total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol increased with CYP2A6 activity, indicating that smokers with greater nicotine metabolism smoke more extensively and have a higher internal NNK dose. The particularly low nicotine metabolism of Japanese smokers may contribute to their previously described decreased lung cancer risk. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3526–35)

Genetic variation in the bioactivation pathway for polycyclic hydrocarbons and heterocyclic amines in relation to risk of colorectal neoplasia

Animal work implicates chemical carcinogens, such as polycyclic aromatic hydrocarbons (PAHs) and heterocyclic aromatic amines (HAAs) as contributing to the development of colorectal cancer (CRC). The epidemiologic evidence, however, remains inconsistent possibly due to intra-individual variation in bioactivation of these compounds. We conducted a case-control study of colorectal adenoma (914 cases, 1185 controls) and CRC (496 cases, 607 controls) among Japanese Americans, European Americans and Native Hawaiians to investigate the association of genetic variation in the PAH and HAA bioactivation pathway (CYP1A1, CYP1A2, CYP1B1, AHR and ARNT) identified through sequencing with risk of colorectal neoplasia, as well as their interactions with smoking and intakes of red meat and HAAs. The A allele for ARNT rs12410394 was significantly inversely associated with CRC [odds ratios (ORs) and 95% confidence intervals (CIs) for GG, AG and AA genotypes: 1.00, 0.66 (0.48-0.89), 0.54 (0.37-0.78), P(trend) = 0.0008] after multiple comparison adjustment. CYP1A2 rs11072508 was marginally significantly associated with CRC, where each copy of the T allele was associated with reduced risk (OR: 0.72, 95% CI: 0.58-0.88, P(trend) = 0.0017). No heterogeneity of genetic effects across racial/ethnic groups was detected. In addition, no significant interaction was observed after adjusting for multiple testing between genetic variants and pack-years of smoking, intake of red meat or HAAs (PhIP, MeIQx, Di-MeIQx or total HAAs) or NAT2 genotype (Rapid versus Slow or Intermediate). This study suggests that the genomic region around ARNT rs12410394 may harbor variants associated with CRC.

Plasma sex hormone concentrations and breast cancer risk in an ethnically diverse population of postmenopausal women: the Multiethnic Cohort Study

To add to the existing evidence that comes mostly from White populations, we conducted a nested case-control study to examine the association between sex hormones and breast cancer risk within the Multiethnic Cohort that includes Japanese American, White, Native Hawaiian, African American, and Latina women. Of the postmenopausal women for whom we had a plasma sample, 132 developed breast cancer during follow-up. Two controls per case, matched on study area (Hawaii, Los Angeles), ethnicity/race, birth year, date and time of blood draw and time fasting, were randomly selected from the women who had not developed breast cancer. Levels of estradiol (E(2)), estrone (E(1)), androstenedione, dehydroepiandrosterone (DHEA), and testosterone were quantified by RIA after organic extraction and Celite column partition chromatography. E(1) sulfate, DHEA sulfate (DHEAS), and sex hormone-binding globulin (SHBG) were quantified by direct immunoassays. Based on conditional logistic regression, the sex hormones were positively associated and SHBG was negatively associated with breast cancer risk. All associations, except those with DHEAS and testosterone showed a significant linear trend. The odds ratio (OR) associated with a doubling of E(2) levels was 2.26 (95% confidence interval (CI) 1.58-3.25), and the OR associated with a doubling of testosterone levels was 1.34 (95% CI 0.98-1.82). The associations in Japanese American women, who constituted 54% of our sample, were similar to or nonsignificantly stronger than in the overall group. This study provides the best evidence to date that the association between sex hormones and breast cancer risk is generalizable to an ethnically diverse population.

Type 2 diabetes risk variants and colorectal cancer risk: the Multiethnic Cohort and PAGE studies

Background Diabetes has been positively associated with the risk of colorectal cancer. This study investigated whether recently established risk variants for diabetes also have effects on colorectal cancer. Methods 19 single nucleotide repeats (SNPs) associated with type 2 diabetes in genome-wide association studies were tested in a case–control study of 2011 colorectal cancer cases and 6049 controls nested in the Multiethnic Cohort study as part of the Population Architecture using Genomics and Epidemiology (PAGE) initiative. ORs and 95% CIs were estimated by unconditional logistic regression to evaluate the association between SNPs and colorectal cancer risk, adjusting for age, sex and race/ethnicity. Permutation testing was conducted to correct for multiple hypothesis testing. Results Four type 2 diabetes SNPs were associated with colorectal cancer risk: rs7578597 (THADA), rs864745 (JAZF1), rs5219 (KCNJ11) and rs7961581 (TSPAN8, LGR5). The strongest association was for the rs7578597 (THADA) Thr1187Ala missense polymorphism (Ptrend=0.004 adjusted for multiple testing), with the high risk allele for colorectal cancer being the low risk allele for diabetes. Similar patterns of associations were seen with further adjustment for diabetes status and body mass index. The association of diabetes status with colorectal cancer risk was somewhat weakened after adjustment for these SNPs. Conclusion The findings suggest that diabetes risk variants also influence colorectal cancer susceptibility, possibly through mechanisms different from those for diabetes.

Exposure to the carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in smokers from 3 populations with different risks of lung cancer.

Native Hawaiian smokers are at higher risk and Japanese‐American smokers at lower risk of lung cancer (LC), compared with white smokers, even after accounting for smoking history. Because variation in carcinogen exposure/metabolism may occur separately of smoking amount, we compared urinary biomarkers of uptake and detoxification of 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone (NNK)—a potent lung carcinogen—among 578 smokers in these ethnic/racial groups in Hawaii. We measured the NNK metabolite 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanol (NNAL) and its glucuronide (NNAL‐Gluc) and examined total NNAL (NNAL + NNAL‐Gluc) and the NNAL detoxification ratio (NNAL‐Gluc:NNAL). Native Hawaiians and Japanese–Americans had lower age‐ and sex‐adjusted mean total NNAL, compared with whites. When further adjusting for urinary nicotine equivalents (the sum of nicotine, cotinine, trans‐3′‐hydroxycotinine and their respective glucuronides), only the difference between Japanese–Americans and whites was eliminated. Therefore, consistent with their lower LC risk, a lower cigarette smoke exposure explains the lower NNK dose of Japanese–Americans, but it does not explain that of Native Hawaiians. The mean detoxification ratio was also lower in Native Hawaiians and Japanese–Americans, compared with whites, even after adjusting for nicotine equivalents (p < 0.0001). Lower NNAL glucuronidation in Native Hawaiians might contribute to their increased LC risk; however, this is inconsistent with the low glucuronidation ratio similarly observed in the low‐risk Japanese‐American group and because Native Hawaiians had lower total NNAL levels. Thus, exposure and detoxification of NNK are unlikely to explain, by themselves, the differences in LC risk among the 3 populations studied.

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

Objective Genome-wide association studies 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 hypothesised 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. Design We examined 13 338 colorectal cancer cases and 40 967 controls from three consortia: Population Architecture using Genomics and Epidemiology (PAGE), Genetic Epidemiology of Colorectal Cancer (GECCO), and the Colon Cancer Family Registry (CCFR). Study-specific logistic regression results, adjusted for age, sex, principal components of genetic ancestry, and/or study specific factors (as relevant) were combined using fixed-effect meta-analyses to evaluate the association between each SNP and colorectal cancer risk. A Bonferroni-corrected p value of 2.92×10−4 was used to determine statistical significance of the associations. Results Two correlated SNPs—rs10090154 and rs4242382—in Region 1 of chromosome 8q24, a prostate cancer susceptibility region, demonstrated statistically significant associations with colorectal cancer risk. The most significant association was observed with rs4242382 (meta-analysis OR=1.12; 95% CI 1.07 to 1.18; p=1.74×10−5), which also demonstrated similar associations across racial/ethnic populations and anatomical sub-sites. Conclusions This is the first study to clearly demonstrate Region 1 of chromosome 8q24 as a susceptibility locus for colorectal cancer; thus, adding colorectal cancer to the list of cancer sites linked to this particular multicancer risk region at 8q24.

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

Background Genome-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. Methods We 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. Results The 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. Conclusions Our findings demonstrate a novel pleiotropic association between the breast cancer LSP1 risk region marked by variant rs3817198 and lung cancer risk.

Plasma Coenzyme Q10 Levels and Postmenopausal Breast Cancer Risk: The Multiethnic Cohort Study

Background: 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. Methods: 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. Results: 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). Conclusions: Higher CoQ10 levels in postmenopausal women may be associated with increased breast cancer risk. Impact: 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. Cancer Epidemiol Biomarkers Prev; 19(9); 2351–6. ©2010 AACR.

Susceptibility variants for obesity and colorectal cancer risk: The multiethnic cohort and PAGE studies

Obesity is a leading contributor to colorectal cancer risk. We investigated whether the risk variants identified in genome‐wide association studies of body mass index (BMI) and waist size are associated with colorectal cancer risk, independently of the effect of obesity phenotype due to a shared etiology. Twenty‐four single nucleotide polymorphisms (SNPs) in 15 loci (BDNF, FAIM2, FTO, GNPDA2, KCTD15, LYPLAL1, MC4R, MSRA, MTCH2, NEGR1, NRXN3, SEC16B, SH2B1, TFAP2B and TMEM18) were genotyped in a case–control study of 2,033 colorectal cancer cases and 9,640 controls nested within the multiethnic cohort study, as part of the population architecture using genomics and epidemiology consortium. Risk alleles for two obesity SNPs were associated with colorectal cancer risk—KCTD15 rs29941 [odds ratio (OR) for C allele = 0.90, 95% confidence interval (CI) 0.83–0.98; p = 0.01] and MC4R rs17782313 (OR for C allele = 1.12, 95% CI 1.02–1.22; p = 0.02). These associations were independent of the effect of BMI. However, none of the results remained significant after adjustment for multiple comparisons. No heterogeneity was observed across race/ethnic groups. Our findings suggest that the obesity risk variants are not likely to affect the risk of colorectal cancer substantially.

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 approximately 16% of all incident cancers in the United States. Although 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 National Human Genome Research Institute (NHGRI) Population Architecture using Genomics and Epidemiology (PAGE) study, we used data from the Multiethnic Cohort (MEC) and Womens Health Initiative (WHI). Incident MPC (IMPC) cases (n = 1,385) were defined as participants diagnosed with more than one incident cancer 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 associations between 188 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% confidence interval (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 ≤ 0.046). These associations did not show significant heterogeneity by smoking status (Pheterogeneity ≥ 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. Cancer Epidemiol Biomarkers Prev; 23(11); 2568–78. ©2014 AACR.