The epidemiologic evidence from observational studies on breast cancer risk and phthalates, endocrine disrupting chemicals, has been inconsistent. In the only previous study based on pre-diagnostic ...urinary phthalates and risk of breast cancer, results were null in mostly white women.
We examined the association between pre-diagnostic urinary phthalates and breast cancer in a nested case-control study within the Multiethnic Cohort (MEC) study, presenting the first data from five major racial/ethnic groups in the USA. We measured 10 phthalate metabolites and phthalic acid, using a sensitive liquid chromatography mass spectrometry assay on 1032 women with breast cancer (48 African Americans, 77 Latinos, 155 Native Hawaiians, 478 Japanese Americans, and 274 Whites) and 1030 matched controls. Conditional logistic regression was used to examine risk with individual metabolites and ratios of primary (MEHP, mono-2-ethylhexyl-phthalate) to secondary (MEHHP, mono(2-ethyl-5-hydroxyhexyl); MEOHP, mono(2-ethyl-5-oxohexy)) metabolites of di-2-ethylhexyl phthalate (DEHP), a widely used plasticizer. In addition, we investigated risk associations with high (∑HMWP) and low molecular weight (∑LMWP) phthalates, as well as total phthalates which included high and low molecular weight phthalates with phthalic acid (∑LMHMPA) or without phthalic acid in molar ratios (∑LMHM
) and adjusted for creatinine and potential confounders.
Among all women, breast cancer risk was higher for those in tertile 2 and tertile 3 of primary to secondary metabolites of DEHP (MEHP/(MEHHP + MEOHP)) in comparison to those in tertile 1; the respective odds ratios were 1.32 (95% CI 1.04-1.68) and 1.26 (95% CI 0.96-1.66) (P
= 0.05). Risk among Native Hawaiian women increased with exposures to eight of ten individual phthalates and total phthalates (∑LMHMPA OR
= 2.66, 95% CI 1.39-5.12, P
= 0.001). In analysis by hormone receptor (HR) status, exposure above the median of ∑LMWP was associated with an increased risk of HR-positive breast cancer (OR = 1.30, 95% CI 1.05-1.60) while above the median exposure to phthalic acid was associated with an increased risk of HR-negative breast cancer (OR
= 1.59, 95% CI 1.01-2.48).
Further investigations of suggestive associations of elevated breast cancer risk with higher ratios of primary to secondary metabolites of DEHP, and differences in risk patterns by race/ethnicity and HR status are warranted.
The mitochondrial genome encodes for the synthesis of 13 proteins that are essential for the oxidative phosphorylation (OXPHOS) system. Inherited variation in mitochondrial genes may influence cancer ...development through changes in mitochondrial proteins, altering the OXPHOS process, and promoting the production of reactive oxidative species. To investigate the role of the OXPHOS pathway and mitochondrial genes in colorectal cancer (CRC) risk, we tested 185 mitochondrial SNPs (mtSNPs), located in 13 genes that comprise four complexes of the OXPHOS pathway and mtSNP groupings for rRNA and tRNA, in 2,453 colorectal cancer cases and 11,930 controls from the Multiethnic Cohort Study. Using the sequence kernel association test, we examined the collective set of 185 mtSNPs, as well as subsets of mtSNPs grouped by mitochondrial pathways, complexes, and genes, adjusting for age, sex, principal components of global ancestry, and self-reported maternal race/ethnicity. We also tested for haplogroup associations using unconditional logistic regression, adjusting for the same covariates. Stratified analyses were conducted by self-reported maternal race/ethnicity. In European Americans, a global test of all genetic variants of the mitochondrial genome identified an association with CRC risk (P = 0.04). In mtSNP-subset analysis, the NADH dehydrogenase 2 (MT-ND2) gene in Complex I was associated with CRC risk at a P-value of 0.001 (q = 0.015). In addition, haplogroup T was associated with CRC risk (OR = 1.66, 95% CI: 1.19-2.33, P = 0.003). No significant mitochondrial pathway and gene associations were observed in the remaining four racial/ethnic groups--African Americans, Asian Americans, Latinos, and Native Hawaiians. In summary, our findings suggest that variations in the mitochondrial genome and particularly in the MT-ND2 gene may play a role in CRC risk among European Americans, but not in other maternal racial/ethnic groups. Further replication is warranted and future studies should evaluate the contribution of mitochondrial proteins encoded by both the nuclear and mitochondrial genomes to CRC risk.
The mitochondrial genome encodes for thirty-seven proteins, among them thirteen are essential for the oxidative phosphorylation (OXPHOS) system. Inherited variation in mitochondrial genes may ...influence cancer development through changes in mitochondrial proteins, altering the OXPHOS process and promoting the production of reactive oxidative species.
To investigate the association between mitochondrial genetic variation and breast cancer risk, we tested 314 mitochondrial SNPs (mtSNPs), capturing four complexes of the mitochondrial OXPHOS pathway and mtSNP groupings for rRNA and tRNA, in 2,723 breast cancer cases and 3,260 controls from the Multiethnic Cohort Study.
We examined the collective set of 314 mtSNPs as well as subsets of mtSNPs grouped by mitochondrial OXPHOS pathway, complexes, and genes, using the sequence kernel association test and adjusting for age, sex, and principal components of global ancestry. We also tested haplogroup associations using unconditional logistic regression and adjusting for the same covariates. Stratified analyses were conducted by self-reported maternal race/ethnicity. No significant mitochondrial OXPHOS pathway, gene, and haplogroup associations were observed in African Americans, Asian Americans, Latinos, and Native Hawaiians. In European Americans, a global test of all genetic variants of the mitochondrial genome identified an association with breast cancer risk (P = 0.017, q = 0.102). In mtSNP-subset analysis, the gene MT-CO2 (P = 0.001, q = 0.09) in Complex IV (cytochrome c oxidase) and MT-ND2 (P = 0.004, q = 0.19) in Complex I (NADH dehydrogenase (ubiquinone)) were significantly associated with breast cancer risk.
In summary, our findings suggest that collective mitochondrial genetic variation and particularly in the MT-CO2 and MT-ND2 may play a role in breast cancer risk among European Americans. Further replication is warranted in larger populations and future studies should evaluate the contribution of mitochondrial proteins encoded by both the nuclear and mitochondrial genomes to breast cancer risk.
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 ( beta sub(meta) = 0.2244 (standard error, 0.0548); P = 4 10 super(-5)) and inversely associated with percentage of calories derived from carbohydrate ( beta sub(meta) = -0.2796 (standard error, 0.0709); P = 8 10 super(-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) super(2)) obtained at 10 years of follow-up (mediation of effect = 0.0823 kg/m super(2), 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.
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.
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.
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.
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 (P(trend)=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.
The findings suggest that diabetes risk variants also influence colorectal cancer susceptibility, possibly through mechanisms different from those for diabetes.
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.
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).
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 Women's 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.
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).
Our study has identified rs578776 and rs11249433 as risk variants for IMPC.
These findings may help to identify genetic regions associated with IMPC risk.
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.
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