Exposure to outdoor ambient air toxics and risk of breast cancer: The multiethnic cohort.

BACKGROUND: A growing literature has reported associations between traffic-related air pollution and breast cancer, however there are fewer investigations into specific ambient agents and any putative risk of breast cancer development, particularly studies occurring in populations residing in higher pollution areas such as Los Angeles. OBJECTIVES: To estimate breast cancer risks related to ambient air toxics exposure at residential addresses. METHODS: We examined the relationships between ambient air toxics and breast cancer risk in the Multiethnic Cohort among 48,665 California female participants followed for cancer from 2003 through 2013. We obtained exposure data on chemicals acting as endocrine disruptors or mammary gland carcinogens from the National-Scale Air Toxics Assessment. Cox proportional hazards models were used to estimate breast cancer risk per one interquartile range (IQR) increase in air toxics exposure lagged by 5-years. Stratified analyses were conducted by race, ethnicity, and hormone receptor types. RESULTS: Among all women, increased risks of invasive breast cancer were observed with toxicants related to industries [1,1,2,2-tetrachloroethane (hazard ratio [HR] = 4.22, 95% confidence interval [95% CI] 3.18-5.60), ethylene dichloride (HR = 2.81, 95% CI 2.20-3.59), and vinyl chloride (HR = 2.27, 95% CI 1.81, 2.85); these 3 agents were correlated (r2 = 0.45-0.77)]. Agents related to gasoline production or combustion were related to increased breast cancer risk [benzene (HR = 1.32, 95% CI 1.24, 1.41), ethylbenzene (HR = 1.20, 95% CI 1.13-1.28), toluene (HR = 1.29, 95% CI 1.20-1.38), naphthalene (HR = 1.11, 95% CI 1.02-2.22), acrolein (HR = 2.26, 95% CI 1.92, 2.65)]. Higher hazard ratios were observed in African Americans and Whites compared to other racial and ethnic groups (p-heterogeneity <0.05 for traffic-related air toxics, acrolein, and vinyl acetate). CONCLUSIONS: Our findings suggest that specific toxic air pollutants may be associated with increase breast cancer risk.

Variation in patterns of second primary malignancies across U.S. race and ethnicity groups: a Surveillance, Epidemiology, and End Results (SEER) analysis.

PURPOSE: One in six incident cancers in the U.S. is a second primary cancer (SPC). Although primary cancers vary considerably by race and ethnicity, little is known about the population-based occurrence of SPC across these groups. METHODS: Using Surveillance, Epidemiology, and End Results (SEER) 12 data and relative to the general population, we calculated standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for SPC among 2,457,756 Hispanics, non-Hispanic Asian American/Pacific Islanders (NHAAPI), non-Hispanic black (NHB), and non-Hispanic whites (NHW) cancer survivors aged 45 years or older when diagnosed with a first primary cancer (FPC) from 1992 to 2015. RESULTS: The risk of second primary bladder cancer after first primary prostate cancer was higher than expected in Hispanic (SIR = 1.18, 95% CI: 1.01-1.38) and NHAAPI (SIR = 1.41, 95% CI: 1.20-1.65) men than NHB and NHW men. Among women with a primary breast cancer, Hispanic, NHAAPI, and NHB women had a nearly 1.5-fold higher risk of a second primary breast cancer, while NHW women had a 6% lower risk. Among men with prostate cancer whose SPC was diagnosed 2 to <12 months, NHB men were at higher risk for colorectal cancer and Hispanic and NHW men for non-Hodgkin's lymphoma. In the same time frame for breast cancer survivors, Hispanic and NHAAPI women were significantly more likely than NHB and NHW women to be diagnosed with a second primary lung cancer. CONCLUSION: Future studies of SPC should investigate the role of shared etiologies, stage of diagnosis, treatment, and lifestyle factors after cancer survival across different racial and ethnic populations.

Tobacco biomarkers and genetic/epigenetic analysis to investigate ethnic/racial differences in lung cancer risk among smokers.

The Multiethnic Cohort Study has demonstrated that African Americans and Native Hawaiians have a higher risk for lung cancer due to cigarette smoking than Whites while Latinos and Japanese Americans have a lower risk. These findings are consistent with other epidemiologic studies in the literature. In this review, we summarize tobacco carcinogen and toxicant biomarker studies and genetic analyses which partially explain these differences. As determined by measurement of total nicotine equivalents in urine, which account for about 85% of the nicotine dose, African Americans take up greater amounts of nicotine than Whites per cigarette while Japanese Americans take up less. There are corresponding differences in the uptake of tobacco smoke carcinogens such as tobacco-specific nitrosamines, polycyclic aromatic hydrocarbons, 1,3-butadiene, and other toxic volatiles. The lower nicotine uptake of Japanese Americans is clearly linked to the preponderance of low activity forms of the primary nicotine metabolizing enzyme CYP2A6 in this ethnic group, leading to more unchanged nicotine in the body and thus lower smoking intensity. But the relatively high risk of Native Hawaiians and the low risk of Latino smokers for lung cancer are not explained by these factors. The possible role of epigenetics in modifying lung cancer risk among smokers is also discussed here. The results of these published studies may lead to a better understanding of susceptibility factors for lung cancer in cigarette smokers thus potentially identifying biomarkers that can detect those individuals at highest risk so that preventive approaches can be initiated at an early stage of the lung cancer development process.

Racial/ethnic differences in lifestyle-related factors and prostate cancer risk: the Multiethnic Cohort Study.

PURPOSE: Older age, African ancestry, and family history of prostate cancer are well-established risk factors for prostate cancer, and all are non-modifiable. Various lifestyle factors have been examined in relation to prostate cancer risk, including diet, obesity, and physical activity; however, none of them has been consistently related to risk. In the Multiethnic Cohort Study, we investigated whether lifestyle-related factors are associated with prostate cancer risk and whether such factors explain the racial/ethnic differences in risk. METHODS: During a mean follow-up of 13.9 years, 7,115 incident cases were identified among 75,216 white, African-American, Native Hawaiian, Japanese American, and Latino men. Cox proportional hazards models were used to calculate relative risks (RRs) and 95 % confidence intervals (95 % CIs) for prostate cancer. RESULTS: Among selected lifestyle-related factors including body mass index, height, education, physical activity, and intakes of alcohol, calcium, legumes, lycopene, and selenium, only smoking (RR for current (≥20 cigarettes/day) vs. never smoking = 0.72; 95 % CI 0.63-0.83) and history of diabetes (RR for yes vs. no = 0.78; 95 % CI 0.72-0.85) were significantly associated with prostate cancer risk. Compared to whites, the risk of incident prostate cancer was twofold higher in African-Americans and 16 % higher in Latinos. Additional adjustment for a history of PSA testing did not change the results. CONCLUSIONS: The findings suggest that racial/ethnic differences in prostate cancer risk are not explained by the lifestyle factors examined and that underlying genetic factors may be involved.

1,3-Butadiene exposure and metabolism among Japanese American, Native Hawaiian, and White smokers.

BACKGROUND: We hypothesize that the differences in lung cancer risk in Native Hawaiians, whites, and Japanese Americans may, in part, be due to variation in the metabolism of 1,3-butadiene, one of the most abundant carcinogens in cigarette smoke. METHODS: We measured two biomarkers of 1,3-butadiene exposure, monohydroxybutyl mercapturic acid (MHBMA) and dihydroxybutyl mercapturic acid (DHBMA), in overnight urine samples among 584 Native Hawaiians, Japanese Americans, and white smokers in Hawaii. These values were normalized to creatinine levels. Ethnic-specific geometric means were compared adjusting for age at urine collection, sex, body mass index, and nicotine equivalents (a marker of total nicotine uptake). RESULTS: We found that mean urinary MHBMA differed by race/ethnicity (P = 0.0002). The values were highest in whites and lowest in Japanese Americans. This difference was only observed in individuals with the GSTT1-null genotype (P = 0.0001). No difference across race/ethnicity was found among those with at least one copy of the GSTT1 gene (P ≥ 0.72). Mean urinary DHBMA did not differ across racial/ethnic groups. CONCLUSIONS: The difference in urinary MHBMA excretion levels from cigarette smoking across three ethnic groups is, in part, explained by the GSTT1 genotype. Mean urinary MHBMA levels are higher in whites among GSTT1-null smokers. IMPACT: The overall higher excretion levels of MHBMA in whites and lower levels of MHBMA in Japanese Americans are consistent with the higher lung cancer risk in the former. However, the excretion levels of MHBMA in Native Hawaiians are not consistent with their disease risk and thus unlikely to explain their high risk of lung cancer.

Pleiotropy of cancer susceptibility variants on the risk of non-Hodgkin lymphoma: the PAGE consortium.

BACKGROUND: Risk of non-Hodgkin lymphoma (NHL) is higher among individuals with a family history or a prior diagnosis of other cancers. Genome-wide association studies (GWAS) have suggested that some genetic susceptibility variants are associated with multiple complex traits (pleiotropy). OBJECTIVE: We investigated whether common risk variants identified in cancer GWAS may also increase the risk of developing NHL as the first primary cancer. METHODS: As part of the Population Architecture using Genomics and Epidemiology (PAGE) consortium, 113 cancer risk variants were analyzed in 1,441 NHL cases and 24,183 controls from three studies (BioVU, Multiethnic Cohort Study, Women's Health Initiative) for their association with the risk of overall NHL and common subtypes [diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL)] using an additive genetic model adjusted for age, sex and ethnicity. Study-specific results for each variant were meta-analyzed across studies. RESULTS: The analysis of NHL subtype-specific GWAS SNPs and overall NHL suggested a shared genetic susceptibility between FL and DLBCL, particularly involving variants in the major histocompatibility complex region (rs6457327 in 6p21.33: FL OR=1.29, p=0.013; DLBCL OR=1.23, p=0.013; NHL OR=1.22, p=5.9 × E-05). In the pleiotropy analysis, six risk variants for other cancers were associated with NHL risk, including variants for lung (rs401681 in TERT: OR per C allele=0.89, p=3.7 × E-03; rs4975616 in TERT: OR per A allele=0.90, p=0.01; rs3131379 in MSH5: OR per T allele=1.16, p=0.03), prostate (rs7679673 in TET2: OR per C allele=0.89, p=5.7 × E-03; rs10993994 in MSMB: OR per T allele=1.09, p=0.04), and breast (rs3817198 in LSP1: OR per C allele=1.12, p=0.01) cancers, but none of these associations remained significant after multiple test correction. CONCLUSION: This study does not support strong pleiotropic effects of non-NHL cancer risk variants in NHL etiology; however, larger studies are warranted.

Tobacco smoking, NBS1 polymorphisms, and survival in lung and upper aerodigestive tract cancers with semi-Bayes adjustment for hazard ratio variation.

PURPOSE: Although single nucleotide polymorphisms (SNPs) of NBS1 have been associated with susceptibility to lung and upper aerodigestive tract (UADT) cancers, their relations to cancer survival and measures of effect are largely unknown. METHODS: Using follow-up data from 611 lung cancer cases and 601 UADT cancer cases from a population-based case-control study in Los Angeles, we prospectively evaluated associations of tobacco smoking and 5 NBS1 SNPs with all-cause mortality. Mortality data were obtained from the Social Security Death Index. We used Cox regression to estimate adjusted hazard ratios (HR) for main effects and ratios of hazard ratios (RHR) derived from product terms to assess hazard ratio variations by each SNP. Bayesian methods were used to account for multiple comparisons. RESULTS: We observed 406 (66 %) deaths in lung cancer cases and 247 (41 %) deaths in UADT cancer cases with median survival of 1.43 and 1.72 years, respectively. Ever tobacco smoking was positively associated with mortality for both cancers. We observed an upward dose-response association between smoking pack-years and mortality in UADT squamous cell carcinoma. The adjusted HR relating smoking to mortality in non-small cell lung cancer (NSCLC) was greater for cases with the GG genotype of NBS1 rs1061302 than for cases with AA/AG genotypes (semi-Bayes adjusted RHR = 1.97; 95 % limits = 1.14, 3.41). CONCLUSIONS: A history of tobacco smoking at cancer diagnosis was associated with mortality among patients with lung cancer or UADT squamous cell carcinoma. The HR relating smoking to mortality appeared to vary with the NBS1 rs1061302 genotype among NSCLC cases.

Genetic variation at 8q24, family history of cancer, and upper gastrointestinal cancers in a Chinese population.

Genetic variation at 8q24 is associated with prostate, bladder, breast, colorectal, thyroid, lung, ovarian, UADT, liver and stomach cancers. However, a role for variation at 8q24 in familial clustering of upper gastrointestinal cancers has not been studied. In order to explore potential inherited susceptibility, we analyzed epidemiologic data from a population-based case-control study of upper gastrointestinal cancers from Taixing, China. The study population includes 204 liver, 206 stomach, and 218 esophageal cancer cases and 415 controls. Associations between 8q24 rs1447295, rs16901979, rs6983267 and these cancers were stratified by family history of cancer. Odds ratios and 95% confidence intervals were adjusted for potential confounders: age, sex, education, tobacco smoking, alcohol consumption, and BMI at interview. We also adjusted for hepatitis B and aflatoxin (liver cancer) and Helicobacter pylori (stomach cancer). In a dominant model, among those with a family history of cancer, rs1447295 was positively associated with liver cancer (OR(adj) 2.80; 95% CI 1.15-6.80). Heterogeneity was observed (P(heterogeneity) = 0.029) with rs6983267 and liver cancer, with positive association in the dominant model among those with a family history of cancer and positive association in the recessive model among those without a family history of cancer. When considered in a genetic risk score model, each additional 8q24 risk genotype increased the odds of liver cancer by two-fold among those with a family history of cancer (OR(adj) 2.00; 95% CI 1.15-3.47). These findings suggest that inherited susceptibility to liver cancer may exist in the Taixing population and that variation at 8q24 might be a genetic component of that inherited susceptibility.

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.

Association of the FTO obesity risk variant rs8050136 with percentage of energy intake from fat in multiple racial/ethnic populations: the PAGE study.

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 (ßmeta = 0.2244 (standard error, 0.0548); P = 4 × 10(-5)) and inversely associated with percentage of calories derived from carbohydrate (ßmeta = -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/m(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.

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.

Risk factors for malignant melanoma in white and non-white/non-African American populations: the multiethnic cohort.

It is unknown whether the established risk factors for malignant melanoma in whites influence malignant melanoma risk in non-whites. We examined the risk factors for melanoma among 39,325 whites and 101,229 non-whites/multiracials [Japanese American (47.5%), Latino American (34.8%), Native Hawaiian (2.1%), and multiracial (15.6%), excluding African Americans] in the Multiethnic Cohort study. With an average follow-up of 12.7 years, 581 invasive malignant melanoma (IMM) and 412 melanoma in situ (MIS) cases were identified, of which 107 IMM and 74 MIS were among non-whites/multiracials. The relative risks (RR) and 95% confidence intervals (CI) were estimated by Cox proportional hazards models using days from cohort entry as the underlying time variable. Among non-white/multiracial males, location of IMM tumors differed from those of white males (P < 0.001); and non-white/multiracial females were more likely to be diagnosed with later stage of disease (P < 0.001). After adjusting for potential confounders, age at cohort entry, male sex, higher education, and sunburn susceptibility phenotypes were associated with an increased risk of IMM in non-whites/multiracials (P < 0.05). The risk estimates for age at cohort entry and lighter hair and eye color were greater in non-whites/multiracials than in whites (P(heterogeneity) = 0.062, 0.016, and 0.005, respectively). For MIS risk, RRs between whites and non-whites/multiracials also differed for study location and education (P(heterogeneity) ≤ 0.015). In conclusion, similar to whites, age at cohort entry, male sex, and susceptibility to sunburn phenotypes may be predictive of malignant melanoma risk in non-white populations excluding African Americans.

Body mass index change in adulthood and lung and upper aerodigestive tract cancers.

Body mass index (BMI) has been inversely associated with lung and upper aerodigestive tract (UADT) cancers. However, only a few studies have assessed BMI change in adulthood in relation to cancer. To understand the relationship between BMI change and these cancers in both men and women, we analyzed data from a population-based case-control study conducted in Los Angeles County. Adulthood BMI change was measured as the proportional change in BMI between age 21 and 1 year before interview or diagnosis. Five categories of BMI change were included, and individuals with no more than a 5% loss or gain were defined as having a stable BMI (reference group). Adjusted odds ratios (ORs) and their 95% confidence intervals (CIs) were estimated using logistic regression models. Potential confounders included age, gender, ethnicity, education, tobacco smoking and energy intake. For UADT cancers, we also adjusted for alcohol drinking status and frequency. A BMI gain of 25% or higher in adulthood was inversely associated with lung cancer (OR 0.53, 95% CI 0.33-0.84) and UADT cancers (OR 0.44, 95% CI 0.27-0.71). In subgroup analyses, a BMI gain of ≥25% was inversely associated with lung and UADT cancers among current and former smokers, as well as among current and former alcohol drinkers. The inverse association persisted among moderate and heavy smokers (≥20 pack-years). The observed inverse associations between adulthood BMI gain and lung and UADT cancers indicate a potential role for body weight-related biological pathways in the development of lung and UADT cancers.

Serum insulin-like growth factor-I and insulin-like growth factor binding protein-3 levels with risk of malignant melanoma.

We examined the relationship of insulin-like growth factor-I (IGF-I) and its primary growth factor, IGF binding protein-3 (IGFBP-3) with malignant melanoma using interview data and sera from cases (n = 286) and controls (n = 289) in a population-based case-control study conducted in 1986-1992 on Oahu, Hawaii. Serum IGF-I and IGFBP-3 concentrations were measured by ELISA. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression and adjusting for age, sex, education, number of blistering sunburns, ability to tan, hair color, energy intake, BMI, height, smoking status, and drinking status. An inverse relationship was found between IGF-I concentration and melanoma (OR for upper vs. lower tertile: 0.44, 95% CI: 0.25-0.79), but clear associations were not observed between malignant melanoma and upper tertiles of IGFBP-3 and the IGF-1/IGFBP-3 molar ratio. The inverse association with IGF-I was strongest among subjects who did not report a history of non-melanoma skin cancer (NMSC) (OR for ≥ vs. < median: 0.39, 95% CI: 0.24-0.65), and a positive association was found among those with such a history (OR: 3.6, 95% CI: 1.0-13; p (interaction) = 0.0035). Our findings observed here between serum IGF-I and malignant melanoma warrants replication in studies with a larger sample size and a prospective design.

The association between change in body mass index and upper aerodigestive tract cancers in the ARCAGE project: multicenter case-control study.

Previous studies reported an inverse relationship between body mass index (BMI) and upper aerodigestive tract (UADT) cancers. Examining change in BMI over time may clarify these previous observations. We used data from 2,048 cases and 2,173 hospital- and population-based controls from ten European countries (alcohol-related cancers and genetic susceptibility in Europe study) to investigate the relationship with BMI and adult change in BMI on UADT cancer risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for associations between BMI at three time intervals and BMI change on UADT cancer development, adjusting for center, age, sex, education, fruit and vegetable intake, smoking and alcohol consumption. We found an inverse relationship between UADT cancers and BMI at time of interview and 2 years before interview. No association was found with BMI at 30 years of age. Regarding BMI change between age 30 and 2 years before interview, BMI decrease (BMI change <-5%) vs. BMI stability (-5% ≤ BMI change <5%) showed no overall association with UADT cancers (OR = 1.15; 95% CI = 0.89, 1.49). An increase in BMI (BMI change ≥+5%) was inversely associated with UADT cancers (OR = 0.74; 95% CI = 0.62, 0.89). BMI gain remained inversely associated across all subsites except for esophageal cancer. When stratified by smoking or by drinking, association with BMI gain was detected only in drinkers and smokers. In conclusion, BMI gain is inversely associated with UADT cancers. These findings may be influenced by smoking and/or drinking behaviors and/or the development of preclinical UADT cancers and should be corroborated in studies of a prospective nature.

Single nucleotide polymorphisms of 8 inflammation-related genes and their associations with smoking-related cancers.

Tobacco smoke and its metabolites are carcinogens that increase tissue oxidative stress and induce target tissue inflammation. We hypothesized that genetic variation of inflammatory pathway genes plays a role in tobacco-related carcinogenesis and is modified by tobacco smoking. We evaluated the association of 12 single nucleotide polymorphisms of 8 inflammation-related genes with tobacco-related cancers (lung, oropharynx, larynx, esophagus, stomach, liver, bladder, and kidney) using 3 case-control studies from: Los Angeles (population-based; 611 lung and 553 upper aero-digestive tract cancer cases and 1,040 controls), Taixing, China (population-based; 218 esophagus, 206 stomach, 204 liver cancer cases, and 415 controls), and Memorial Sloan-Kettering Cancer Center (hospital-based; 227 bladder cancer cases and 211 controls). After adjusting for age, education, ethnicity, gender, and tobacco smoking, IL10 rs1800871 was inversely associated with oropharyngeal cancer (CT+TT vs. CC adjusted odds ratio [aOR]: 0.69, 95% confidence interval [CI]: 0.50-0.95), and was positively associated with lung cancer among never smokers (TT vs. CT+CC aOR: 2.5, 95% CI: 1.3-5.1) and inversely with oropharyngeal cancer among ever smokers (CT+TT vs. CC aOR: 0.63, 95% CI: 0.41-0.95). Among all pooled never smokers (588 cases and 816 controls), TNF rs1799964 was inversely associated with smoking-related cancer (CC vs. CT+TT aOR: 0.36, 95% CI: 0.17-0.77). Bayesian correction for multiple comparisons suggests that chance is unlikely to explain our findings (although epigenetic mechanisms may be in effect), which support our hypotheses, suggesting that IL10 rs1800871 is a susceptibility marker for oropharyngeal and lung cancers, and that TNF rs1799964 is associated with smoking-related cancers among never smokers.

Body size, adult BMI gain and endometrial cancer risk: the multiethnic cohort.

The effect of body size and change in BMI on endometrial cancer risk across different racial/ethnic groups has not been studied. We examined the association between body size and endometrial cancer risk and potential effect modification of other risk factors among 50,376 women in the Multiethnic Cohort Study. During 10.3 years of follow-up, 463 endometrial cancer cases were identified. Epidemiologic data were collected from the baseline questionnaire. "BMI change" was defined as the percentage of body mass index change from age 21 to the time of recruitment. Women who were heavier at age 21 or at baseline (weight > or = 53.5 kg or > or = 63.9 kg, respectively) had an increased endometrial cancer risk compared to the lowest quartile of weight during the respective periods. BMI gain > or = 35% had a RR of 4.12 (95% CI: 2.69, 6.30) compared to the reference group (-5% < or = BMI change <+5%). Women who averaged an annual BMI gain > or = 1% had a >3.21-fold (95% CI: 2.37, 4.33) increased risk compared to women who maintained a stable adult BMI (-0.25 to <+0.25%). The highest risk associated with BMI gain was observed among nulliparous women and postmenopausal women who never used hormone therapy. Although African Americans and Whites showed an increase in risk after > or =35% BMI gain, Japanese Americans showed an increase in risk with much smaller gain (> or =5%). In conclusion, adult obesity and increase in adiposity are risk factors for endometrial cancer; and the risk associated with these factors may vary across racial/ethnic groups.

Genetic variation in immune regulation and DNA repair pathways and stomach cancer in China.

The incidence of stomach cancer is high in certain parts of the world, particularly in China. Chronic Helicobacter pylori infection is the main risk factor, yet the vast majority of infected individuals remain unaffected with cancer, suggesting an important role of other risk factors. We conducted a population-based case-control study including 196 incident stomach cancer cases and 397 matched controls to test the hypothesis that adverse single nucleotide polymorphism (SNP) genotypes and haplotypes within genes of the DNA repair and immune regulatory pathways are associated with increased stomach cancer risk. Genomic DNA isolated from blood samples was used for genotyping, and results were obtained for 57 putatively functional SNPs in 28 genes. Odds ratios (OR) and 95% confidence intervals (95% CI) were obtained from adjusted logistic regression models. For PTGS2, a gene involved in the inflammatory response, associations with stomach cancer risk were observed for TC genotype carriers of rs5279 (OR, 0.24; 95% CI, 0.08-0.73), CT genotype carriers of the 3'-untranslated region SNP rs689470 (OR, 7.49; 95% CI, 1.21-46.20), and CTTC haplotype carriers of rs5277, rs5278, rs5279, and rs689470 (OR, 0.41; 95% CI, 0.18-0.95). For ERCC5, a gene involved in nucleotide excision repair, TC genotype carriers of rs1047768 (OR, 0.65; 95% CI, 0.41-1.03), GC genotype carriers of the nonsynonymous SNP rs2227869 (OR, 0.30; 95% CI, 0.13-0.67), and CCG haplotype carriers of rs1047768, rs17655, and rs2227869 (OR, 0.45; 95% CI, 0.20-1.04) were associated with reduced stomach cancer risk. In conclusion, PTGS2 and ERCC5 were associated with stomach cancer risk in a Chinese population.

Associations between variants of the 8q24 chromosome and nine smoking-related cancer sites.

Recent genome-wide association studies identified key single nucleotide polymorphisms (SNPs) in the 8q24 region to be associated with prostate cancer. 8q24 SNPs have also been associated with colorectal cancer, suggesting that this region may not be specifically associated to just prostate cancer. To date, the association between these polymorphisms and tobacco smoking-related cancer sites remains unknown. Using epidemiologic data and biological samples previously collected in three case-control studies from U.S. and Chinese populations, we selected and genotyped one SNP from each of the three previously determined "regions" within the 8q24 loci, rs1447295 (region 1), rs16901979 (region 2), and rs6983267 (region 3), and examined their association with cancers of the lung, oropharynx, nasopharynx, larynx, esophagus, stomach, liver, bladder, and kidney. We observed noteworthy associations between rs6983267 and upper aerodigestive tract cancers [adjusted odds ratio (ORadj), 1.69; 95% confidence interval (95% CI), 1.28-2.24], particularly in oropharynx (ORadj, 1.80; 95% CI, 1.30-2.49) and larynx (ORadj, 2.04; 95% CI, 1.12-3.72). We also observed a suggestive association between rs6983267 and liver cancer (ORadj, 1.51; 95% CI, 0.99-2.31). When we stratified our analysis by smoking status, rs6983267 was positively associated with lung cancer among ever-smokers (ORadj, 1.45; 95% CI, 1.05-2.00) and inversely associated with bladder cancer among ever-smokers (ORadj, 0.35; 95% CI, 0.14-0.83). Associations were observed between rs16901979 and upper aerodigestive tract cancer among never-smokers and between rs1447295 and liver cancer among ever-smokers. Our results suggest variants of the 8q24 chromosome may play an important role in smoking-related cancer development. Functional and large epidemiologic studies should be conducted to further investigate the association of 8q24 SNPs with smoking-related cancers.