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Background: Racial/ethnic disparities in health reflect a combination of genetic and environmental causes, and DNA methylation may be an important mediator. We compared in an exploratory manner the blood DNA methylome of Japanese Americans (JPA) versus European Americans (EUA)., Methods: Genome-wide buffy coat DNA methylation was profiled among healthy Multiethnic Cohort participant women who were Japanese (JPA; n = 30) or European (EUA; n = 28) Americans aged 60-65. Differentially methylated CpGs by race/ethnicity (DM-CpGs) were identified by linear regression (Bonferroni-corrected P < 0.1) and analyzed in relation to corresponding gene expression, a priori selected single nucleotide polymorphisms (SNPs), and blood biomarkers of inflammation and metabolism using Pearson or Spearman correlations (FDR < 0.1)., Results: We identified 174 DM-CpGs with the majority of hypermethylated in JPA compared to EUA (n = 133), often in promoter regions (n = 48). Half (51%) of the genes corresponding to the DM-CpGs were involved in liver function and liver disease, and the methylation in nine genes was significantly correlated with gene expression for DM-CpGs. A total of 156 DM-CpGs were associated with rs7489665 (SH2B1). Methylation of DM-CpGs was correlated with blood levels of the cytokine MIP1B (n = 146). We confirmed some of the DM-CpGs in the TCGA adjacent non-tumor liver tissue of Asians versus EUA., Conclusion: We found a number of differentially methylated CpGs in blood DNA between JPA and EUA women with a potential link to liver disease, specific SNPs, and systemic inflammation. These findings may support further research on the role of DNA methylation in mediating some of the higher risk of liver disease among JPA., (© 2021. The Author(s).)

Background: Risk variants identified so far for colorectal cancer explain only a small proportion of familial risk of this cancer, particularly in Asians., Methods: We performed a genome-wide association study (GWAS) of colorectal cancer in East Asians, including 23,572 colorectal cancer cases and 48,700 controls. To identify novel risk loci, we selected 60 promising risk variants for replication using data from 58,131 colorectal cancer cases and 67,347 controls of European descent. To identify additional risk variants in known colorectal cancer loci, we performed conditional analyses in East Asians., Results: An indel variant, rs67052019 at 1p13.3, was found to be associated with colorectal cancer risk at P = 3.9 × 10 -8 in Asians ( OR per allele deletion = 1.13, 95% confidence interval = 1.08-1.18). This association was replicated in European descendants using a variant (rs2938616) in complete linkage disequilibrium with rs67052019 ( P = 7.7 × 10 -3 ). Of the remaining 59 variants, 12 showed an association at P < 0.05 in the European-ancestry study, including rs11108175 and rs9634162 at P < 5 × 10 -8 and two variants with an association near the genome-wide significance level (rs60911071, P = 5.8 × 10 -8 ; rs62558833, P = 7.5 × 10 -8 ) in the combined analyses of Asian- and European-ancestry data. In addition, using data from East Asians, we identified 13 new risk variants at 11 loci reported from previous GWAS., Conclusions: In this large GWAS, we identified three novel risk loci and two highly suggestive loci for colorectal cancer risk and provided evidence for potential roles of multiple genes and pathways in the etiology of colorectal cancer. In addition, we showed that additional risk variants exist in many colorectal cancer risk loci identified previously., Impact: Our study provides novel data to improve the understanding of the genetic basis for colorectal cancer risk., (©2019 American Association for Cancer Research.)

Objective: To measure the validity of a quantitative food frequency questionnaire (QFFQ). Design : A cross-sectional validation study of the QFFQ against a four-day food record (4DR) using Spearman correlation, cross-classification, kappa statistics, and Bland-Altman plotting. Setting : The Gastroenterology Department of Kaiser Permanente Hawaii. Subjects: 76 healthy Japanese American men and women, aged 40-75 years. Results : Somewhat stronger average correlations were observed between the QFFQ and the 4DR for macronutrients compared to micronutrients (Spearman rho of 0.47 vs. 0.35). Moderate correlations between the two tools were observed for macronutrients (including saturated fatty acids and dietary fibre), iron, β-carotene, vitamin C, and ethanol ( rho : 0.38-0.58). Overall, stronger correlations were found among men than women between the two tools (mean rho 0.41 vs. 0.26). In a cross classification analysis, for more than 75% of the observations, a complete to relative agreement between the two methods was observed for fat, α-carotene, folate, vitamin D, and ethanol. Sex difference in agreement was minimal in cross-classification (overall extreme misclassification of 9.80% for men and 12.40% for women). Bland-Altman plots showed over-estimations of dietary fibre and α-carotene intake and an under-estimation of cholesterol intake by the QFFQ at high levels of consumption. However, the QFFQ estimation for fat, dietary fibre, folate, cholesterol, α-carotene, vitamins D and C, and ethanol intake was less than 7% different compared to the 4DR. Conclusions: The QFFQ has an adequate validity for fat, folate, vitamin D, and ethanol and can correctly categorize participants for intakes of cholesterol, dietary fibre, α-carotene, and zinc.

Background/objectives: As cocoa products may be protective against chronic disease due to their polyphenol content, the current study determined the association of chocolate consumption and flavanol intake with type-2 diabetes (T2D) incidence in the Multiethnic Cohort (MEC) Study., Subjects/methods: The analysis included 151,691 participants of Native Hawaiian, Japanese American, Latino, African American, and white ancestry with 8487 incident T2D cases after 7.8 ± 3.5 years of follow-up. T2D status was based on three self-reports and confirmed by at least one of three administrative data sources. Dietary intake was assessed using a validated quantitative food frequency questionnaire, and flavanols from cocoa products were estimated from self-reported consumption of chocolate candy and drinks. Cox hazard regression, adjusted for potential confounders was applied to estimate hazard ratios (HR) and 95% confidence intervals (CI)., Results: For chocolate candy, both the highest vs. lowest (≥10 vs. <1 g/day) consumption (HR = 0.90; 95% CI, 0.83-0.97; p trend  = 0.01) and the frequency (≥4/week vs. <1/month) of intake (HR = 0.81; 95% CI, 0.72-0.91; p trend  = 0.0002) were inversely associated with T2D. The estimated flavanol intake from cocoa products (≥3 vs. <1 mg/day) also showed an inverse association with T2D risk (HR = 0.93; 95% CI, 0.88-0.99; p trend  = 0.02). Significant interaction terms indicated that the inverse relation was limited to Japanese Americans, normal-weight individuals, and to those without comorbidities., Conclusions: The current study confirms previous reports that participants with high intake of chocolate products and cocoa-derived flavanols experience a reduced risk of developing T2D even after controlling for sugar intake, diet quality, and other aspects of the diet.

Background & Aims: We compared fat storage in the abdominal region among individuals from 5 different ethnic-racial groups to determine whether fat storage is associated with disparities observed in metabolic syndrome and other obesity-associated diseases., Methods: We collected data from 1794 participants in the Multiethnic Cohort Study (60-77 years old; of African, European [white], Japanese, Latino, or Native Hawaiian ancestry) with body mass index values of 17.1-46.2 kg/m 2 . From May 2013 through April 2016, participants visited the study clinic to undergo body measurements, an interview, and a blood collection. Participants were evaluated by dual-energy x-ray absorptiometry and abdominal magnetic resonance imaging. Among ethnic groups, we compared adiposity of the trunk, intra-abdominal visceral cavity, and liver, adjusting for total fat mass; we evaluated the association of adult weight change with abdominal adiposity; and we examined the prevalence of metabolic syndrome mediated by abdominal adiposity., Results: Relative amounts of trunk, visceral, and liver fat varied significantly with ethnicity-they were highest in Japanese Americans, lowest in African Americans, and intermediate in the other groups. Compared with African Americans, the mean visceral fat area was 45% and 73% greater in Japanese American men and women, respectively, and the mean measurements of liver fat were 61% and 122% greater in Japanese American men and women. The visceral and hepatic adiposity associated with weight gain since participants were 21 years old varied in a similar pattern among ethnic-racial groups. In the mediation analysis, visceral and liver fat jointly accounted for a statistically significant fraction of the difference in metabolic syndrome prevalence, compared with white persons, for African Americans, Japanese Americans, and Native Hawaiian women, independently of total fat mass., Conclusions: In an analysis of data from the participants in the Multiethnic Cohort Study, we found extensive differences among ethnic-racial groups in the propensity to store fat intra-abdominally. This observation should be considered by clinicians in the prevention and early detection of metabolic disorders., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Common variants have explained less than the amount of heritability expected for complex diseases, which has led to interest in less-common variants and more powerful approaches to the analysis of whole-genome scans. Because of low frequency (low statistical power), less-common variants are best analyzed using SNP-set methods such as gene-set or pathway-based analyses. However, there is as yet no clear consensus regarding how to focus in on potential risk variants following set-based analyses. We used a stepwise, telescoping approach to analyze common- and rare-variant data from the Illumina Metabochip array to assess genomic association with colorectal cancer (CRC) in the Japanese sub-population of the Multiethnic Cohort (676 cases, 7180 controls). We started with pathway analysis of SNPs that are in genes and pathways having known mechanistic roles in colorectal cancer, then focused on genes within the pathways that evidenced association with CRC, and finally assessed individual SNPs within the genes that evidenced association. Pathway SNPs downloaded from the dbSNP database were cross-matched with Metabochip SNPs and analyzed using the logistic kernel machine regression approach (logistic SNP-set kernel-machine association test, or sequence kernel association test; SKAT) and related methods., Results: The TGF-β and WNT pathways were associated with all CRC, and the WNT pathway was associated with colon cancer. Individual genes demonstrating the strongest associations were TGFBR2 in the TGF-β pathway and SMAD7 (which is involved in both the TGF-β and WNT pathways). As partial validation of our approach, a known CRC risk variant in SMAD7 (in both the TGF-β and WNT pathways: rs11874392) was associated with CRC risk in our data. We also detected two novel candidate CRC risk variants (rs13075948 and rs17025857) in TGFBR2, a gene known to be associated with CRC risk., Conclusions: A stepwise, telescoping approach identified some potentially novel risk variants associated with colorectal cancer, so it may be a useful method for following up on results of set-based SNP analyses. Further work is required to assess the statistical characteristics of the approach, and additional applications should aid in better clarifying its utility.

Dietary indices have been related to risk for type 2 diabetes (T2D) predominantly in white populations. The present study evaluated this association in the ethnically diverse Multiethnic Cohort and examined four diet quality indices in relation to T2D risk, homoeostatic model assessment-estimated insulin resistance (HOMA-IR) and biomarkers of dyslipidaemia, inflammation and adipokines. The T2D analysis included 166 550 white, African American, Native Hawaiian, Japanese American and Latino participants (9200 incident T2D cases). Dietary intake was assessed at baseline using a quantitative FFQ and T2D status was based on three self-reports and confirmed by administrative data. Biomarkers were assessed about 10 years later in a biomarker subcohort (n 10 060). Sex- and ethnicity-specific hazard ratios were calculated for the Healthy Eating Index-2010 (HEI-2010), the alternative HEI-2010 (AHEI-2010), the alternate Mediterranean diet score (aMED) and the Dietary Approaches to Stop Hypertension (DASH). Multivariable-adjusted means of biomarkers were compared across dietary index tertiles in the biomarker subcohort. The AHEI-2010, aMED (in men only) and DASH scores were related to a 10-20 % lower T2D risk, with the strongest associations in whites and the direction of the relationships mostly consistent across ethnic groups. Higher scores on the four indices were related to lower HOMA-IR, TAG and C-reactive protein concentrations, not related to leptin, and the DASH score was directly associated with adiponectin. The AHEI-2010 and DASH were directly related to HDL-cholesterol in women. Potential underlying biological mechanisms linking diet quality and T2D risk are an improved lipid profile and reduced systemic inflammation and, with regards to DASH alone, an improved adiponectin profile.

Although Japanese in Japan and the USA are high-risk populations for colorectal cancer, the prevalence of obesity, one of the established risk factors for this disease, is low in these populations compared with other high-risk populations. To understand this inconsistency, we compared plasma obesity-related biomarkers in cross-sectional studies carried out in Tokyo, São Paulo, and Hawaii. We measured plasma levels of insulin-like growth factor-I (IGF-I), insulin-like growth factor-binding protein (IGFBP)-1, IGFBP-3, C-peptide, adiponectin, leptin, tumor necrosis factor-α, and interleukin-6 by immunoassay and total C-reactive protein, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides using a clinical chemistry autoanalyzer. A total of 299 participants were included in the present analysis, comprising 142 Japanese in Tokyo, 79 Japanese Brazilians in São Paulo, and 78 Japanese Americans in Hawaii. We found significantly lower plasma levels of C-peptide and IGF-I in Japanese in Tokyo than in Japanese Americans, and lower levels of leptin and triglycerides and higher levels of adiponectin, IGFBP-3, and high-density lipoprotein cholesterol in Japanese in Tokyo than in the other two populations. We also observed a significantly higher plasma IGFBP-1 level in Japanese Brazilians, and lower plasma levels of total cholesterol and low-density lipoprotein in Japanese Americans than in the other two populations. We observed significant differences in obesity-related biomarkers between the three Japanese populations. If our results are confirmed, the risk of colorectal cancer predicted on the basis of these biomarkers would be lowest for Japanese in Tokyo, followed by Japanese Brazilians and Japanese Americans.

Heterocyclic aromatic amines formed in cooked meat may be an underlying mechanism for the red meat-colorectal cancer (CRC) association. These compounds require bioactivaction by N-acetyltransferase 2 (NAT2). An interaction effect between red meat consumption and NAT2 in increasing CRC risk has been inconsistently reported in whites. We investigated this interaction in two populations in which the high-activity rapid NAT2 phenotype is 10- and 2-fold more common than in whites. We meta-analyzed four studies of Japanese (2,217 cases, 3,788 controls) and three studies of African Americans (527 cases, 4,527 controls). NAT2 phenotype was inferred from an optimized seven-SNP genotyping panel. Processed and total red meat intakes were associated with an increased CRC risk in Japanese and in both ethnic groups combined (P's ≤ 0.002). We observed an interaction between processed meat intake and NAT2 in Japanese (P = 0.04), African Americans (P = 0.02), and in both groups combined (P = 0.006). The association of processed meat with CRC was strongest among individuals with the rapid NAT2 phenotype (combined analysis, OR for highest vs. lowest quartile: 1.62, 95% CI: 1.28-2.05; Ptrend = 8.0×10-5), intermediate among those with the intermediate NAT2 phenotype (1.29, 95% CI: 1.05-1.59; Ptrend = 0.05) and null among those with the slow phenotype (Ptrend = 0.45). A similar interaction was found for NAT2 and total red meat (Pinteraction = 0.03). Our findings support a role for NAT2 in modifying the association between red meat consumption and CRC in Japanese and African Americans.

Studies have provided evidence of an inverse association between atopic allergic conditions (AACs) and invasive colorectal cancer (CRC) incidence and mortality in predominantly white populations. We examined the association between AACs (asthma, hay fever, or allergy) and CRC among white, African-American, Native Hawaiian, Japanese-American, and Latino men and women in the Multiethnic Cohort Study within Hawaii and Los Angeles, California. The prospective analysis included 4,834 incident CRC cases and 1,363 CRC-related deaths ascertained between 1993 and 2010. We examined associations by ethnicity, location, stage, and potential effect modification by CRC risk factors. AACs were associated with a reduced risk of CRC incidence among both men and women (relative risk (RR) = 0.86, 95% confidence interval (CI): 0.80, 0.92). The reduction in risk was noted in all populations except Latinos and was significant in whites (RR = 0.85, 95% CI: 0.73, 0.98), African Americans (RR = 0.81, 95% CI: 0.70, 0.95), Native Hawaiians (RR = 0.72, 95% CI: 0.54, 0.96), and Japanese Americans (RR = 0.87, 95% CI: 0.78, 0.98). Individuals with AACs also had a 20% reduction in CRC-related mortality (P = 0.001). These findings provide evidence for the potential protective role of the reactive immune system in colorectal cancer., (© The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Previous studies of Japanese migrants have suggested that the increase in colorectal cancer rates occurring after migration is slower among Japanese Brazilians than among Japanese Americans. We hypothesized that this difference may partly reflect differences in vegetable and fruit intake between the populations. Using data from validation studies of food frequency questionnaires being used in comparative case-control studies of colorectal adenoma in Tokyo, São Paulo, and Hawaii, plasma carotenoid, retinol, tocopherol, and coenzyme Q10 levels were measured by high-performance liquid chromatography, and 25-hydroxy vitamin D levels were estimated by enzyme-linked immunosorbent assay. Plasma levels were compared by analysis of covariance between 142 Japanese in Tokyo, 79 Japanese Brazilians in São Paulo, and 78 Japanese Americans in Hawaii. Overall, we found significantly lower plasma carotenoid levels, except for lycopene levels, and retinol levels in Japanese Americans compared with Japanese in Tokyo and Japanese Brazilians. The plasma total carotenoid level was highest in Japanese Brazilians. Compared with the mean level among Japanese Brazilians (1741.2 ng/ml), P for difference was 0.03 among Japanese in Tokyo (1514.4 ng/ml) and less than 0.01 for Japanese Americans (1257.7 ng/ml). Plasma lycopene and tocopherol levels did not substantially differ between the three populations. We also found significantly lower plasma levels of 25-hydroxy vitamin D and total coenzyme Q10 in Japanese in Tokyo than in Japanese Americans and Japanese Brazilians. Higher levels of plasma carotenoids among Japanese Brazilians than among Japanese in Tokyo and Hawaii may have contributed to the slower pace of the increase in colorectal cancer rates observed in that population after migration.

Background: Healthy dietary patterns have been linked positively with health and longevity. However, prospective studies in diverse populations in the United States addressing dietary patterns and mortality are limited., Objective: We assessed the ability of the following 4 diet-quality indexes [the Healthy Eating Index-2010 (HEI-2010), the Alternative HEI-2010 (AHEI-2010), the alternate Mediterranean diet score (aMED), and the Dietary Approaches to Stop Hypertension (DASH)] to predict the reduction in risk of mortality from all causes, cardiovascular disease (CVD), and cancer., Design: White, African American, Native Hawaiian, Japanese American, and Latino adults (n = 215,782) from the Multiethnic Cohort completed a quantitative food-frequency questionnaire. Scores for each dietary index were computed and divided into quintiles for men and women. Mortality was documented over 13-18 y of follow-up. HRs and 95% CIs were computed by using adjusted Cox models., Results: High HEI-2010, AHEI-2010, aMED, and DASH scores were all inversely associated with risk of mortality from all causes, CVD, and cancer in both men and women (P-trend < 0.0001 for all models). For men, the HEI-2010 was consistently associated with a reduction in risk of mortality for all causes (HR: 0.75; 95% CI: 0.71, 0.79), CVD (HR: 0.74; 95% CI: 0.69, 0.81), and cancer (HR: 0.76; 95% CI: 0.70, 0.83) when lowest and highest quintiles were compared. In women, the AHEI and aMED showed large reductions for all-cause mortality (HR: 0.78; 95% CI: 0.74, 0.82), the AHEI showed large reductions for CVD (HR: 0.76; 95% CI: 0.69, 0.83), and the aMED showed large reductions for cancer (HR: 0.84; 95% CI: 0.76, 0. 92)., Conclusion: These results, in a US multiethnic population, suggest that consuming a dietary pattern that achieves a high diet-quality index score is associated with lower risk of mortality from all causes, CVD, and cancer in adult men and women., (© 2015 American Society for Nutrition.)

The genetic basis of sporadic colorectal cancer (CRC) is not well explained by known risk polymorphisms. Here we perform a meta-analysis of two genome-wide association studies in 2,627 cases and 3,797 controls of Japanese ancestry and 1,894 cases and 4,703 controls of African ancestry, to identify genetic variants that contribute to CRC susceptibility. We replicate genome-wide statistically significant associations (P<5 × 10(-8)) in 16,823 cases and 18,211 controls of European ancestry. This study reveals a new pan-ethnic CRC risk locus at 10q25 (rs12241008, intronic to VTI1A; P=1.4 × 10(-9)), providing additional insight into the aetiology of CRC and highlighting the value of association mapping in diverse populations.

Purpose: Given the relation between screening and improved cancer outcomes and the persistence of ethnic disparities in cancer mortality, we explored ethnic differences in colonoscopy, prostate-specific antigen (PSA), and mammography screening in the Multiethnic Cohort Study., Methods: Logistic regression was applied to examine the influence of ethnicity as well as demographics, lifestyle factors, comorbidities, family history of cancer, and previous screening history on self-reported screening participation collected in 1999-2002., Results: The analysis included 140,398 participants who identified as white, African American, Native Hawaiian, Japanese American, US born-Latino, or Mexican born-Latino. The screening prevalences overall were mammography: 88% of women, PSA: 45% of men, and colonoscopy: 35% of men and women. All minority groups reported 10-40% lower screening utilization than whites, but Mexican-born Latinos and Native Hawaiian were lowest. Men were nearly twice as likely to have a colonoscopy (OR=1.94, 95% CI=1.89-1.99) as women. A personal screening history, presence of comorbidities, and family history of cancer predicted higher screening utilization across modalities, but to different degrees across ethnic groups., Conclusions: This study confirms previously reported sex differences in colorectal cancer screening and ethnic disparities in screening participation. The findings suggest it may be useful to include personal screening history and family history of cancer into counseling patients about screening participation., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Higher sunlight exposure is correlated with lower incidence of breast cancer in ecological studies, but findings from prospective studies regarding the association of circulating levels of vitamin D with the risk of breast cancer have been null. The objective of this study was to examine the relation between plasma levels of vitamin D and the risk of postmenopausal breast cancer., Methods: We conducted a nested case-control study within the Multiethnic Cohort Study of five race/ethnic groups (white, African-American, Native Hawaiian, Japanese, and Latino) from Hawaii and Los Angeles between 2001 and 2006. Pre-diagnostic plasma levels of 25-hydroxyvitamin D2 [25(OH)D2], 25-hydroxyvitamin D3 [25(OH)D3] and 25(OH)D (sum of 25(OH)D2 and 25(OH)D3) were examined among 707 postmenopausal breast cancer cases and matched controls., Results: Using conditional logistic regression models, 20 ng/mL increases of plasma 25(OH)D3 (odds ratio (OR) 0.28; 95% confidence interval (CI) 0.14-0.56) and 25(OH)D (OR 0.43; 95% CI 0.23-0.80) were inversely associated with breast cancer risk among white women, but not among women in other race/ethnic groups. Using two-segmented, piecewise-linear logistic regression models, the change-points of the ORs, either for 25(OH)D3 or for 25(OH)D, were detected as 20 ng/mL among whites., Conclusions: Circulating 25(OH)D3 and 25(OH)D were associated with a reduced risk of postmenopausal breast cancer among whites, but not in other ethnic groups, who reside in low latitude regions.

Background: There have been few genome-wide association studies (GWAS) of prostate cancer among diverse populations. To search for novel prostate cancer risk variants, we conducted GWAS of prostate cancer in Japanese and Latinos. In addition, we tested prostate cancer risk variants and developed genetic risk models of prostate cancer for Japanese and Latinos., Methods: Our first-stage GWAS of prostate cancer included Japanese (cases/controls = 1,033/1,042) and Latino (cases/controls = 1,043/1,057) from the Multiethnic Cohort (MEC). Significant associations from stage I (P < 1.0 × 10(-4)) were examined in silico in GWAS of prostate cancer (stage II) in Japanese (cases/controls = 1,583/3,386) and Europeans (cases/controls = 1,854/1,894)., Results: No novel stage I single-nucleotide polymorphism (SNP) outside of known risk regions reached genome-wide significance. For Japanese, in stage I, the most notable putative novel association was seen with 10 SNPs (P ≤ 8.0 × 10(-6)) at chromosome 2q33; however, this was not replicated in stage II. For Latinos, the most significant association was observed with rs17023900 at the known 3p12 risk locus (stage I: OR = 1.45; P = 7.01 × 10(-5) and stage II: OR = 1.58; P = 3.05 × 10(-7)). The majority of the established risk variants for prostate cancer, 79% and 88%, were positively associated with prostate cancer in Japanese and Latinos (stage I), respectively. The cumulative effects of these variants significantly influence prostate cancer risk (OR per allele = 1.10; P = 2.71 × 10(-25) and OR = 1.07; P = 1.02 × 10(-16) for Japanese and Latinos, respectively)., Conclusion and Impact: Our GWAS of prostate cancer did not identify novel genome-wide significant variants. However, our findings show that established risk variants for prostate cancer significantly contribute to risk among Japanese and Latinos., (©2012 AACR.)

Genome-wide association studies have identified common genetic variants that can contribute specifically to the risk of abdominal adiposity, as measured by waist circumference or waist-to-hip ratio. However, it is unknown whether these genetic risk factors affect relative body fat distribution in the abdominal visceral and subcutaneous compartments. The association between imaging-based abdominal fat mass and waist-size risk variants in the FTO, LEPR, LYPLAL1, MSRA, NRXN3, and TFAP2B genes was investigated. A cross-sectional sample of 60 women was selected among study participants of The Multiethnic Cohort, who were aged 60 to 65 years, of European or Japanese descent, and with a body mass index (calculated as kg/m(2)) between 18.5 and 40. Dual-energy x-ray absorptiometry and abdominal magnetic resonance imaging scans were used to measure adiposity. After adjustments for age, ethnicity, and total fat mass, the FTO variants showed an association with less abdominal subcutaneous fat and a higher visceral-to-subcutaneous abdominal fat ratio, with the variant rs9941349 showing significant associations most consistently (P=0.003 and 0.03, respectively). Similarly, the LEPR rs1137101 variant was associated with less subcutaneous fat (P=0.01) and a greater visceral-to-subcutaneous fat ratio (P=0.03) and percent liver fat (P=0.007). MSRA rs545854 variant carriers had a lower percent of leg fat. Our findings provide initial evidence that some of the genetic risk factors identified for larger waist size might also contribute to disproportionately greater intra-abdominal and liver fat distribution in postmenopausal women. If replicated, these genetic variants can be incorporated with other biomarkers to predict high-risk body fat distribution., (Copyright © 2012 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

We have previously reported multiple loci associated with prostate cancer susceptibility in a Japanese population using a genome-wide association study (GWAS). To identify additional prostate cancer susceptibility loci, we genotyped nine SNPs that were nominally associated with prostate cancer (P < 1 × 10(-4)) in our previous GWAS in three independent studies of prostate cancer in Japanese men (2,557 individuals with prostate cancer (cases) and 3,003 controls). In a meta-analysis of our previous GWAS and the replication studies, which included a total of 7,141 prostate cancer cases and 11,804 controls from a single ancestry group, three new loci reached genome-wide significance on chromosomes 11q12 (rs1938781; P = 1.10 × 10(-10); FAM111A-FAM111B), 10q26 (rs2252004; P = 1.98 × 10(-8)) and 3p11.2 (rs2055109; P = 3.94 × 10(-8)). We also found suggestive evidence of association at a previously reported prostate cancer susceptibility locus at 2p11 (rs2028898; P = 1.08 × 10(-7)). The identification of three new susceptibility loci should provide additional insight into the pathogenesis of prostate cancer and emphasizes the importance of conducting GWAS in diverse populations.

Background: Characterization of abdominal and intra-abdominal fat requires imaging, and thus is not feasible in large epidemiologic studies., Objective: We investigated whether biomarkers may complement anthropometry (body mass index [BMI], waist circumference [WC], and waist-hip ratio [WHR]) in predicting the size of the body fat compartments by analyzing blood biomarkers, including adipocytokines, insulin resistance markers, sex steroid hormones, lipids, liver enzymes and gastro-neuropeptides., Methods: Fasting levels of 58 blood markers were analyzed in 60 healthy, Caucasian or Japanese American postmenopausal women who underwent anthropometric measurements, dual energy X-ray absorptiometry (DXA), and abdominal magnetic resonance imaging. Total, abdominal, visceral and hepatic adiposity were predicted based on anthropometry and the biomarkers using Random Forest models., Results: Total body fat was well predicted by anthropometry alone (R(2) = 0.85), by the 5 best predictors from the biomarker model alone (leptin, leptin-adiponectin ratio [LAR], free estradiol, plasminogen activator inhibitor-1 [PAI1], alanine transaminase [ALT]; R(2) = 0.69), or by combining these 5 biomarkers with anthropometry (R(2) = 0.91). Abdominal adiposity (DXA trunk-to-periphery fat ratio) was better predicted by combining the two types of predictors (R(2) = 0.58) than by anthropometry alone (R(2) = 0.53) or the 5 best biomarkers alone (25(OH)-vitamin D(3), insulin-like growth factor binding protein-1 [IGFBP1], uric acid, soluble leptin receptor [sLEPR], Coenzyme Q10; R(2) = 0.35). Similarly, visceral fat was slightly better predicted by combining the predictors (R(2) = 0.68) than by anthropometry alone (R(2) = 0.65) or the 5 best biomarker predictors alone (leptin, C-reactive protein [CRP], LAR, lycopene, vitamin D(3); R(2) = 0.58). Percent liver fat was predicted better by the 5 best biomarker predictors (insulin, sex hormone binding globulin [SHBG], LAR, alpha-tocopherol, PAI1; R(2) = 0.42) or by combining the predictors (R(2) = 0.44) than by anthropometry alone (R(2) = 0.29)., Conclusion: The predictive ability of anthropometry for body fat distribution may be enhanced by measuring a small number of biomarkers. Studies to replicate these data in men and other ethnic groups are warranted.

Background: A recent genome-wide association study (GWAS) of prostate cancer in a Japanese population identified five novel regions not previously discovered in other ethnicities. In this study, we attempt to replicate these five loci in a series of nested prostate cancer case-control studies of European ancestry., Methods: We genotyped five single-nucleotide polymorphism (SNP): rs13385191 (chromosome 2p24), rs12653946 (5p15), rs1983891 (6p21), rs339331 (6p22), and rs9600079 (13q22), in 7,956 prostate cancer cases and 8,148 controls from a series of nested case-control studies within the National cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3). We tested each SNP for association with prostate cancer risk and assessed whether associations differed with respect to disease severity and age of onset., Results: Four SNPs (rs13385191, rs12653946, rs1983891, and rs339331) were significantly associated with prostate cancer risk (P values ranging from 0.01 to 1.1 × 10(-5)). Allele frequencies and ORs were overall lower in our population of European descent than in the discovery Asian population. SNP rs13385191 (C2orf43) was only associated with low-stage disease (P = 0.009, case-only test). No other SNP showed association with disease severity or age of onset. We did not replicate the 13q22 SNP, rs9600079 (P = 0.62)., Conclusions: Four SNPs associated with prostate cancer risk in an Asian population are also associated with prostate cancer risk in men of European descent., Impact: This study illustrates the importance of evaluation of prostate cancer risk markers across ethnic groups.

Prostate specific antigen (PSA) is widely used as a diagnostic biomarker for prostate cancer (PC). However, due to its low predictive performance, many patients without PC suffer from the harms of unnecessary prostate needle biopsies. The present study aims to evaluate the reproducibility and performance of a genetic risk prediction model in Japanese and estimate its utility as a diagnostic biomarker in a clinical scenario. We created a logistic regression model incorporating 16 SNPs that were significantly associated with PC in a genome-wide association study of Japanese population using 689 cases and 749 male controls. The model was validated by two independent sets of Japanese samples comprising 3,294 cases and 6,281 male controls. The areas under curve (AUC) of the model were 0.679, 0.655, and 0.661 for the samples used to create the model and those used for validation. The AUCs were not significantly altered in samples with PSA 1-10 ng/ml. 24.2% and 9.7% of the patients had odds ratio <0.5 (low risk) or >2 (high risk) in the model. Assuming the overall positive rate of prostate needle biopsies to be 20%, the positive biopsy rates were 10.7% and 42.4% for the low and high genetic risk groups respectively. Our genetic risk prediction model for PC was highly reproducible, and its predictive performance was not influenced by PSA. The model could have a potential to affect clinical decision when it is applied to patients with gray-zone PSA, which should be confirmed in future clinical studies.

Primary Objective: To calculate the nutritional composition of commonly consumed Brazilian foods and beverages to analyze dietary intake data obtained with a quantitative food frequency questionnaire in a colorectal adenoma case-control study in Japanese Brazilians., Methods and Procedures: Weighed recipes were collected in São Paulo, Brazil and analyzed using NutriBase Clinical Nutrition Manager., Main Outcomes and Results: A total of 387 recipes for 76 dishes commonly consumed by Japanese Brazilians were collected: 30 composite main course dishes, 26 composite vegetable dishes, 19 snack foods and desserts, and one beverage. The nutritional composition (energy and 32 macronutrients and micronutrients) was calculated per 100 g for each dish., Conclusions: We provided, for the first time, complete and up-to-date calculated nutritional composition data for commonly consumed Brazilian food items, which are essential to assess the current dietary intake among Japanese Brazilians.

Background: Genome-wide association studies have identified three chromosomal regions at 15q25, 5p15, and 6p21 as being associated with the risk of lung cancer. To confirm these associations in independent studies and investigate heterogeneity of these associations within specific subgroups, we conducted a coordinated genotyping study within the International Lung Cancer Consortium based on independent studies that were not included in previous genome-wide association studies., Methods: Genotype data for single-nucleotide polymorphisms at chromosomes 15q25 (rs16969968, rs8034191), 5p15 (rs2736100, rs402710), and 6p21 (rs2256543, rs4324798) from 21 case-control studies for 11 645 lung cancer case patients and 14 954 control subjects, of whom 85% were white and 15% were Asian, were pooled. Associations between the variants and the risk of lung cancer were estimated by logistic regression models. All statistical tests were two-sided., Results: Associations between 15q25 and the risk of lung cancer were replicated in white ever-smokers (rs16969968: odds ratio [OR] = 1.26, 95% confidence interval [CI] = 1.21 to 1.32, P(trend) = 2 x 10(-26)), and this association was stronger for those diagnosed at younger ages. There was no association in never-smokers or in Asians between either of the 15q25 variants and the risk of lung cancer. For the chromosome 5p15 region, we confirmed statistically significant associations in whites for both rs2736100 (OR = 1.15, 95% CI = 1.10 to 1.20, P(trend) = 1 x 10(-10)) and rs402710 (OR = 1.14, 95% CI = 1.09 to 1.19, P(trend) = 5 x 10(-8)) and identified similar associations in Asians (rs2736100: OR = 1.23, 95% CI = 1.12 to 1.35, P(trend) = 2 x 10(-5); rs402710: OR = 1.15, 95% CI = 1.04 to 1.27, P(trend) = .007). The associations between the 5p15 variants and lung cancer differed by histology; odds ratios for rs2736100 were highest in adenocarcinoma and for rs402710 were highest in adenocarcinoma and squamous cell carcinomas. This pattern was observed in both ethnic groups. Neither of the two variants on chromosome 6p21 was associated with the risk of lung cancer., Conclusions: In this international genetic association study of lung cancer, previous associations found in white populations were replicated and new associations were identified in Asian populations. Future genetic studies of lung cancer should include detailed stratification by histology.

Background: Circulating levels of insulin and insulin-like growth factor (IGF) hormones have been associated with colorectal cancer risk, but few studies have examined their associations with colorectal adenoma., Methods: We measured plasma C-peptide, a marker of insulin secretion, and IGF hormones in a case-control study of 554 pathologically confirmed, first-time adenoma cases and 786 controls with normal endoscopy among Caucasians, Japanese, and Native Hawaiians in Hawaii., Results: High plasma levels of C-peptide were statistically significantly associated with risk of colorectal adenoma [multivariate odds ratio (95% confidence interval) for increasing quartiles: 1.0, 0.91 (0.65-1.27), 1.21 (0.86-1.71), and 1.79 (1.23-2.60); P(trend) = 0.0002]. We also observed a statistically significant inverse association between levels of plasma IGF binding protein-1 (IGFBP-1) and adenoma risk [1.0, 0.97 (0.70-1.34), 0.82 (0.58-1.15), and 0.47 (0.32-0.70); P(trend) <0.0001]. These associations remain significant after adjusting for each other and were not confounded by known risk factors. IGF-I, IGFBP-3, body mass index, and waist or hip circumference were not independently associated with adenoma risk., Conclusion: These results provide evidence for an association of insulin and IGFBP-1 levels with colorectal adenoma., Impact: This study suggests that hyperinsulinemia and IGF hormones may act as etiologic factors in colorectal carcinogenesis, as early as during adenoma formation., (Copyright 2010 AACR.)

Cytochrome P450 2E1 (CYP2E1) is involved in the metabolic activation of a wide variety of potential carcinogens, and functional polymorphisms in the CYP2E1 gene have been investigated in relation to colorectal cancer. We examined the relation of the CYP2E1 RsaI and 96-bp insertion polymorphisms to colorectal cancer risk and the interaction between these polymorphisms and some lifestyle risk factors. Subjects were 685 incident cases of colorectal cancer and 778 community controls. Statistical adjustment was made for alcohol use, body mass index, physical activity, and other factors. The RsaI c2 allele was associated with a decreased risk of rectal cancer [adjusted odds ratio for at least one c2 allele, 0.71; 95% confidence interval (95% CI), 0.53-0.95], and an increased risk of rectal cancer was observed among individuals having one or two 96-bp insertion alleles (adjusted odds ratio, 1.40; 95% CI, 1.06-1.85). Individuals with two 96-bp insertion alleles showed a 2.28-fold increase in colon cancer risk (95% CI, 1.29-4.01). The two polymorphisms were in almost complete linkage disequilibrium (D' = 0.94). A positive association between alcohol intake and colorectal cancer was observed only in individuals without RsaI c2 allele (P(trend) = 0.03) or in those without 96-bp insertion allele (P(trend) = 0.009). Colon cancer risk was increased in relation to red meat intake only in individuals having one or two 96-bp insertion alleles (P(interaction) = 0.03). The present study suggests that variation in activity and inducibility of CYP2E1, in relation to alcohol or red meat intake, contributes to the development of colorectal cancer.

Myeloperoxidase, which is released from neutrophils in response to various pulmonary insults including tobacco smoke, is suspected to play a carcinogenic role in the lung. A G-to-A substitution polymorphism in the promoter region of the MPO gene has been suggested in in vitro studies to decrease gene transcription. We tested the association of this polymorphism with lung cancer in a population-based case-control study of 323 cases and 437 controls of Caucasian, Japanese, or Native Hawaiian ancestry in Hawaii. We found a marked difference in the frequency of the variant A allele among Caucasians (26%), Japanese (17%), and Hawaiians (13%). Overall, the variant allele was somewhat less frequent in cases than controls (P = 0.13). Individuals with the A/A genotype were found to be at a 50% decreased risk compared to those with two G alleles (95% confidence interval, 0.2-1.3). Although not statistically significant, this inverse association was suggested in both sexes and two of the three ethnic groups studied. Heterozygotes were at no decreased risk. Further work needs to clarify the functional relevance of the A allele in vivo and to confirm the inverse association of the A/A genotype with lung cancer in large epidemiological studies.

The NAD(P)H:quinone oxidoreductase gene, NQO1, often carries a C-->T transition at bp 609, which has been associated with a reduced enzymatic activity and which may result in altered metabolic activation of tobacco smoke procarcinogens. We tested the association of this polymorphism with lung cancer risk in a population-based case-control study of 327 cases and 440 controls of Caucasian, Japanese, or Native Hawaiian ancestry in Hawaii. We found a notable difference in the frequency of the variant allele among Japanese (38%), Caucasians (20%), and Hawaiians (22%). Overall, the variant allele was less frequent in cases than in controls (P = 0.03). A significant inverse association was found in Japanese, with adjusted odds ratios of 0.8 (95% confidence interval, 0.4-1.5) and 0.3 (0.1-0.7) for the heterozygous and homozygous variant genotypes, respectively, compared with the homozygous wild-type genotype (P for genetic trend, 0.02). The association did not reach statistical significance in Caucasians and Hawaiians but was in the same direction.

Cytochrome P4502E1 (CYP2E1) is considered to play an important role in the metabolic activation of procarcinogens such as N-nitrosoamines and low molecular weight organic compounds. An RsaI polymorphism is present in the 5'-flanking region of the CYP2E1 gene, which could possibly affect its transcription. However, the relationship between genotype and the phenotypic catalytic activity of the enzyme has not been defined. Also, the effects in humans of specific dietary factors, other than ethanol, which have been shown in animal and in vitro studies to modulate CYP2E1 activity, are unknown. Accordingly, the CYP2E1-mediated metabolism of chlorzoxazone to its 6-hydroxy metabolite was investigated in 50 healthy Japanese of both sexes in Hawaii. The oral clearance of the in vivo probe, the trait measure of CYP2E1 activity, was smaller than that reported in European-Americans. Significantly, after adjustment for age and sex, the oral clearance of chlorzoxazone decreased with the number of variant c2 alleles, and its mean in the c2/c2 genotype (147 ml/min) was statistically lower (P < or = 0.05) than that for either the homozygous wild-type (238 ml/min) or the heterozygote (201 ml/min) genotypes. Stepwise multiple regression analysis indicated that body weight was a major contributor to the interindividual variability in the oral clearance of chlorzoxazone, accounting for 43% of the variance. Consumption of lettuce, broccoli, and black tea explained additional components of the variability (7, 5, and 6%, respectively), as did medication use (3%), age (4%), and CYP2E1 genotype (5%). Overall, 73% of the variance could be accounted for by these variables. Body weight, lettuce, and use of medications were associated with increased CYP2E1 activity, and the other covariates were associated with reduced enzyme function. Because of the role that CYP2E1 plays in procarcinogen activation, especially of N-nitrosamines involved in lung cancer, the identified factors may account in part for observed differences in individual susceptibility to disease and may also have implications for cancer prevention.

Objectives: An understanding of factors associated with interest in genetic counseling and intentions to obtain colorectal cancer susceptibility testing is an important foundation for developing education, counseling, and genetic services and policies., Materials and Methods: A survey was mailed to first-degree relatives of patients diagnosed with colorectal cancer. The respondents (n = 426, 77% response rate) are siblings and adult children of Caucasian, Japanese, and Hawaiian ethnicity. Data collection was guided by a conceptual framework and included questions on demographics, family cancer history, predisposing factors (cancer worry, perceived risk, well-being), and enabling factors (decision preferences, social support, and health care factors). Logistic regression analysis on two binary dependent variables (interest in counseling and intentions to get genetic testing) was performed using Generalized Estimating Equations to account for family clusters., Results: Forty-five % of respondents were interested in genetic counseling, and 26% "definitely" intended to get genetic testing for colon cancer when available. For counseling interest, the most important predictors were education, Hawaiian ethnicity, cancer worry, and family support. Cancer worry, perceived risk, and age (older) were directly, and Japanese ethnicity was inversely, associated with testing intentions., Conclusions: High rates of interest in cancer genetic testing are similar to those found in other studies. Ethnic differences reveal a paradox between objective population risk (higher for Japanese) and greater concerns (among Hawaiians). The substantial lack of awareness of family history warrants further research. Culturally sensitive education and counseling are needed for managing the likely high demand for personalized information about hereditary cancer risk.

Colorectal cancer (CRC) rates for Japanese migrants to the United States increased rapidly to surpass the level of the host population. CRC rates for the Japanese in Hawaii and California are now the highest in the world. Rates for this disease have also increased in Japan, presumably as the result of the westernization of the diet. A series of population-based studies in Hawaii was undertaken to determine which dietary factors are responsible for this remarkable susceptibility of the Japanese to CRC and whether genetic factors are also involved. A first case-control study suggested that a high intake of red meat is a major risk factor for the disease in Hawaii Japanese men and that family history of CRC among first-degree relatives may strongly modify this association. A case-control family study is currently being completed to explore further the interaction between family history and the intake of red meat after adjustment for environmental covariates among family members. Also, a segregation analysis will guide gene discovery studies among high-risk Japanese families being recruited in the Cooperative Family Registry for Colorectal Cancer Studies. Retrospective and prospective studies are also ongoing to test associations of CRC with specific polymorphisms in genes controlling the metabolic activation or detoxification of the carcinogens associated with a diet high in red meat. Preliminary results suggest an association of the combined rapid NAT2 genotype and rapid CYP1A2 phenotype with CRC in individuals consuming well-done red meat. Populations in which dramatic changes in cancer incidence have occurred may offer opportunities to identify gene-environment interactions.

Temporal trend and migrant studies have indicated that the etiology of colorectal cancer is predominantly environmental and, hence, modifiable. Animal fat intake has been frequently, but inconsistently, associated with the risk of this disease. We conducted a population-based case-control study in Hawaii (United States) among ethnic groups at different risks of the disease to evaluate the role of dietary lipids and foods of animal origin on the risk of colorectal cancer. We interviewed 698 male and 494 female Japanese, Caucasian (White), Filipino, Hawaiian, and Chinese patients diagnosed during 1987-91 with pathologically confirmed adenocarcinoma of the colon or rectum, and 1,192 population controls matched to cases on age, gender and ethnicity. Odds ratios (OR), adjusted for caloric intake and other dietary and non-dietary risk factors, were estimated using conditional logistic regression. Intakes of total fat, saturated fat (S) and polyunsaturated fat (P) were not related to the risk of colorectal cancer. However, an inverse association was found for the P/S ratio, with ORs of 0.6 in both genders (95 percent confidence interval [CI] = 0.4-1.0 for males; CI = 0.3-0.9 for females) for the highest compared with the lowest quartile (P < 0.05 for trend). Intakes of red meat and processed meat were associated with the risk of cancer in the right colon and rectum, respectively, in men only. Fat-trimmed red meat and fish intakes were not related to risk. Chicken eaten without skin was associated inversely with risk in both genders. The strongest association was found for eggs, with an OR of 2.7 (CI = 1.7-4.0) and 2.3 (CI = 1.4-3.7) for the highest compared with the lowest quartile of intake in men and women, respectively (P < 0.001 for trend). This association was dose-dependent, not explained by known confounders or other dietary variables, and was very consistent between genders, among ethnic groups, and across all segments of the large bowel. These data suggest that the ratio of polyunsaturated to saturated fat may be a better indicator of colorectal cancer risk than the absolute amount of specific fats in the diet. They also suggest that eggs and, possibly, untrimmed red meat and processed meat increase, and chicken eaten without skin decreases, colorectal cancer risk.

Increased risk of colorectal cancer in individuals with family history of the disease has been observed consistently in past studies. However, limited attention has been given to the influence of ethnicity, the characteristics of the proband's tumor, and kinship. A population-based case-control study was conducted between 1987 and 1991 in Hawaii among 1,192 incident colorectal cancer cases and 1,192 sex-, age-, and ethnicity-matched population controls. The study identified 7,673 relatives for the cases and 7,823 relatives for the controls. With an estimating equation-based regression method, relatives of cases were found to have a 2.5-fold increased risk of colorectal cancer compared with relatives of controls (95% confidence interval (CI) 1.8-3.4) after adjustment for covariates. This increase in risk was greater for Japanese (odds ratio (OR) = 3.0, 95% CI 1.7-5.4) than Caucasians (OR = 1.8, 95% CI 1.2-2.9), for siblings (OR = 3.1, 95% CI 2.1-4.6) than parents (OR = 2.0, 95% CI 1.1-3.1), and when the index patient was diagnosed before the age of 55 years (OR = 4.1, 95% CI 2.1-8.0) with multiple tumors (OR = 9.5, 95% CI 4.4-20.6), with a distant stage (OR = 4.6, 95% CI 2.7-7.8), or with cancer of the right colon (OR = 3.0, 95% CI 2.0-4.4) or the rectum (OR = 3.0, 95% CI 1.8-4.8). The increase in risk was not affected by the relative's sex. Relatives of cases were not at increased risk for other common cancers. It is estimated that approximately 11.1% and 6.5% of colorectal cancers are attributable to a first degree family history of the disease for Japanese and Caucasians, respectively. These data and those of previous studies strongly suggest that individuals with a family history of colorectal cancer in a first degree relative are at increased risk for the disease and should receive regular diagnostic screening. Characteristics of the index case, such as age and stage at diagnosis, subsite and number of tumors, and race, as well as kinship, may be important in assessing the colorectal cancer risk of a relative.

Mortality trends and ecological data strongly suggest that the lung cancer risk associated with smoking is greater among Hawaiians than among the other ethnic groups in Hawaii. The authors combined data from two consecutive population-based case-control studies to formally test this hypothesis among 740 cases and 1616 controls. A multiple logistic regression analysis adjusting for pack-years of smoking, occupation, education, and age revealed that Hawaiian, Filipino, and Caucasian male smokers were at 121%, 53%, and 46% greater risk for lung cancer than Japanese male smokers. These risk differences were statistically significant, were consistent across sexes and histological types, and were not explained by the type of cigarettes, the level of inhalation, or by cholesterol or beta-carotene intake. Additionally, an increased lung cancer risk unrelated to smoking was observed among Chinese women. The possibility that other dietary antioxidants and/or genetic risk factors are responsible for these ethnic differences needs to be investigated.

This paper describes the progressive changes in cancer incidence that have been observed among Japanese after their migration to Hawaii. It reviews descriptive and analytic epidemiologic data suggesting a role for genetic susceptibilities in explaining the high risk of Japanese for colon cancer and their low risk for lung cancer, when compared to Caucasians. Differences in certain pharmacogenetic polymorphisms may explain these risk patterns. This research may lead to a better characterization of cancer risk at the individual level and, consequently, to improved methods of prevention.

Intercountry, as well as intracountry, survival comparisons have revealed some differences in breast cancer survival among various ethnic populations. Most of these differences are probably explained by factors related to socioeconomic status. However, the well documented survival advantage of Japanese patients compared to Caucasian patients remains unexplained. Some recent studies suggest an adverse prognostic effect for obesity. Although still inconclusive, these findings raise the possibility that the better survival of Japanese patients may be in part related to their lower mean body weight. An effect of the lower fat intake of the Japanese in explaining their breast cancer survival advantage has little support at present, but, like the obesity hypothesis, deserves further study.

182 Japanese and 161 Caucasian breast cancer patients participated in an epidemiologic case-control study from 1975-1980. They were subsequently followed until the end of 1987 to determine their survival status. Among the Japanese, patients with regional or distant disease had a relative risk (RR) of death of 13.0 (95% Confidence Interval (CI), 4.3-39.1) compared to those with in situ or localized disease, and obese patients had a RR of death of 3.5 (95% CI, 1.3-10.0) compared to non-obese subjects. Among the Caucasians, patients with advanced disease had a RR of death of 4.3 (95% CI, 1.8-10.5) compared to those with in situ or localized disease, and patients with a high fat intake had a RR of 3.2 (95% CI, 1.2-8.6) compared to subjects with a low fat intake. Menopausal status (pre- or postmenopausal) and replacement estrogen use were not related to survival from breast cancer in either ethnic group. When Japanese and Caucasian patients were compared with each other, there was no significant difference in survival between them.

This study examines whether the improvement in breast cancer survival in Hawaii suggested by an earlier analysis might be explained by concomitant temporal variations in prognostic factors. Characteristics at diagnosis and survival experience were compared for 1251 Caucasian, 1015 Japanese and 505 Hawaiian women diagnosed with invasive breast carcinoma during 1960-1979 and followed until the end of 1982. Time-trends were present for the patients' stage at diagnosis, age and socioeconomic status. A multivariate analysis using the Cox proportional hazards regression model revealed that adjustment for temporal variations in stage and age at diagnosis yielded a positive survival trend of a greater magnitude than that observed without adjustment, indicating that multivariate methods should be considered in time-trend analyses of cancer survival. Further analysis revealed that such improvement in breast cancer survival occurred for certain race-stage groups of patients only. Possible reasons for these trends in breast cancer prognostic factors and survival are discussed, along with potential biases. The data suggest that early detection might explain most of the survival improvement in Hawaii during the period of the study.