© 1999 by Oxford University Press
Journal of the National Cancer Institute Monographs, No. 26, 101-105,
1999
© 1999 Oxford University Press
IV. APPLICATIONS PANEL |
Combined Influence of Genetic and Dietary Factors on Colorectal Cancer Incidence in Japanese Americans
Correspondence to: Loïc Le Marchand, M.D., Ph.D., Etiology Program, Cancer Research Center of Hawaii, University of Hawaii, 1236 Lauhala St., Suite 407, Honolulu, HI 96813 (e-mail: loic{at}crch.hawaii.edu).
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ABSTRACT |
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 Top Abstract IntroductionJapanese Migrants to HawaiiDescriptive Epidemiology of CRC...Case-Control Study of Lifestyle...Case-Control Family StudyRetrospective and Prospective...NoteReferences |
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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.
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INTRODUCTION |
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TopAbstractIntroductionJapanese Migrants to HawaiiDescriptive Epidemiology of CRC...Case-Control Study of Lifestyle...Case-Control Family StudyRetrospective and Prospective...NoteReferences |
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Gene-environment interactions have rarely been studied as possible explanations for epidemiologic patterns of cancer in populations. More commonly, investigators have focused on environmental factors in attempting to explain temporal trends or international differences in cancer rates. This approach has been useful in identifying reproductive, lifestyle, and infectious risk factors for cancer and has led to the acceptance of the predominant role of the environment in cancer causation. However, genetic factors may play an important role in modifying the cancer risk of a population. This role is epitomized by the skin cancer epidemic that has resulted from an increase in recreational UV exposure among Western populations during the past 30 years. This increase in rates has been largely limited to populations with light pigmentation, a genetically determined trait.
The public health impact of a gene-environment interaction may be large if the at-risk genotype and exposure are common. Thus, such interactions could be especially relevant to populations in which changes in cancer rates have been particularly dramatic. The rapid increase in colorectal cancer (CRC) rates experienced by Japanese migrants to Hawaii might offer a unique opportunity to investigate such interactions.
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JAPANESE MIGRANTS TO HAWAII |
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TopAbstractIntroductionJapanese Migrants to HawaiiDescriptive Epidemiology of CRC...Case-Control Study of Lifestyle...Case-Control Family StudyRetrospective and Prospective...NoteReferences |
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Between 1886 and 1924, approximately 214 000 rural Japanese were brought to Hawaii from the southern prefectures of Hiroshima, Fukuoka, Yamaguchi, and Okinawa to provide laborers to the sugar plantations (1). No sizable migration from Japan to Hawaii has taken place since the 1920s and, up until the most recent generation, there has been very little admixture of the Japanese with other ethnic groups in Hawaii. Thus, these migrants and their descendants, at least in the age group affected by common cancers, appear to have been quite homogeneous genetically. Because of a high birth rate during the first half of the century, Japanese now represent 30% of the state population.
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DESCRIPTIVE EPIDEMIOLOGY OF CRC IN HAWAII JAPANESE |
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TopAbstractIntroductionJapanese Migrants to HawaiiDescriptive Epidemiology of CRC...Case-Control Study of Lifestyle...Case-Control Family StudyRetrospective and Prospective...NoteReferences |
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The incidence of CRC for Japanese in Hawaii increased markedly on migration, presumably, as a result of a dietary change (2). However, whereas Japanese incidence rates for other cancer sites, such as breast and stomach cancers, took two generations or more to approach those of the Caucasians, Japanese CRC rates increased faster and matched those of Caucasians as early as the first generation (Fig. 1
) (2). The same observations were reported
for Japanese migrants to California (3,4). Japanese Americans
in Hawaii and Los Angeles in 1983-1987 had the first and second
highest incidence rates for CRC, respectively, among more than 175
populations followed for cancer incidence worldwide (5).
Similarly, as the diet in Japan has become more westernized, incidence
for this cancer in Japan over the past 20 years has increased even more
rapidly than for other cancers (6,7). As
shown in Fig. 2, in comparison to several
representative populations, CRC incidence in Japan has now reached the
level of the U.K. (5). These observations suggest that
Japanese may be particularly susceptible to CRC because of an
especially pronounced exposure to lifestyle risk factors in the United
States, to the modifying influence of genetic susceptibility factors,
or to both (8). A strong genetic predisposition as a result of
a founder effect in some large families of Japanese migrants to Hawaii
could also be present but seems less likely because an increase in CRC
rates has taken place in Japanese populations elsewhere.
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Dietary surveys conducted during the 1970s and 1980s have consistently shown that the first and subsequent generations of Japanese migrants to Hawaii have retained some elements of their ethnic diet, and, in particular, their fat intake has remained distinctly lower than that of Caucasians (1,9). With the objective of identifying the specific lifestyle changes responsible for the sharp increase in CRC risk in Japanese Americans, we first conducted a population-based, case-control study of the disease in Hawaii.
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CASE-CONTROL STUDY OF LIFESTYLE AND CRC |
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TopAbstractIntroductionJapanese Migrants to HawaiiDescriptive Epidemiology of CRC...Case-Control Study of Lifestyle...Case-Control Family StudyRetrospective and Prospective...NoteReferences |
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We interviewed 698 men and 494 women diagnosed from 1987 through 1991 with adenocarcinoma of the colon or rectum and 1192 population control subjects matched to case patients on age, sex, and ethnicity. Fifty percent of the subjects were of Japanese ancestry, whereas 25% were Caucasians and the rest Filipino, Hawaiians, or Chinese. The questionnaire inquired about usual intake of more than 280 food items as well as about detailed ethnic background, lifetime recreational and occupational physical activity, smoking, medical history, family history of cancer, and body size. Consistent with studies conducted in other populations (10), the main lifestyle factors found to be directly associated with risk in this study were the intake of beef and processed meat (in males only), consumption of eggs, smoking, alcohol use, and obesity (11-13). Inverse associations were found with the intake of vegetable fiber and calcium and with lifetime recreational physical activity (12-14). With the use of the population controls to compare the dietary intakes of the various ethnic groups, we found, as expected, that Japanese had a lower fat intake than Caucasians (Table 1
). More surprising was
the finding that Japanese consumed more red meat, particularly beef,
and processed meats as well as less fiber and vegetables than
Caucasians (Table 1). Thus, these dietary factors could contribute to
the higher CRC risk of the Japanese.
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For all subjects combined, we also found a 2.5-fold increased risk (95% confidence interval [CI] = 1.2-2.9) of CRC in first-degree relatives of case patients compared with relatives of control subjects (15). The magnitude of this association was greater for case patients with a right-sided tumor, multiple tumors, and, especially, early age at diagnosis. Of interest, we also found that the risk associated with family history was stronger in Japanese than in Caucasians, with an odds ratio of 3.0 (95% CI = 2.1-4.6) and 1.8 (95% CI = 1.2-2.9), respectively (15). The difference between these odds ratios was of borderline statistical significance (P = .07). These results suggest that the genetic component of the disease may be stronger in Japanese than in Caucasians, perhaps because of a gene-environment interaction.
A recent analysis (14) also explored interactions between the lifestyle
risk factors identified in this study and the family history of the disease among first-degree
relatives. In an analysis conducted on all ethnic groups and adjusting for all lifestyle main effects
and interactions, statistically significant interactions with family history were observed for the
intakes of beef and alcohol in males. Only the data on beef will be discussed here. Relative to men
without a family history of the disease and whose intake of beef fell in the lower third, odds ratio
for CRC for men with a family history and in the upper tertile of intake was 10.8 (95% CI
= 4.2-27.6) for beef intake (Fig. 3). The corresponding odds ratio
for men without a family history and in the upper tertile of beef intake was 1.5 (1.0-2.3). This
interaction appeared to be stronger in Japanese than in Caucasians, although the power of these
ethnic-specific analyses was limited. No interactions were found in women, possibly because of
the smaller sample size and lower consumption of beef or because of some underlying biologic
differences (14). This analysis suggested that family history increases risk
of CRC in men mainly through a strong interaction with a high intake of beef and alcohol (14). However, because of the high number of statistical tests performed
and the discrepancy between sexes, these findings need replication.
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In summary, this first case-control study suggested that a high intake of red meat may contribute to the high CRC risk of Japanese in Hawaii and that family history of the disease among first-degree relatives may strongly modify this association. To investigate these associations further, we are currently conducting two types of studies: a case-control family study is exploring the familial aggregation of CRC and interaction of family history with lifestyle factors while taking into account the potential confounding effects of covariates in relatives, and a second case-control study and a prospective study are testing associations with candidate genes that may modify the association between the intake of red meat and CRC.
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CASE-CONTROL FAMILY STUDY |
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TopAbstractIntroductionJapanese Migrants to HawaiiDescriptive Epidemiology of CRC...Case-Control Study of Lifestyle...Case-Control Family StudyRetrospective and Prospective...NoteReferences |
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One objective of this genetic epidemiology study is to separate the environmental (dietary and lifestyle) and genetic components of the familial aggregation of CRC and explore gene-environment interactions for the disease in our population. To increase the efficiency of the study, only case patients diagnosed before age 60 years and their sex-, age- and race-matched control subjects are included as probands. Subjects are of Japanese, Caucasian, Hawaiian, or Chinese origin. Parents and siblings are contacted by mail to collect information on their demographics, medical background, family history of cancer, and environmental exposures (diet, smoking, physical activity, and body size). The statistical analysis will explore patterns of familial aggregation after adjusting for environmental covariates for both probands and relatives and will investigate interactions between family history and lifestyle factors, such as the intake of red meat (16,17). The second objective of this study is to perform a segregation analysis after adjusting for environmental covariates to explore various models of inheritance for susceptibility to CRC in our population (18). This analysis may guide gene discovery studies among the high-risk Hawaii families that are being enrolled in the Cooperative Family Registry for Colorectal Cancer Studies (CFRCCS) supported by the National Cancer Institute.
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RETROSPECTIVE AND PROSPECTIVE ASSOCIATION STUDIES |
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TopAbstractIntroductionJapanese Migrants to HawaiiDescriptive Epidemiology of CRC...Case-Control Study of Lifestyle...Case-Control Family StudyRetrospective and Prospective...NoteReferences |
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These studies are testing whether exposure to a diet high in red meat or well-done meat, combined with specific genotypes associated with altered activities of type I and II carcinogen metabolizing enzymes, may explain the high CRC risk of Japanese Americans. The well-established association of red meat with CRC (10) may be due in part to the formation of heterocyclic aromatic amines (HAAs) by pyrolysis of creatin and creatinine in meats cooked at high temperature (e.g., panfrying, broiling, or barbecuing) (19). Levels of HAAs in meat greatly depend on the duration of cooking. HAAs are highly carcinogenic to the large bowel in rodents and are suspected to be carcinogenic to humans as well (19). HAAs require metabolic activation by CYP1A2 and N-acetyltransferase to bind to DNA and exert their genotoxicity (20). It has been hypothesized that persons with the rapid N-oxidation and rapid NAT2 phenotypes are at higher risk for CRC, especially when they consume their meat well done (21,22). Of interest, the fast acetylator genotype is especially common in Japanese (90%) compared with Caucasians (45%), whereas the frequency of the CYP1A2 susceptible phenotype is similar in the two groups (23-25).
We are completing a second case-control study of CRC, following the same population-based
design and including the same ethnic groups as in the first study. Case patients were diagnosed
between 1994 and 1999. An interviewer-administered, quantitative food-frequency questionnaire
assesses total diet as well as intake of red meat cooked by different methods to various levels of
doneness. Blood and urine samples are collected. Subjects are genotyped for NAT2*4,
NAT2*5A, NAT2*6A, and NAT2*7A by a polymerase chain reaction-based method (26) and phenotyped for CYP1A2 activity by the caffeine test (27). Preliminary results from this new study appear to confirm an association of the
combined rapid NAT2 genotype and rapid CYP1A2 phenotype with CRC that is limited to
individuals consuming their red meat well done (Table 2). The prevalence
of eating well-done meat was similar in Japanese and Caucasians, and the "meat
preference" of those who reported not to eat red meat was set to
"rare/medium" in this analysis. No main effect was found for the NAT2 rapid
acetylator genotype alone. Future analyzes will estimate the CRC risk associated with intakes of
the main HAAs (PhIP and MeIQx).
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Because exposure information in case-control studies may be plagued by differential recall, we are attempting to reproduce this association in a prospective study in which diet information was collected before diagnosis. This study is following for cancer occurrence approximately 215 000 Japanese, Caucasian, African-American, Hispanic, and Native Hawaiian residents of Hawaii and Los Angeles who mailed back a detailed epidemiologic questionnaire between 1993 and 1996 (28). Blood samples are being collected from incident CRC case patients and a subset of the cohort members to conduct a nested case-control study.
Although some of the findings obtained to date are still preliminary, this research suggests that consumption of well-done red meat, combined with a specific genotype (NAT2*4/*4 and rapid CYP1A2), may increase CRC risk substantially. Because both this dietary exposure and genotype are more common in Japanese Americans, they may contribute to the high risk of the disease in this population. Other polymorphic metabolic genes for which the at-risk genotype is common in Japanese may also be involved (29-31). Linkage studies in multiplex Japanese families may also identify other genes that may contribute to the strong familial aggregation of the disease in this ethnic group in Hawaii.
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NOTE |
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Supported in part by Public Health Service (PHS) grants P01CA33619, R01CA60987, and U01CA74806 and by PHS contract N01PC67001 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.
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TopAbstractIntroductionJapanese Migrants to HawaiiDescriptive Epidemiology of CRC...Case-Control Study of Lifestyle...Case-Control Family StudyRetrospective and Prospective...NoteReferences |
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