Prospective study of serum cholesterol levels and large-bowel cancer.

Based on previous reports, it is uncertain whether serum cholesterol levels are inversely related to colon cancer risk. In this study, serum cholesterol levels were measured in 7926 Japanese-American men who were followed for over 20 years. Two hundred thirty-one incident cases of colon cancer and 97 cases of rectal cancer were identified. An increase in serum cholesterol levels was associated with a decrease in risk for colon cancer (P value for trend = .01) but not for rectal cancer. This association appeared stronger as the site of cancer moved from the sigmoid colon to the cecum. The data were further analyzed by interval from examination to diagnosis. The inverse association was present for colon cancer cases diagnosed within 10 years of examination (P value for trend less than .01), especially for cecum-ascending colon cancer cases (P less than .01). A similar inverse pattern was found for cecum-ascending colon cancer cases diagnosed after 10 years, but the association was not statistically significant. The results suggest that the preclinical effects of undiagnosed colon cancer contributed to the inverse association, but these effects do not entirely explain why the relationship with hypocholesterolemia was stronger in men who were subsequently diagnosed with right-sided colon cancer.

Dietary fat and prostate cancer: current status.

Efforts to elucidate the causes of prostate cancer have met with little success to date. All that is known with certainty is that the incidence increases exponentially with age, varies by geography and by race or ethnicity, and is higher among men whose father or brother had the disease. Because the incidence changes in migrants and their offspring, exogenous factors certainly contribute to the risk of prostate cancer. Early epidemiologic studies implicated dietary fat as a likely causal factor for this cancer. However, scientific support for such an association has diminished in recent years as more epidemiologic evidence has accrued. Accordingly, we reviewed the relevant English language literature on this topic, including epidemiologic and animal studies, as well as current concepts regarding the involvement of fat in carcinogenesis to re-examine the fat-prostate cancer hypothesis. We conclude that dietary fat may indeed be related to prostate cancer risk, although the specific fat components that are responsible are not yet clear. Given the diverse effects of fatty acids on cellular biology and chemistry, it seems likely that the relationship is complex, involving the interplay of fat with other dietary factors, such as antioxidant vitamins and minerals, or with genetic factors that influence susceptibility. Some suggestions for further research are offered.

Relationship of ethnicity and other prognostic factors to breast cancer survival patterns in Hawaii.

The survival experience of 2,956 invasive breast carcinoma cases identified among the 5 major ethnic groups in Hawaii between 1960 and 1979 was studied. The study population consisted of 1,174 Caucasian, 972 Japanese, 458 Hawaiian, 226 Chinese, and 126 Filipino women. A multivariate analysis based on the proportional hazards regression model revealed that after simultaneous adjustment for stage of disease, age, and socioeconomic status (SES), Filipino and Hawaiian patients had significantly poorer survival than Japanese and Caucasian patients. Hawaiian women also had a significantly poorer survival than Chinese women. Survival was higher in patients between the ages of 45 and 54 years compared to those younger or older, in patients with localized tumors compared to those with more advanced tumors, and in patients with middle or high SES compared to those with the low SES. Histology and marital status were not associated with survival. The possibility that other factors such as obesity, estrogen receptor status, treatment, and nutritional and hormonal status could explain the remaining observed racial differences in breast cancer survival is discussed.

Digital dermal patterns in large-bowel cancer.

The digital dermal patterns of 149 patients with large-bowel cancer and 298 population-based controls were studied. The patterns were very similar between the 2 groups. Also, no significant differences were found in total ridge counts, which suggests that antenatal factors, related to the formation of digital patterns, are not associated with the risk of large-bowel cancer.

An epidemiologic study on the association between diet and breast cancer.

A case-control study of breast cancer was conducted in Hawaii with Japanese and Caucasian women between ages 45 and 74. Each case was matched to one hospital and one neighborhood control. In all, 183 sets of Japanese and 161 sets of Caucasian subjects were interviewed. No statistically significant differences were found between cases and controls in their mean intake of total fat, saturated fat, oleic acid, linoleic acid, animal protein, and cholesterol. Although there was a suggestion that cases consumed more saturated fat and oleic acid than neighborhood controls, the differences were not impressive. Consistent with other case-control studies, the present investigation did not provide strong support for the hypothesis that a high-fat diet is a risk factor for breast cancer. Further work is suggested to clarify the role of diet in determining breast cancer risk.

Serum cholesterol and colon cancer incidence in Hawaiian Japanese men.

A prospective study of cancer and coronary heart disease (CHD) in 8,006 Hawaiian Japanese men, aged 45-68 years, showed that serum cholesterol levels below 180 mg/dl predicted low rates of CHD and high rates of colon cancer. Men with colon cancer had lower mean serum cholesterol levels than did other members of the cohort, including those with cancer at other sites. The lowest serum cholesterol levels were obtained from men who died as a result of colon cancer. The lack of such an association with other cancers and the persistence of this inverse association in colon cancer patients diagnosed 5-9.9 years after examination suggest that the low serum cholesterol was not due to preexisting disease. Right colon tumors showed the strongest inverse association with serum cholesterol. The differences between CHD and colon cancer in respect to serum cholesterol indicate that different subsets of the westernized Japanese population are affected.

Mutations of p53 gene in hepatocellular carcinoma: roles of hepatitis B virus and aflatoxin contamination in the diet.

BACKGROUND: Mutations of the p53 tumor suppressor gene have been reported in 50% of patients with hepatocellular carcinoma (HCC) from China and South Africa. These reports suggested an association of p53 mutations with high levels of aflatoxin in the diet. Most studies of p53 and HCC, however, have not fully evaluated the possible role of the hepatitis B virus (HBV). Aflatoxin is a substance produced by food mold that is known to cause HCC in experimental animals. PURPOSE: The purpose of this study was to evaluate the relationship of p53 gene mutation to high or low levels of aflatoxin in the diet and to HBV infection. METHODS: p53 protein and hepatitis B surface antigen (HBsAg) were evaluated by immunohistochemistry using the avidin-biotin-peroxidase system in paraffin-embedded specimens of HCC and of adjacent nontumorous liver tissue from 43 patients. Tissue specimens from three normal human livers were also evaluated. HCCs and adjacent nontumorous liver tissues were obtained from 23 patients from Qidong, China, where aflatoxin levels in the diet are high, and from 20 patients from two regions in the United States (patients from the National Institutes of Health, Bethesda, Md., and Kuakini Medical Center, Honolulu, Hawaii), where aflatoxin levels in the diet are low. RESULTS: Mutant p53 protein was detected in the nuclei of HCCs from 14 (61%) of 23 patients from China and from three (30%) of 10 patients and six (60%) of 10 patients, respectively, from the two regions of the United States. A statistically significant association between detection of mutant p53 protein in HCC cells and the detection of HBsAg in hepatocytes of the adjacent nontumorous liver tissue was observed in patients from China and the United States considered together. CONCLUSION: Mutations of the tumor suppressor gene p53 in hepatocellular carcinomas are not limited to patients from geographic regions where the ingestion of aflatoxin is high. In many patients, these mutations may be associated with HBV infection. IMPLICATIONS: The possible interaction of chronic HBV infection and p53 gene mutation, suggested by these data, indicates a mechanism by which HBV infection beginning early in life could contribute to the subsequent development of HCC.

Serum alpha-tocopherol concentration in relation to subsequent colorectal cancer: pooled data from five cohorts.

BACKGROUND: Vitamin E is an antioxidant that inhibits mutagenesis and cell transformation. Previous findings in five prospective epidemiologic studies suggested that the level of serum alpha-tocopherol, the predominant form of vitamin E in the blood, was lower in subjects who subsequently developed colorectal cancer than in control subjects. However, the difference was neither obvious nor statistically significant in any one of these five studies. PURPOSE: To evaluate in greater detail the association between serum alpha-tocopherol concentration and risk of colorectal cancer, we pooled and analyzed the original data from the five studies. Our analyses were designed to (a) test the hypothesis with greater statistical power, (b) examine the association after adjustment for serum cholesterol levels, and (c) evaluate the association after uniform exclusion of cases diagnosed shortly after blood specimens were drawn. METHODS: Data for individual subjects were analyzed. To make the design of the component investigations uniformly nested case-control studies with individual matching, we matched controls to cases in two of the cohorts. Subjects were categorized according to study-specific quartile of serum alpha-tocopherol level within the study. The pooled analysis included 289 cases of colorectal cancer and 1267 matched controls. RESULTS: For cancers of the colon and rectum combined, the matched odds ratio (OR) for the highest quartile of serum alpha-tocopherol concentration compared with the lowest was 0.6 (95% confidence interval [CI] = 0.4-1.0). Adjustment for serum cholesterol level attenuated the OR to 0.7 (95% CI = 0.4-1.1). CONCLUSION: The results suggest that serum alpha-tocopherol concentration may be inversely related to risk of colorectal cancer. It is unclear whether an association exists, however, because the association between serum alpha-tocopherol level and decreased risk of colorectal cancer was modest, the CIs were wide, and, overall, the tests for trend in effect were not significant. IMPLICATIONS: Larger observational studies with concurrent dietary data are needed to determine whether vitamin E has a modest but potentially important protective effect against colorectal cancer.

Relative weight, weight change, height, and breast cancer risk in Asian-American women.

BACKGROUND: Breast cancer incidence rates have historically been four to seven times higher in the United States than in China or Japan, although the reasons remain elusive. When Chinese, Japanese, or Filipino women migrate to the United States, their breast cancer risk rises over several generations and reaches that for white women in the United States, indicating that modifiable exposures are involved. In a previous report on this case-control study of breast cancer in Asian-American women, designed to take advantage of their diversity in risk and lifestyle, we demonstrated a sixfold gradient in risk by migration history, comparable to the international differences in breast cancer incidence rates. PURPOSE: In this analysis, we have examined the roles of adult height, adiposity, and weight change in breast cancer etiology. METHODS: A population-based, case-control study of breast cancer was conducted among women of Chinese, Japanese, and Filipino ethnicities, aged 20-55 years, living in San Francisco-Oakland (CA), Los Angeles (CA), and Oahu (HI) during the period from April 1, 1983, through June 30, 1987. We successfully interviewed 597 (70%) of 852 eligible case subjects and 966 (75%) of 1287 eligible control subjects from August 1985 through February 1989. Subjects were asked about current height, usual adult weight, and usual weight in each decade of life, excluding the most recent 3 years and any periods of pregnancy. RESULTS: Height, recent adiposity (weight in the current decade of life/height 1.5), and recent weight change (between the current and preceding decades of life) were strong predictors of breast cancer risk after adjustment was made for accepted breast cancer risk factors. Risk doubled (relative risk [RR] = 2.01; 95% confidence interval [CI] = 1.16-3.49) over the 7-inch (17.8-cm) range in height (two-sided P for trend = .003), with comparable effects in both premenopausal and postmenopausal women. Except for reduced risk in the heavy, younger women (weight/height 1.5 > 29 kg/m 1.5 and < 40 years old), risk was positively associated with usual adult adiposity. Trends in risk became more striking as adiposity in each succeeding decade of adult life was considered. Women in their 50s and in the top quintile for their age group had twice the breast cancer risk (RR = 2.13; 95% CI = 1.17-3.87) of women in the bottom quintile (two-sided P for trend = .004). Women in their 50s, above the median adiposity for their age group, and with a recent gain of more than 10 pounds had three times the risk (RR = 3.01; 95% CI = 1.45-6.25) of women below the median adiposity and with no recent weight change. Recent weight loss was consistently associated with reduced risk (RRs of approximately 0.7) relative to no recent weight change. CONCLUSIONS: Adult adiposity, weight change, and height are critical determinants of breast cancer risk. Increased adiposity and weight gain in the decade preceding diagnosis are especially influential, suggesting that excess weight may function as a late stage promoter. IMPLICATIONS: Weight maintenance and/or reduction as an adult, possibly accompanied by specific changes in diet and physical activity, may have a significant and rapid impact on breast cancer risk.

Migration patterns and breast cancer risk in Asian-American women.

BACKGROUND: Breast cancer incidence rates have historically been 4-7 times higher in the United States than in China or Japan, although the reasons remain elusive. When Chinese, Japanese, or Filipino women migrate to the United States, breast cancer risk rises over several generations and approaches that among U.S. Whites. PURPOSE: Our objective was to quantify breast cancer risks associated with the various migration patterns of Asian-American women. METHODS: A population-based, case-control study of breast cancer among women of Chinese, Japanese, and Filipino ethnicities, aged 20-55 years, was conducted during 1983-1987 in San Francisco-Oakland, California, Los Angeles, California, and Oahu, Hawaii. We successfully interviewed 597 case subjects (70% of those eligible) and 966 control subjects (75%). RESULTS: A sixfold gradient in breast cancer risk by migration patterns was observed. Asian-American women born in the West had a breast cancer risk 60% higher than Asian-American women born in the East. Among those born in the West, risk was determined by whether their grandparents, especially grandmothers, were born in the East or the West. Asian-American women with three or four grandparents born in the West had a risk 50% higher than those with all grandparents born in the East. Among the Asian-American women born in the East, breast cancer risk was determined by whether their communities prior to migration were rural or urban and by the number of years subsequently lived in the West. Migrants from urban areas had a risk 30% higher than migrants from rural areas. Migrants who had lived in the West for a decade or longer had a risk 80% higher than more recent migrants. Risk was unrelated to age at migration for women migrating at ages less than 36 years. Ethnic-specific incidence rates of breast cancer in the migrating generation were clearly elevated above those in the countries of origin, while rates in Asian-Americans born in the West approximated the U.S. White rate. CONCLUSIONS: Exposure to Western lifestyles had a substantial impact on breast cancer risk in Asian migrants to the United States during their lifetime. There was no direct evidence of an especially susceptible period, during either menarche or early reproductive life. IMPLICATIONS: Because heterogeneity in breast cancer risk in these ethnic populations is similar to that in international comparisons and because analytic epidemiologic studies offer the opportunity to disentangle correlated exposures, this study should provide new insights into the etiology of breast cancer.

Dietary fat and the risk of colorectal cancer.

The relationship between the intake of dietary fat and subsequent colorectal cancer during a 15-year follow-up was investigated in 7074 men of Japanese ancestry, 45 to 68 years old and living in Hawaii. Data on fat intake were obtained by 24-hr recall records at base-line examination. We found a statistically significant, negative association between colon cancer and the intake of saturated fat, whether assessed on the basis of g per day or as a percentage of the caloric intake. There was a similar association with total fat intake when expressed in terms of percentage of total calories. The strongest negative relationship was found in cancer of the right colon. In contrast, rectal cancer showed a weakly positive relationship to the intake of saturated fat when assessed on the basis of percentage of caloric intake.

Dietary fat intake and cancer incidence among five ethnic groups in Hawaii.

Average daily intakes of several components of fat in the diets of the five main ethnic groups in Hawaii were determined from personal interviews of 4137 subjects regarding their food consumption in a usual week. In general, fat intake was highest among Caucasians and lowest among Filipinos. Cholesterol intake did not follow the same pattern as that of the other fat components. The intake of total fat showed good correlation with the ethnic-specific incidence rates of breast cancer in Hawaii but not with colon or prostate cancer rates. There was no correlation of cholesterol intake with colon cancer incidence.

A prospective study of demographics, diet, and prostate cancer among men of Japanese ancestry in Hawaii.

Prostate cancer incidence was prospectively studied among 7999 men of Japanese ancestry who were first examined between 1965 and 1968 and then followed through 1986. During this surveillance period, 174 incident cases of prostate cancer were recorded. Prostate cancer was not associated with any measure of socioeconomic status, including amount of education, type of occupation, and type of residence. There was also no relationship with the number of children, as a surrogate measure of sexual activity. Increased consumption of rice and tofu were both associated with a decreased risk of prostate cancer, while consumption of seaweeds was associated with an increased risk of prostate cancer. There was no relationship between prostate cancer and the intake of various nutrients, including total fat and total protein. Etiological implications of these associations are discussed, but more research is needed on these dietary factors and the subsequent development of prostate cancer before any firm conclusions can be drawn.

A case-cohort study of diet and stomach cancer.

In this case-cohort study, from 1965 to 1968, 8006 Hawaiian men of Japanese ancestry were interviewed with a 24-h dietary recall questionnaire. After a follow-up period of 18 years, 111 stomach cancer incident cases were identified. Dietary data from these patients and from 361 cancer-free men were analyzed for intake of selected foods, food groups, and nutrients. We found that the consumption of all types of vegetables was protective against stomach cancer. Specifically, subjects in the highest group of vegetable consumption (greater than or equal to 80 g/day) had a relative risk of 0.6 (95% confidence interval, 0.3-0.9) in comparison with nonconsumers. This statistically significant inverse trend persisted after adjustment for age at examination and cigarette-smoking status. Similar but weaker protective effects from consumption of green and cruciferous vegetables were also observed. In addition, an inverse association between stomach cancer risk and intake of fruits was noted (P = 0.05), but this inverse trend was weakened after the effect of cigarette smoking was taken into account. There were no other dietary factors significantly associated with the risk of gastric cancer.

Role of diet in cancer incidence in Hawaii.

Incidence rates for many sites of cancer show wide variations among the main ethnic groups in Hawaii (Caucasians, Japanese, Chinese, Filipinos, and Hawaiians). Major shifts in cancer rates among migrants to the islands suggest that environmental factors are at least in part responsible for these variations. One prominent area of difference among these ethnic populations is their diets, which can vary substantially, not only in the consumption of particular food items but also in mean nutrient intakes. In aggregate correlational analyses based on data from representative samples of these ethnic groups and corresponding population-based cancer incidence rates, we found significant associations between ethnic-sex-specific intakes of dietary fat (including total fat, as well as animal, saturated, and unsaturated fats) and breast, endometrial, and prostate cancers. Animal protein intake showed associations similar to those for dietary fat, but these two nutrients were highly correlated in the data. Cholesterol intake showed significant correlations with lung and laryngeal cancers. Analyses of both nutrient and food item data suggested an association of stomach cancer incidence with the consumption of fish products, particularly dried/salted fish, and with a lower intake of vitamin C. Preliminary findings from ongoing case-control studies showed the following relationships: an inverse association between lung cancer risk and the intake of food sources of vitamin A, especially foods containing carotenes; an inverse association between cancers of the lower urinary tract and vitamin A consumption, especially from supplements; a positive association between prostate cancer risk and dietary fat intake in men above age 69, but not in younger men; and a positive association between breast cancer risk and the intake of dietary fat (particularly saturated fat) and animal protein in postmenopausal women, especially the Japanese. Two large cohorts (50,000 and 5,000 subjects) on whom dietary information was collected between 1975 and 1980 are being followed prospectively for their occurrence of cancer.

Serum vitamin levels and the risk of cancer of specific sites in men of Japanese ancestry in Hawaii.

Serum specimens were obtained from over 6800 men of Japanese ancestry in Hawaii from 1971 to 1975. Since then, the following numbers of newly diagnosed cancer cases have been identified: 81 colon, 74 lung, 70 stomach, 32 rectum, and 27 urinary bladder. The stored sera of the cases and 302 controls were tested to determine their beta-carotene, vitamin A, and vitamin E levels. There was no association of either vitamin A or E with any of the cancers. For serum beta-carotene, there was a significant association only with lung cancer (20.0 micrograms/dl in cases versus 29.0 in controls, P less than 0.005). The lung cancer odds ratio for men in the lowest quintile of beta-carotene was 3.4 relative to men in the highest quintile. These findings suggest that a low serum beta-carotene level is a predictor of increased lung cancer risk in men.

Fecal neutral steroids in two Japanese populations with different colon cancer risks.

Several workers have associated fecal neutral steroids with colon cancer frequency. They suggested that the risk for colon cancer increases with a rise in the level of total and certain neutral steroids. The Japanese in Hawaii, who are at high risk for this cancer, had a higher concentration of cholesterol and total animal steroids in their fecal specimens than did the people in Akita, Japan, who are at low risk. However, the rest of the findings on neutral steroids were unremarkable or inconsistent in comparison with those of other studies. These data are suggestive but not strongly supportive of a relationship between fecal neutral steroid patterns and colon cancer risk.

Cytochrome P450c17alpha gene (CYP17) polymorphism predicts use of hormone replacement therapy.

We investigated whether a polymorphism in the cytochrome P450c17alpha gene (CYP17), which is associated with higher endogenous hormone levels, influences the use of hormone replacement therapy (HRT). The study included 749 postmenopausal women ages 44-75 years at baseline randomly selected from a larger multiethnic cohort. African-American, Japanese, Latina, and white women were included in the study. Women who carry the CYP17 A2/A2 genotype were about half as likely as women with the A1/A1 genotype to be current HRT users (odds ratio = 0.52; 95% confidence interval, 0.31-0.86). This association was present in all four racial/ethnic groups and for women above and below the median weight of 150 pounds. These findings suggest that the actual risk of breast cancer associated with HRT use may be higher than previously reported.

Auto-inactivation by cleavage within the dimer interface of Kaposi's sarcoma-associated herpesvirus protease.

An autolysis site of functional and structural significance has been mapped within the dimer interface of Kaposi's sarcoma-associated herpesvirus protease. Cleavage 27 residues from the C terminus of the 230 amino acid residue, 25 kDa protein was observed to cause a loss of dimerization and proteolytic activity, even though no active site moieties were lost. Gel-filtration chromatography and analytical ultracentrifugation were used to analyze the changes in oligomerization upon autolysis. The selective auto-disruption of this essential protein-protein interface by proteolytic cleavage resulted in a 60 % loss in mean residue ellipticity by circular dichroism as well as a 20 % weaker, 10 nm red-shifted intrinsic protein fluorescence emission spectrum. These apparent conformational changes induced a strict inhibition of enzymatic activity. An engineered substitution at the P1' position of this cleavage site attenuated autolysis by the enzyme and restored wild-type dimerization. In addition to retaining full proteolytic activity in a continuous fluorescence-based enzyme assay, this protease variant allowed the determination of the enzyme's dimerization dissociation constant of 1.7 (+/-0.9) microM. The structural perturbations observed in this enzyme may play a role in viral maturation, and offer general insight into the allosteric relationship between the dimer interface and active site of herpesviral proteases. The functional coupling between oligomerization and activity presented here may allow for a better understanding of such phenomena, and the design of an enzyme variant stabilized to autolysis should further the structural and mechanistic characterization of this viral protease.

Serum cholesterol and mortality among Japanese-American men. The Honolulu (Hawaii) Heart Program.

Hawaiian men of Japanese ancestry followed up for 18 or more years after a baseline examination showed a quadratic distribution of death rates at different levels of serum cholesterol. Mortality from cancer progressively decreased and mortality from coronary heart disease progressively increased with rising levels of serum cholesterol. There was a positive association between baseline serum cholesterol levels and deaths from coronary heart disease at 0 to 6 years, 7 to 12 years, and 13 years and longer after examination. The inverse relationship between cancer and serum cholesterol levels was stronger in the first 6 years than in the next 6 years and, although still inverse, lost statistical significance after 13 years. Cancers of the colon and lung showed the strongest association with low baseline serum cholesterol levels, while gastric or rectal cancer failed to show this association. Organ specificity and persistence of the inverse association beyond 6 years suggest that the nutritional demands of cancers may not entirely explain the inverse association with some cancers. The quadratic distribution of deaths in this cohort remained after coronary heart disease, stroke, and cancer were removed from the analysis. For the entire period of observation, the lowest mortalities were found in men with serum cholesterol levels between 4.65 and 6.18 mmol/L (between 180 and 239 mg/dL). Manipulation of serum cholesterol levels below this level would not be desirable if this were to result in increased risk of death from cancer or other disease. This study does not rule out this possibility.