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.

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.

Prospective study of coffee consumption and the risk of cancer.

Information on coffee consumption was obtained from 7,355 men clinically examined from 1965 to 1968, as part of a prospective cohort study. Since examination, the following numbers of newly diagnosed cancer cases have been identified: 110 lung, 108 colon, 108 prostate, 106 stomach, 60 rectum, 39 bladder, 21 pancreas, and 120 other sites. Coffee intake did not significantly increase the risk for any of the cancers in this study. There was a slight suggestion of a positive association between heavy coffee intake and the risk for lung and urinary bladder cancer, but it could be attributed to the confounding effects of cigarette smoking among the male coffee drinkers. Overall, there was no strong evidence that coffee intake increased the risk for any of the common cancers in this study.

Body mass index as a predictor of cancer in men.

In this prospective study 8,006 Japanese men, age 45-68 years, were examined between 1965 and 1968. Their height and weight were measured and they were asked for their weight at age 25. After a surveillance period of almost 15 years, 646 incident cases of the following cancers were identified: 104 stomach, 101 colon, 101 lung, 96 prostate, 63 rectum, and 181 cancers of other sites. Body mass index (BMI = weight/height2) at time of examination and weight gain since age 25 were positively associated with an increased risk for colon cancer in subjects age 55 or older at the time of examination. No other cancer had a significant positive association with either BMI at the time of examination or with weight gain since age 25. In contrast, a low BMI at examination and weight loss since age 25 were associated with an increased risk for stomach cancer, whereas only weight loss since age 25 was associated with an increased risk for lung cancer. These two cancers accounted for the overall significant association of weight loss with total cancer incidence.

Serum selenium and the risk of cancer, by specific sites: case-control analysis of prospective data.

From 1971 to 1975, serum specimens were obtained from 6,860 men of Japanese ancestry in Hawaii. Since then, the following numbers of newly diagnosed cases with epithelial cancer have been identified: 82 colon, 71 lung, 66 stomach, 32 rectum, and 29 urinary bladder. The stored sera of the 280 cases and of 293 randomly selected controls were tested to determine their levels of selenium. There was no association of serum selenium with lung, stomach, or rectal cancer. An increase in relative risk (RR) was noted only for subjects in the lowest quintile of selenium values, as compared to the RR for subjects in the highest quintile, for colon (RR = 1.8) and urinary bladder cancer (RR = 3.1), but neither of these RR estimates was statistically significant (P = .09 and P = .07, respectively). Further work is needed to determine whether the antioxidant properties of selenium protect against specific types of cancer.

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.

Mutagens in extracts of human gastric mucosa.

Extracts of mucosa from 53 stomachs were tested for mutagenicity with the use of Salmonella typhimurium strains TA98 and TA100. Mutagenic activity was observed in nonneoplastic mucosa from seven stomachs with S. typhimurium strain TA98 without the S-. mix (a rat liver microsomal enzyme preparation) and in three stomachs with TA100 without S-. mix. All of the TA98 mutagenic samples were derived from stomachs showing evidence of intestinal metaplasia. The exception was an extract of corpus mucosa that was mutagenic with strain TA100. "Transnitrosoase" activity was found in 12 of 53 samples, all of which showed TA98 mutagenicity. Whether the presence of mutagens and transnitrosoase activity causes intestinal metaplasia or results from it is uncertain.

Trends in frequency of latent prostate carcinoma in Japan from 1965-1979 to 1982-1986.

By analyzing serial step-sections of whole prostate obtained at autopsy, we determined the chronologic change of the frequency of latent prostate tumor in Japan in two periods: 1965-1979 and 1982-1986. Methods of specimen preparation and examination were identical for both periods. The frequency with which latent prostate carcinoma was found in the 660 samples for 1982-1986 was 34.6% and was significantly higher than the 22.5% seen in the 576 observed for 1965-1979 (P less than .0001). This significant finding can be attributed to an increase in the frequency of latent infiltrative tumor (LIT). However, the increase in the frequency of noninfiltrative tumor (LNT) was less significant (P = .045). Both sets of specimens were subsequently combined and reanalyzed according to the year of birth of the decedents. The LIT has progressively increased in frequency in each age-specific category. By morphometry, we determined that the mean tumor volume decreased due to an increase in the number of smaller tumors during the study periods. Although the frequency of latent prostate carcinoma and the LIT:LNT in the samples obtained most recently were comparable to those of U.S. whites, cancer incidence and mortality rates remain lower in Japan. Apparently, the initial step in the induction of prostate carcinoma in indigenous Japanese is now similar to that in U.S. whites. The rates of clinical carcinoma in Japan are still low when compared with those in the United States and countries in Western Europe, but our findings may presage a time when these differences may be greatly reduced or nonexistent.

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.

Intestinal metaplasia in Japan: association with diet.

Of 1,749 volunteers in a screening program for gastric cancer in Japan, 206 men and 181 women received a systematic gastroscopic examination and responded to a dietary questionnaire estimating their quantitative intake of 33 food items during the past weeks. When diet was correlated with intestinal metaplasia (a precursor lesion of gastric carcinoma) found in gastroscopic biopsies, it was observed that more dried fish consumption and less vitamin A intake increased the extent of intestinal metaplasia in men. For women, there was a significant negative association of ume (pickled plum) intake with intestinal metaplasia. The implications of these findings were discussed in relation to gastric 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.

A prospective study of stomach cancer and its relation to diet, cigarettes, and alcohol consumption.

From 1965 to 1968 in Hawaii, 7990 American men of Japanese ancestry were interviewed and examined in a cohort study. The intake of 20 separate foods in a food frequency questionnaire and the intake of carbohydrate and other nutrients, based on a 24-h diet recall history, were recorded. Since then, 150 incident cases of stomach cancer have been identified. Although men with stomach cancer (cases) consumed pickles and ham/bacon/sausages more often and fruits and fried vegetables less often than men without cancer (noncases), none of the differences was statistically significant. Current cigarette smokers had an increased risk (relative risk = 2.7; 95% confidence interval = 1.8 to 4.1) compared with nonsmokers, but there was no dose-response effect with heavier cigarette smoking. The consumption of alcohol, either from beer, spirits, or wine, did not affect the incidence of stomach cancer. The failure to detect an association with dietary foods in this study may be due to the omission of many oriental foods in the questionnaire and the limitations of the 24-h diet recall history.

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.

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.

Prediagnostic serum hormones and the risk of prostate cancer.

Serum samples were obtained from 6860 men during their study examination from 1971 to 1975. After a surveillance period of about 14 years, 98 incident cases of prostate cancer were identified. Their stored sera and that of 98 matched controls from the study population were tested for the following: testosterone, dihydrotestosterone, estrone, estradiol, and sex hormone globulin. There was a suggestion that serum dihydrotestosterone levels were lower and the testosterone/dihydrotestosterone ratios were higher in the prostate cancer cases compared with their controls. However, none of these associations or that of the other hormones was strongly significant. Further work is needed to clarify the relationship between sex hormones and prostate cancer risk.

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.

Infection with Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of the stomach.

To determine whether infection with a Helicobacter pylori strain possessing cagA is associated with an increased risk of development of adenocarcinoma of the stomach, we used a nested case-control study based on a cohort of 5443 Japanese-American men in Oahu, Hawaii, who had a physical examination and a phlebotomy during 1967 to 1970. We matched 103 H. pylori-infected men who developed gastric cancer during a 21-year surveillence period with 103 H. pylori-infected men who did not develop gastric cancer and tested stored serum specimens from patients and controls for the presence of serum IgG to the cagA product of H. pylori using an ELISA. The serum IgG assay using a recombinant CagA fragment had a sensitivity of 94.4% and a specificity of 92.5% when used in a clinically defined population; serological results were stable for more than 7 years. For men with antibodies to CagA, the odds ratio of developing gastric cancer was 1.9 (95% confidence interval, 0.9-4.0); for intestinal type cancer of the distal stomach, the odds ratio was 2.3 (95% confidence interval, 1.0-5.2). Age < 72 years and advanced tumor stage at diagnosis were significantly associated with CagA seropositivity. We conclude that infection with a cagA-positive H. pylori strain in comparison with a cagA-negative strain somewhat increases the risk for development of gastric cancer, especially intestinal type affecting the distal stomach.

Fecal bile acids in two Japanese populations with different colon cancer risks.

Some workers have associated fecal bile acids with colon cancer frequency. They suggest that the risk for colon cancer increases with a rise in the level of total and degraded fecal bile acids. The Japanese in Hawaii, who are at high risk for this cancer, had higher concentrations of deoxycholic acid (a degraded bile acid) in their fecal specimens than did the people in Akita, Japan, who are at low risk. However, the findings for the other bile acids were unremarkable or inconsistent. These data were suggestive, but not strongly supportive, of a relationship between fecal bile acid patterns and colon cancer risk.

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.

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.