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Background: Oral contraceptives (OC) are associated with a decreased risk of colorectal cancers; however, a recent study reported an increased risk of small colorectal adenomas associated with OC use. To determine if these results were replicable in a different study population, we investigated the relationship between OC use and other reproductive factors and risk of colorectal polyps in a case-control study in western Washington., Methods: Study participants were 24-79-year-old female enrollees at an integrated health care system in western Washington who were diagnosed as having adenomas (n = 299), serrated polyps (n = 337), both types of polyps (n = 105) or as polyp-free controls (n = 615) through an index colonoscopy and completed a structured interview to collect reproductive history information. Multivariable polytomous logistic regression was used to compare case groups to controls and to each other; odds ratios (OR) and 95% confidence intervals were estimated., Results: There was no association between OC use, duration of use, or recency of use and the risk of either adenomas or serrated polyps [adjusted OR for OC ever use (95% CI) 0.85 (0.58-1.23) and 0.96 (0.66-1.40), respectively], and associations did not differ by lesion severity within the adenoma or serrated pathways. Further, no associations were observed between other reproductive factors and risk of colorectal polyp subtypes., Conclusions: Our results suggest that reproductive factors, including OC use, are not associated with early colorectal cancer precursor lesions.

Purpose: Studies linking cholesterol levels to the development of colorectal neoplasia are inconsistent, and Mendelian randomization has been suggested as a way to help avoid problems with confounding and reverse causation., Methods: We genotyped individuals who received a colonoscopy at Group Health (1998-2007) for 96 of 102 single-nucleotide polymorphisms identified by the Global Lipids Genetics Consortium. Participants included 139 advanced adenoma cases, 518 non-advanced adenoma cases, 380 non-adenomatous polyp cases, and 754 polyp-free controls. All had at least one available pre-colonoscopy lipid measurement from electronic records maintained by Group Health., Results: Advanced adenoma cases were more likely than controls to have higher pre-colonoscopy zenith low-density lipoprotein (LDL), triglycerides (TG), and total cholesterol (TC) (odds ratio, OR per 20 mg/dL LDL increase: 1.16, 95 % confidence interval, CI 1.03-1.30; per 40 mg/dL TG increase: 1.09, 1.03-1.16; and per 20 mg/dL TC increase: 1.09, 1.02-1.18). For these traits, genotype-polyp ORs using weighted allele scores were not statistically significant (OR per increase in score scaled to a 20 mg/dL LDL increase: 1.17, 0.78-1.75; a 40 mg/dL TG increase: 1.12, 0.91-1.38; a 20 mg/dL TC increase: 0.99, 0.71-1.38)., Conclusions: Cholesterol levels may be associated with advanced adenomas, but larger studies are warranted to determine whether this association can be attributed to genetics.

Purpose: Eating frequency is a modifiable aspect of dietary behavior that may affect risk of colorectal cancer (CRC). Although most previous case-control studies indicate a positive association, two prospective studies suggest an inverse association between eating frequency and CRC risk, with evidence of effect modification by diet composition. We examined the association between eating frequency and CRC in a large, prospective cohort study, and explored whether this relationship was modified by sex, coffee consumption, or dietary glycemic load., Methods: Between 2000 and 2002, 67,912 western Washington residents aged 50-76 reported average daily meal and snack frequency using a mailed questionnaire as part of the vitamins and lifestyle study. Participants were followed for CRC through linkage with SEER through 2008, over which time 409 CRC cases developed. Hazard Ratios and 95 % Confidence Intervals were obtained using Cox regression., Results: In age- and sex-adjusted models higher (5+ times/d) vs. lower (1-2 times/d) eating frequency was associated with a HR of 0.62 (95 % CI 0.43-0.88, Ptrend = 0.001). However, following further adjustment for BMI, race/ethnicity, alcohol, and other known CRC risk factors, the relationship was no longer statistically significant (HR: 0.76; 95 % CI 0.51, 1.14). No effect modification was observed by sex (Pinteraction = 0.45), coffee consumption (Pinteraction = 0.44), or dietary glycemic load (Pinteraction = 0.90). In subgroup analyses by tumor site, higher vs. lower eating frequency was associated with lower risk for colon (HR 0.65 95 % CI 0.39-1.07, Ptrend = 0.04), but not rectal cancers (HR = 1.08 95 % CI 0.54-2.18, Ptrend = 0.94)., Conclusion: The weak inverse association observed between eating frequency and CRC is consistent with findings from other prospective studies. Modification of this relationship by diet quality and participant characteristics should be considered in the future studies.

Purpose: Nonsteroidal anti-inflammatory drugs (NSAIDs) target the prostaglandin H synthase enzymes, cyclooxygenase (COX)-1 and COX-2, and reduce colorectal cancer risk. Genetic variation in the genes encoding these enzymes may be associated with changes in colon and rectal cancer risk and in NSAID efficacy., Methods: We genotyped candidate polymorphisms and tag SNPs in PTGS1 (COX-1) and PTGS2 (COX-2) in a population-based case–control study (Diet, Activity and Lifestyle Study, DALS) of colon cancer (n = 1,470 cases/1,837 controls) and rectal cancer (n = 583/775), and independently among cases and controls from the Colon Cancer Family Registry (CCFR; colon n = 959/1,535, rectal n = 505/839)., Results: In PTGS2, a functional polymorphism (-765G[C; rs20417) was associated with a twofold increased rectal cancer risk (p = 0.05) in the DALS. This association replicated with a significant nearly fivefold increased risk of rectal cancer in the CCFR study (ORCC vs. GG = 4.88; 95 % CI 1.54–15.45; ORGC vs. GG = 1.36; 95 %CI 0.95–1.94). Genotype–NSAID interactions were observed in the DALS for PTGS1 and rectal cancer risk and for PTGS2 and colon cancer risk, but were no longer significant after correcting for multiple comparisons and did not replicate in the CCFR. No significant associations between PTGS1 polymorphisms and colon or rectal cancer risk were observed.

Purpose: Use of non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the incidence of several cancers. A recent meta-analysis of randomized trials of aspirin reported a reduction in cancer mortality; however, few studies have investigated whether aspirin or other NSAIDs reduce overall cancer risk., Methods: 64,847 residents of western Washington State, aged 50-76, completed a baseline questionnaire in 2000-2002 and reported on their use of individual NSAIDs over the past 10 years. Behavior was categorized as non-use, low (<4 days/week or <4 years), and high (≥4 days/week and ≥4 years). Over 7 years of follow-up, 5,946 incident invasive cancer cases were identified. Multivariable proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI)., Results: Relative to non-use, high 10-year use of regular-strength NSAIDs was inversely associated with total cancer risk in men (HR 0.88, 95% CI: 0.79-0.97) and not associated with risk in women (HR 1.10, 95% CI: 0.96-1.25; p interaction <0.01). Use of regular-strength NSAIDs was strongly and inversely associated with colorectal cancer risk in men and women, but differentially associated with sex-specific risk of shared cancer sites other than colorectal cancer (men: HR 0.83, 95% CI: 0.71-0.97; women: HR 1.18, 95% CI: 0.97-1.44; p interaction < 0.01)., Conclusions: Long-term use of NSAIDs was associated with a reduced risk of total cancer among men and colorectal cancer among both sexes. Our findings do not support NSAID use for overall cancer prevention among women. Additional high-quality studies with long-term follow-up for cancer among women are needed before a public health recommendation can be made.

CYP19A1, or aromatase, influences estrogen-metabolizing enzymes and may influence cancer risk. We examine variation in the CYP19A1 gene and risk of colorectal cancer using data from population-based case-control studies (colon n = 1,574 cases, 1,970 controls; rectal n = 791 cases, 999 controls). Four SNPs were statistically significantly associated with colon cancer and four were associated with rectal cancer. After adjustment for multiple comparisons, the AA genotype of rs12591359 was associated with an increased risk of colon cancer (OR 1.44 95% CI 1.16-1.80) and the AA genotype of rs2470144 was associated with a reduced risk of rectal cancer (OR 0.65 95% CI 0.50-0.84). Variants of CYP19A1 were associated with CIMP+ and CIMP+/KRAS2-mutated tumors. CT/TT genotypes of rs1961177 were significantly associated with an increased likelihood of a MSI+ colon tumor (OR 1.77 95% CI 1.26-2.37). We observed statistically significant interactions between genetic variation in NFκB1 and CYP19A1 for both colon and rectal cancer. Our data suggest the importance of CYP19A1 in the development of colon and rectal cancer and that estrogen may influence risk through an inflammation-related mechanism.

Objective: Studies of folate intake and colorectal cancer risk have been inconsistent. We examined the relation with colon cancer risk in a series of 13 prospective studies., Methods: Study- and sex-specific relative risks (RRs) were estimated from the primary data using Cox proportional hazards models and then pooled using a random-effects model., Results: Among 725,134 participants, 5,720 incident colon cancers were diagnosed during follow-up. The pooled multivariate RRs (95% confidence interval [CI]) comparing the highest vs. lowest quintile of intake were 0.92 (95% CI 0.84-1.00, p-value, test for between-studies heterogeneity = 0.85) for dietary folate and 0.85 (95% CI 0.77-0.95, p-value, test for between-studies heterogeneity = 0.42) for total folate. Results for total folate intake were similar in analyses using absolute intake cutpoints (pooled multivariate RR = 0.87, 95% CI 0.78-0.98, comparing ≥ 560 mcg/days vs. <240 mcg/days, p-value, test for trend = 0.009). When analyzed as a continuous variable, a 2% risk reduction (95% CI 0-3%) was estimated for every 100 μg/day increase in total folate intake., Conclusion: These data support the hypothesis that higher folate intake is modestly associated with reduced risk of colon cancer.

Objective: Vitamin E and selenium are promising nutrients for the prevention of prostate cancer, and both are currently being tested in a large randomized trial for prostate cancer. However, results are not expected for at least 6 years. We aimed to investigate the association of vitamin E and selenium supplementation with prostate cancer in the VITamins And Lifestyle (VITAL) study, a cohort study specifically designed to examine supplement use and future cancer risk., Methods: In a prospective design, 35,242 men recruited between 2000 and 2002 from western Washington State completed a questionnaire, including detailed questions about vitamin E and selenium supplement intake during the past 10 years from brand-specific multivitamins and single supplements. Using linkage to the western Washington SEER cancer registry, we documented 830 new cases of prostate cancer from baseline through December 2004., Results: A 10-year average intake of supplemental vitamin E was not associated with a reduced prostate cancer risk overall [hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.65-1.1 for > or =400 IU/day vs. non-use, p for trend 0.36]; however, risk for advanced prostate cancer (regionally invasive or distant metastatic, n = 123) decreased significantly with greater intake of supplemental vitamin E (HR 0.43, 95% CI 0.19-1.0 for 10-year average intake > or =400 IU/day vs. non-use, p for trend 0.03). There was no association between selenium supplementation and prostate cancer risk (HR 0.90, 95% CI 0.62-1.3 for 10-year average intake >50 microg/day vs. non-use, p for trend 0.97)., Conclusions: In this prospective cohort, long-term supplemental intake of vitamin E and selenium were not associated with prostate cancer risk overall; however, risk of clinically relevant advanced disease was reduced with greater long-term vitamin E supplementation.

Inflammation appears to play a key role in the development of colorectal cancer (CRC). In this study we examine factors involved in the regulation of inflammation and risk of CRC. Data from a multi-center case-control study of colon (N = 1579 cases and N = 1977 controls) and rectal (N = 794 cases and N = 1005 controls) cancer were used to evaluate the association between the rs1800795 and rs1800796 IL6 polymorphisms and CRC. We evaluated the joint effects of IL6 single nucleotide polymorphisms and regular use of aspirin/NSAIDs and vitamin D receptor (VDR) genotype. Having a C allele of the rs1800796 IL6 polymorphisms and the GG genotype of the rs1800795 IL6 polymorphisms was associated with a statistically significantly reduced the risk of colon (OR 0.76 95% CI 0.57, 1.00), but not rectal (OR 1.49 95% CI 1.02,2.16) cancer. Both IL6 polymorphisms were associated with significant interaction with current use of aspirin/NSAIDs to alter risk of colon cancer: individuals with a C allele in either polymorphism who were current users of aspirin/NSAIDs had the lowest colon cancer risk. CRC risk also was associated with an interaction between VDR and IL6 genotypes that was modified by current use of aspirin/NSAIDs. This study provides further support for inflammation-related factors in the etiology of CRC. Other studies are needed to explore other genes in this and other inflammation-related pathways.

We hypothesize that the peroxisome proliferator-activated receptor-gamma (PPARgamma) is associated with colorectal cancer given its association with insulin, diabetes, obesity, and inflammation. In this study, we evaluated the association between colorectal cancer and specific tumor mutations and the Pro12Ala (P12A) PPARgamma polymorphism. We also evaluated interactions between the PPARgamma gene and other insulin-related genes and use of aspirin and non-steroidal anti-inflammatory drug use. Data were available from 1,577 cases of colon cancer that were matched to 1,971 population-based controls and 794 cases of rectal cancer that were matched to 1,001 population-based controls. Colon tumors from the case subjects were evaluated for p53 and Ki-ras mutations and microsatellite instability (MSI). Insulin-related genes evaluated were the Bsm1, polyA, and Fok1 polymorphisms of the VDR gene; the G972R IRS1 polymorphism; the G1057D IRS2 polymorphism; the 19CA repeat polymorphism of the IGF1 gene; and the -200A>C IGFBP3 polymorphism. The odds ratio (OR) between the PA/AA genotypes and proximal tumors was 0.83 (95% CI: 0.69-1.01); for distal tumors was 1.00 (95% CI: 0.83-1.21); and for rectal tumors was 1.04 (95% CI: 0.86-1.25). Evaluation of specific types of tumor mutations showed that colon cancer cases with the PA or AA genotypes were less likely to have p53 tumor mutations (OR 0.78; 95% CI: 0.62-0.99), specifically transition mutations (OR 0.74; 95% CI: 0.56-0.97). Colon cancer cases also were less likely to have a tumor with MSI if they had the PA or AA PPARgamma genotype (OR 0.68; 95% CI: 0.47-0.98); differences in Ki-ras mutations were not seen in colon tumors by PPARgamma genotype. Those who did not take ibuprofen-type drugs and had the PA or AA genotypes were at a significantly greater risk of rectal cancer (OR 2.11; 95% CI: 1.52-2.92; p interaction 0.03) than people with the PP genotype regardless of ibuprofen-type drug use. There was a significant interaction between the -200A>C IGFBP3 polymorphism and the Pro12Ala PPARgamma polymorphism and risk of colon cancer (p for interaction = 0.02) with individuals being at significantly lower risk if they had both the CC IGFBP3 genotype and the PA/AA PPARgamma genotype. For rectal cancer there was a significant interaction between the Bsm1/polyA polymorphisms (p = 0.001) of the VDR gene and the PA/AA Pro12Ala PPARgamma polymorphism with the highest risk group being those with both the PA/AA Pro12Ala PPARgamma and the BB/SS VDR genotypes. These data suggest that PPARgamma may be associated with many aspects of colorectal cancer including insulin- and inflammation-related mechanisms.

Objective: Chinese women residing in Asia and Hawaii have low consumption of tobacco but a high incidence of lung cancer. To explore this question further, we conducted a study of lung cancer among Chinese women residing in mainland US., Methods: Using data from NCI's SEER program, we identified residents of Los Angeles County, the San Francisco Metropolitan Area, and the Seattle-Puget Sound Area who were 50 years or older, diagnosed with cancer of the lung or bronchus in 1999-2001, with race specified as non-Hispanic white (n = 18,493), Chinese (n = 853), Filipino (n = 615), or Japanese (n = 282). The sex-specific observed number of lung cancer cases among each Asian sub-group was compared to the expected number of lung cancer cases for each Asian sub-group. The expected number was determined by multiplying the age-, sex-, and geographic area-adjusted incidence rates for non-Hispanic whites by the age- and sex-specific ratio of percentage of current smokers in each Asian sub-group to whites in 1990, and then by the size of the respective Asian populations., Results: Chinese women had a four-fold increased risk of lung cancer, and Filipino women a two-fold increased risk, compared to that expected based on rates in US non-Hispanic whites with a similar proportion of cigarette smokers. Lung cancer among Chinese, Filipino, and Japanese males, as well as Japanese females, did not deviate from expected risk. Among Chinese women, the increased risk was largely restricted to adenocarcinoma and large cell undifferentiated carcinoma., Conclusions: Chinese female residents of the western US mainland have a much higher risk of lung cancer than would be predicted from their tobacco use patterns, just as they do in Asia.

Insulin-like growth factors (IGFs) play an important role in cell proliferation and apoptosis, and recent epidemiologic studies have suggested that circulating IGF-1 and IGF binding protein-3 (IGFBP-3) may be related to colorectal, breast, and prostate cancer risk. The purpose of this analysis was to investigate the role of various personal and lifestyle factors in the inter-individual variation of circulating IGF-1 and IGFPB-3. We measured plasma levels of IGF-1 and IGFBP-3 in a sequential sample of 333 population-based control subjects enrolled in the Seattle Colorectal Cancer Family Registry from August 1999 through December 2001, who had provided a blood sample. Total IGF-1 and IGFBP-3 were measured from plasma samples using ELISA assays. Interviewer-administered questionnaires collected data on various personal and lifestyle factors. Multivariate-adjusted linear regression was used to assess the associations between specific personal and lifestyle factors with IGF-1 and IGFBP-3 levels. Age, body mass index, and postmenopausal hormone use were statistically significantly inversely related to IGF-1 concentrations, and milk consumption was significantly positively related to IGF-1 levels. Only age was significantly related to circulating IGFBP-3. Although the sources of inter-individual variation of IGF-1 and IGFB-3 are not yet fully understood, this analysis provides some insights into factors that may contribute.

This review aims to provide a concise summary of the DCM associated mutations identified in the proteins of the sarcomere and cytoskeleton, and discuss the reported effects of the mutations, as determined by functional studies, and in relation to the known structure of the protein affected. The mechanisms by which single missense mutations in the proteins of the sarcomere can lead to similar diseases as those caused by mutations in the proteins of the sarcolemma and cytoskeleton, are still unknown. However, a wide variety of mutations being associated with DCM suggests a complex mechanism shared by the proteins affected. The DCM mutations reviewed here are those of the beta-myosin heavy chain (beta-MHC), myosin binding protein-C (MyBP-C), actin, alpha- tropomyosin (Tm), troponin T (TnT), troponin I (TnI), troponin C (TnC), of the sarcomere, and titin, T-cap, desmin, vinculin, and muscle LIM protein (MLP) of the cytoskeleton.

Introduction: Colorectal cancer is the second leading cause of cancer death among US men and women. A number of studies report that hormone replacement therapy (HRT) reduces the risk of colorectal cancer, but fewer studies have examined the relation between HRT use and survival after diagnosis and none examined this relation by anatomic location of the primary colon tumor., Methods: Data from a cohort of 699 women 50-79 years of age diagnosed with colon cancer between 1980 and 1998 in a large Health Maintenance Organization based in Seattle, Washington were analyzed to examine the relation between HRT use prior to diagnosis and survival. Use of HRT was ascertained from a computerized pharmacy database., Results: HRT use was associated with a 41% reduction in risk of death after adjustment for age, stage, and diagnosis year (p= 0.037). The association between HRT use and colon cancer survival was strongest among women with cancer in the distal colon (hazard rate ratio 0.33, 95% confidence interval, 95% CI: 0.13-0.83), while little or no association between HRT use and survival was observed among women with proximal tumors (HRR 0.78, 95% CI: 0.42-1.44)., Conclusions: These findings suggest that HRT use is associated with improved survival from colon cancer. Future observational and laboratory studies should shed light on how hormones may be related to reduced incidence and improved prognosis.

The hypothesis that antibiotic use may increase cancer risk was first proposed several decades ago and some research suggests an increased risk of breast cancer among women with conditions likely to require long-term antibiotic use (e.g., acne, recurrent urinary-tract infections, UTI). However, this hypothesis has not been verified and the possible biological mechanisms are not entirely clear. A recent cohort study in Finland reported an increased risk of breast-cancer associated with antibiotic use for UTI. The effect of antibiotics on the ability of intestinal microflora to metabolise phytochemicals from edible plants into compounds that may protect against cancer was proposed as a potential mechanism. We extend this hypothesis by proposing that antibiotic use may be associated with breast-cancer risk through effects on immune and inflammatory factors, such as cytokines, T lymphocytes, prostaglandins, and matrix metalloproteinases, as well as disruption of phytochemical and oestrogen metabolism by intestinal microflora. We suggest that some mechanisms may increase breast-cancer risk, while others may decrease risk, depending on the antibiotic classification.

Objective: Postmenopausal hormone use and risk of breast cancer by histopathology was examined in a large multi-centered population-based case-control study., Methods: Women younger than 75 years newly diagnosed with invasive breast cancer between 1988 and 1991 were identified from statewide tumour registries in Wisconsin, Massachusetts, New Hampshire, and Maine. Only postmenopausal women were included in this analysis. Breast cancer cases (lobular (n = 219), ductal, NOS (n = 2172), and specific ductal subtypes (n = 242)) were compared with randomly selected population controls (n = 3179) using adjusted multi-variable polytomous logistic regression to estimate odds ratios (OR) and 95% confidence intervals (95%CI) for each histology., Results: Lobular carcinoma was associated with recent (within 2 years) estrogen therapy (OR: 1.8, 95% CI: 1.0-3.4) and recent use of combined estrogen-plus-progestin therapy (OR:3.6, 95%CI: 1.8-7.6). Risk of ductal carcinoma was not associated with recent use of either estrogen alone (OR: 0.9, 95% CI: 0.7-1.2) or combined therapy (OR:0.9, 95% CI: 0.6-1.3). No associations were found with ductal subtypes., Conclusions: The association between postmenopausal hormone use and risk of breast cancer may depend on histopathology. Of particular interest is the association between combined hormone therapy and increased risk of lobular carcinoma. This lesion is increasingly common but, nonetheless, comprises fewer than 10% of invasive breast cancers.

Objective: The association between body mass index (BMI) and colon cancer has been reported to be different for men and women. No prior literature has examined if estrogen influences these differences., Methods: Using data from an incident population-based case (n = 1,972) and control (n = 2386) study of colon cancer we evaluated if estrogen modifies the association between BMI and risk of colon cancer., Results: Women who were estrogen-negative (postmenopausal women not taking hormone replacement therapy, HRT) were at increased risk of colon cancer regardless of indicator of estrogen status used (i.e. estrogen-negative compared to estrogen-positive women defined as either being premenopausal or postmenopausal women using HRT, OR 1.54, 95% CI 1.23-1.93; no recent exposure to estrogens compared to current or HRT use within the past 2 years, OR 1.58, 95% CI 1.24-2.00; postmenopausal women not currently using HRT compared to postmenopausal women taking HRT, OR 1.65, 95% CI 1.29-2.12). BMI (kg/m2) was not associated with an increased risk of colon cancer among women who were estrogen-negative. However, women who were estrogen-positive experienced a greater than two-fold increase in colon cancer risk if they had a BMI of > 30 relative to those who had a BMI of <23 (for estrogen-positive, OR, 2.50, 95% CI 1.51-4.13; premenopausal, OR 2.19, 95% CI 0.94-5.07; postmenopausal using HRT, OR 3.36, 95% CI 1.58-7.13). Among men the colon cancer risk associated with BMI decreased with advancing age. Physical activity modified the increased colon cancer risk associated with a large BMI., Conclusions: These data suggest the importance of estrogen in colon cancer etiology. Being estrogen-negative resulted in a significant increased risk of colon cancer. However, BMI significantly increased the risk of colon cancer among women who were estrogen-positive. We hypothesize that estrogen up-regulates IGF-I receptors and IRS-I levels in the colon, which in turn increases susceptibility to obesity-induced increased levels of insulin. We further hypothesize that androgens may have similar effects in men given the decline in colon cancer risk associated with BMI with advancing age.

Background: Endogenous sex hormones, particularly estrogens, modulate the immune system, and non-Hodgkin lymphoma (NHL) is a tumor that is related to immunologic status., Methods: Self-reported menstrual and reproductive history and risk of NHL were evaluated in a cohort of 37,934 Iowa women who were aged 55-69 years when first enrolled in 1986. Through 1998, 261 cases of NHL were identified by linkage to the Iowa SEER Cancer Registry., Results: After multivariate adjustment there was no association between NHL incidence and age at menarche, age at menopause, type of menopause, history of infertility, number of miscarriages, or history of induced abortion, while there were suggestive inverse associations with nulliparity (RR=0.65; 95% CI 0.36-1.16) and years of ovulation (RR = 0.76 for >37 compared to <28 ovulatory years: p-trend = 0.07). Among parous women there was no association with number of livebirths or age at first livebirth, but there was an inverse association with number of children who were breast-fed (RR=0.52 for breast-feeding >2 children versus none; 95% CI 0.33-0.82)., Conclusions: Overall, menstrual and reproductive factors were not strongly related to NHL incidence. The inverse association with breast-feeding is novel but requires confirmation in other studies.

Objective: Epidemiologic studies on calcium, vitamin D and colon cancer are inconsistent, whereas experimental studies more regularly show a protective effect. To evaluate potential sources of inconsistencies, data from a large case-control study were analyzed, stratifying on potential effect modifiers., Methods: Data were collected by certified interviewers in Northern California, Utah and Minnesota. Analyses included 1993 incident colon cancer cases and 2410 population-based controls. Multivariate logistic regression models included age, sex, BMI, family history, physical activity, intake of energy, dietary fiber, aspirin and NSAIDs., Results: Dietary calcium was inversely associated with colon cancer risk in men (OR highest vs lowest quintile = 0.6, 95% CI = 0.5-0.9) and women (OR = 0.6, 95% CI = 0.4-0.9). No statistically significant associations were observed for dietary vitamin D or sunshine exposure. Consumption of total low-fat dairy products was associated with a statistically significantly decreased risk in men and women (ORs highest vs lowest category of intake = 0.8 and 0.7 respectively). Calcium supplement use was inversely associated with risk in both sexes (ORs use vs non-use = 0.8). Vitamin D supplements were inversely associated with risk in men (OR = 0.5) and women (OR = 0.6) but confidence limits included 1.0., Conclusions: These data provide additional support of an inverse association between high levels of calcium intake and colon cancer risk.

Objectives: To examine the incidence of colorectal cancer among Asian residents of the United States according to country of birth., Methods: We determined the incidence of colorectal cancer during 1973-1986 among Asian residents in three areas of the western United States (Hawaii, San Francisco/Oakland SMSA, and western Washington state) in relation to country of birth. Numerators for the rates were obtained from the Surveillance, Epidemiology and End Results (SEER) program; a special tabulation of the 1980 US Census was used to estimate the size and composition of the population at risk., Results: US-born Japanese men experienced incidence rates of colorectal cancer twice as high as foreign-born Japanese men and about 60% higher than those of US-born white men. Incidence among US-born Japanese women was about 40% higher than that among Japanese women born in Japan or US-born white women. Foreign-born Chinese men had about the same incidence of colorectal cancer as US-born white men, while US-born Chinese men experienced slightly reduced rates. Chinese women had rates that were generally 30-40% lower than that of US-born white women, regardless of place of birth. Incidence rates for both US-born and foreign-born Filipinos were 20-50% those of US-born whites., Conclusions: These findings suggest that one or more exposures or characteristics that differ between Japanese migrants and their descendants affect the development of colorectal cancer.

Objectives: To test the hypothesis that childhood acute lymphoblastic leukemia (ALL) is associated with allergic disorders., Methods: We compared the histories of selected allergic disorders (asthma, hay fever, food or drug allergies, eczema, and hives) of 1842 cases of ALL with those of 1986 individually matched controls. The histories of the allergic disorders among siblings of cases and controls were also compared., Results: The combined history of any one or more of the five allergic disorders evaluated was associated with a significant reduced risk of ALL (adjusted OR = 0.7, 95% CI 0.6-0.8), as were histories of four specific allergic disorders (asthma, hay fever, food or drug allergies, and eczema). The combined history of any one or more of the five allergic disorders among any of the siblings of the study subjects also revealed a significantly inverse association (adjusted OR = 0.9, 95% CI 0.8-1.0)., Conclusion: The results from this study, in agreement with most previous studies on adult cancer, suggest that allergic disorders may be associated with a reduced risk of childhood ALL.

Objective: In this study we examine the combined effects of Western diet, age at diagnosis, and genetic susceptibility., Methods: We use data collected as part of an incident case-control study of colon cancer. Family history of colorectal cancer, N-acetyltransferase (NAT2), and glutathione-S-transferase (GSTM-1) are studied with Western diet and age at diagnosis., Results: A significant interaction between age at time of diagnosis, Western dietary pattern, and family history of colorectal cancer (p for interaction = 0.03) was detected. Those with a family history of colorectal cancer who ate a predominantly Western diet were at increased risk of colon cancer (OR 14.0, 95% CI 3.9-50.1 for < or = 55 years; OR 7.7, 95% CI 2.0-29.1 for 56-66 years; OR 1.6, 95% CI 0.8-3.2 for > or = 67 years) compared to those without a family history of colorectal cancer and low levels of a Western diet. Associations with the Western diet were stronger than individual components of the dietary pattern. Neither NAT2 nor GSTM-1 showed significant interaction with Western diet., Conclusion: The extent to which diet comprising a Western dietary pattern influences risk of colon cancer is dependent on age. This dietary pattern also appears to modulate the colon cancer risk associated with a family history of colon cancer.

Objectives: Hormone replacement therapy (HRT) has been inversely associated with colon cancer incidence in several epidemiologic studies. In this study we used data from a population-based incident case-control study of colon cancer to evaluate the role of HRT use in survival after diagnosis with colon cancer., Methods: Data from 815 postmenopausal women living in Utah, California, and Minnesota diagnosed between 1 September 1991 and 30 September 1994 were used to examine associations between HRT and survival., Results: After adjusting for age at time of diagnosis, stage of disease at time of diagnosis, study center, and body mass index (BMI), we observed that women who had ever used HRT had a 30% lesser probability of dying of any cause and a 40% lower probability of dying from colon cancer specifically during the follow-up period. Further evaluation by years of HRT use showed that those who had used HRT for 4 or more years had the lowest risk of dying of colon cancer (hazard rate ratio 0.5, 95% confidence interval 0.3-0.9). Evaluation of other lifestyle variables with HRT use did not show significant confounding or effect modification., Conclusions: These findings suggest that HRT use may improve short-term survival after diagnosis with colon cancer; there is no suggestion that HRT use is detrimental to survival.

Objectives: Substantial decline of ovarian hormones at menopause plays an important role in breast cancer etiology. Hormones must bind to specific receptors to elicit biological responses, however. We therefore hypothesized and examined whether the age-specific risk of breast cancer, especially its change at menopause, differs by estrogen and progesterone receptor (ER/PR) status., Methods: Age-specific incidence rates, stratified by ER/PR status, were estimated by multiplying the age-specific ER/PR distribution among 3359 cases in the Danish Breast Cancer Cooperative Group by Danish national age-specific incidence rates. International variations in the age-incidence curve were also reviewed in relation to the hypothesis., Results: The incidence of ER +/PR + subtype (62.9% of all cases) increased with age continually, with a sudden decrease in the rate of increase around age 44. The incidence of ER-/PR- subtype (17.6%) increased with age prior to about age 50 but remained unchanged subsequently. The incidence of ER+ /PR- subtype (13.9%) increased rapidly during the menopausal period but only slightly afterwards. The incidence of ER-/PR+ subtype (5.6%) increased until about age 43 and decreased subsequently. The international comparison revealed Western women, particularly the elderly, might be at substantially higher risk for ER+ /PR+ subtype compared to Japanese women., Conclusion: Age-specific risk of breast cancer differs by ER/PR status. The large international variation of breast cancer incidence rates may be explained largely by the risk difference for ER+ /PR+ subtype.

This report reviews published epidemiologic research on the associations of vitamin and mineral supplementation with cancer risk. Although the literature on nutrition and cancer is vast, few reports to date have addressed supplemental nutrients directly (seven clinical trials, 16 cohort, and 36 case-control studies). These studies offer insight into effects of nutrients that are distinguishable from effects of other biologically active compounds in foods. Randomized clinical trials have not shown significant protective effects of beta-carotene, but have found protective effects of: alpha-tocopherol against prostate cancer; mixtures of retinol/zinc and beta-carotene/alpha-tocopherol/selenium against stomach cancer; and selenium against total, lung, and prostate cancers. Cohort studies provide little evidence that vitamin supplements are associated with cancer. Case-control studies have reported an inverse association between bladder cancer and vitamin C; oral/pharyngeal cancer and several supplemental vitamins; and several cancers and vitamin E. A randomized clinical trial, a cohort study, and a case-control study have all found inverse associations between colon cancer and vitamin E. Overall, there is modest evidence for protective effects of nutrients from supplements against several cancers. Future studies of supplement use and cancer appear warranted; however, methodologic problems that impair ability to assess supplement use and statistical modeling of the relation between cancer risk and supplement use need attention.

Plant foods have been associated inversely with colon cancer. Since a major focus of this study was to identify components of plant foods which may account for their association with colon cancer, nutrients which are commonly found in plant foods also were evaluated. A population-based case-control study was conducted in Northern California, Utah, and the 'Twin Cities' area of Minnesota (United States). Complete data were available from interviewer-administered questionnaires on 1,993 cases and 2,410 controls. Higher intakes of vegetables (for highest relative to lowest quintile of intake) were associated inversely with colon cancer risk: the odds ratio (OR) was 0.7 for both men (95 percent [CI] confidence interval = 0.5-0.9) and women (CI = 0.5-1.0). Associations were stronger among those with proximal tumors. Total fruit intake was not associated with colon cancer risk although, among men, higher levels of whole grain intake were associated with a decreased risk (OR = 0.6, CI = 0.4-0.9 for older men); high intakes of refined grains were associated with an increased risk (OR = 1.5, CI = 1.1-2.1). Dietary fiber intake was associated with a decreased risk of colon cancer: OR = 0.5 (CI = 0.3-0.9) for older men; OR = 0.7 (CI = 0.4-1.2) for older women; OR = 0.6 (CI = 0.4-1.0) for men with proximal tumors; OR = 0.5 (CI = 0.3-0.9) for women with proximal tumors. Other nutrients, for which plant foods were the major contributor--such as vitamin B6, thiamin, and niacin (women only)--also were associated inversely with colon cancer. Neither beta-carotene nor vitamin C was protective for colon cancer. Adjustment of plant foods for nutrients found in plant foods or for supplement use did not appreciably alter the observed associations between plant foods and colon cancer.

The objective of this study was to examine the effects of the intake of dietary fat upon colorectal cancer risk in a combined analysis of data from 13 case-control studies previously conducted in populations with differing colorectal cancer rates and dietary practices. Original data records for 5,287 cases of colorectal cancer and 10,470 controls were combined. Logistic regression analysis was used to estimate odds ratios (OR) for intakes of total energy, total fat and its components, and cholesterol. Positive associations with energy intake were observed for 11 of the 13 studies. However, there was little, if any, evidence of any energy-independent effect of either total fat with ORs of 1.00, 0.95, 1.01, 1.02, and 0.92 for quintiles of residuals of total fat intake (P trend = 0.67) or for saturated fat with ORs of 1.00, 1.08, 1.06, 1.21, and 1.06 (P trend = 0.39). The analysis suggests that, among these case-control studies, there is no energy-independent association between dietary fat intake and risk of colorectal cancer. It also suggests that simple substitution of fat by other sources of calories is unlikely to reduce meaningfully the risk of colorectal cancer.

Hormonal factors have been inconsistently associated with colon cancer risk in women. The associations between reproductive events, menstrual factors, exogenous hormones, and colon cancer were evaluated in a large case-control study (894 female cases and 1,120 female age-matched population-based controls) in the United States, stratifying by age at diagnosis, tumor site, family history and other potential risk factors. Overall, higher parity was associated with a marginally decreased risk of colon cancer (five or more births compared with nulliparous: odds ratio [OR] = 0.75, 95 percent confidence interval [CI] = 0.53-1.06) after adjusting for age at diagnosis, family history of colorectal cancer, vigorous lifetime physical activity, body mass index (BMI) (wt/ht1.5), total energy intake, and aspirin use. No important associations were observed for other reproductive or menstrual events. An inverse association between recent use of hormone replacement therapy (HRT) and colon cancer was observed (OR = 0.71, CI = 0.56-0.89). Although interaction terms were not significant, this inverse association appeared to be more pronounced for those with an older age at diagnosis; for those without a first-degree relative with colorectal cancer; and for those with a relatively low BMI. The reduced risk associated with HRT use did not appear to be explained by other behaviors related to HRT use.

Nearly 80 percent of infant leukemias present with an abnormality involving the MLL gene at 11q23. Moreover, secondary acute myeloid leukemias (AML) that occur as the result of chemotherapy agents, which are known to inhibit DNA topoisomerase II, often manifest the same MLL abnormalities. It has been hypothesized that de novo infant leukemias may occur as a result of maternal exposure to agents in diet and medications that inhibit DNA topoisomerase II. Three epidemiologic studies of childhood leukemia with similar methodologies were conducted in the United States and Canada over the past 10 years by the Children's Cancer Group (CCG). Of the total 771 mothers of infants diagnosed at one year of age or less (< 12.5 months) who originally were interviewed (303 infant cases and 468 matched controls) across the three studies, follow-up questionnaire data on maternal exposure to potential DNA topoisomerase II inhibitors during pregnancy were available on 84 cases and 97 matched controls in the US. For maternal diet, a composite variable was created that consisted of 10 foods identified alpha priori as containing DNA topoisomerase II inhibitors. There were no significant trends with increasing maternal consumption for either the overall group, or the acute lymphoblastic leukemia (ALL) stratum. However, within the AML stratum, there was a statistically significant positive association (P trend = 0.04) with increasing consumption of DNA topoisomerase II-inhibitor containing foods (odds ratio [OR] = 9.8, 95 percent confidence interval [CI] = 1.1-84.8; OR = 10.2, CI = 1.1-96.4; for medium and high consumption, respectively). Other potential topoisomerase II inhibitors were explored; no significant findings were found. Results of this preliminary study, in combination with molecular data, should be used in future investigations of childhood leukemia (particularly, infant) to justify the incorporation of a detailed dietary history.

Epidemiologic evidence on the relation between nutrition and colorectal cancer is reviewed. Colon cancer varies approximately 20-fold internationally. Although there is clear evidence of genetic predisposition to colon cancer, much of this variation appears to be related to differences in dietary habits. At present, the data suggest that vegetables are associated with lower risk, and that fiber alone does not account for this association. Further, meat consumption is associated with increased risk but this, too, is not explained solely by its fat content. Several microconstituents of the diet may be associated with reduced risk--including folate and calcium--but phytochemicals of other sorts may be relevant. Mutagenic compounds, particularly heterocyclic amines, produced when protein is cooked, plausibly explain the meat association. The most consistent inverse association is with physical activity. Alcohol is associated, though inconsistently, with increased risk. Rectal cancer is less well studied but, at present, there are few data to suggest that the dietary risk factors are markedly different. Physical activity does not appear to be associated with a lower risk. Colorectal adenomatous polyps also appear to share the spectrum of risk factors seen with colon cancer, although, for adenomas, tobacco smoking is also a clear and consistent risk factor. There are a variety of links between the dietary epidemiology and physiology of colorectal neoplasia and the relevant pathologic and molecular changes. Other causal connections remain to be explicated.

High vegetable and fruit (V&F) intake has been associated with a lower risk of many cancers. However, the specific V&F, the active compounds present in V&F, and the dose at which they confer protection are unknown. Standard methods for assessing, classifying, and quantifying V&F exposures in epidemiologic studies have not been established. Differences among studies occur due to inherent differences among V&F, and across dietary assessment methods, study populations, etiologic hypotheses, and analytic methods. The V&F classification scheme presented here characterizes and quantifies V&F consumption for elucidating risk relationships, identifying chemopreventive compounds present in V&F, and facilitating identification of potential biomarkers of V&F intake. Broad criteria define which plant foods count as V&F. Formation of food groups is based on proposed biological mechanisms of action. Five main groups are included: Total V&F; Total Vegetables; Total Fruits; and two groups orthogonal to these -- the Botanical and Phytochemical groups. Subgroups are specified within each main group. V&F exposure is quantified as the absolute amount consumed (weight) or as the number of household servings. This classification scheme has public health applications and may be used to examine associations with chronic diseases other than cancer.

We examined whether associations of adult weight gain with the risk of postmenopausal breast cancer vary by stature, waist-hip ratio (WHR), and early adult size in a cohort of 37,105 Iowa (United States) women. Both low body mass index (kg/m2) (BMI) at age 18 and high subsequent weight-gain were associated independently with increased risk of incident postmenopausal breast cancer. After stratifying on BMI at age 18, high weight gain was associated with increased risk irrespective of whether early BMI was low (relative risk [RR] = 1.92, 95 percent confidence interval [CI] = 1.45-2.53) or high (RR = 1.59, Ci = 1.19-2.12). Women with lower BMI at 18 were at a higher risk at all levels of weight change, but having low BMI at age 18 and low subsequent weight gain conferred no significantly excess risk over those with high BMI at 18 and low gain. An inconsistent increase in risk was associated with taller stature; there was no additional risk associated with high WHR. Part of the observed risk from lower early size may reflect greater weight gain by lighter women. Limiting adult weight gain thus may be a feasible method to avoid increasing an individual's risk of breast cancer. Reasons for different effects of early cf late weight gain are not established, but benefits of a greater size at age 18 are likely to be offset by increased risks of other weight-related diseases at older ages.

Data from two population-based case-control studies were used to investigate the effect of age on colon cancer risk. Dietary intake data were assessed from a study conducted in Utah (United States) between 1979 and 1983; reproductive data were assessed from a study conducted in Adelaide (Australia) between 1979 and 1980. Data from both studies were assessed for their impact on those less than 65 years of age and those 65 or more years of age. Intake of energy, fat, and protein had a greater impact on risk among older men than among younger men. Risk estimates for the upper quartile of intake relative to the lowest quartile of intake were 8.5 (95 percent confidence interval [CI] = 1.7-43.0) for energy, 8.2 (CI = 1.6-41.3) for protein, and 7.2 (CI = 1.6-31.4) for total fat for older men, while comparable risk estimates were 2.4 (CI = 0.6-9.1) for energy, 3.0 (CI = 0.7-13.6) for protein, and 1.9 (CI = 0.5-7.1) for total fat among younger men. Similar trends were seen for older women for energy and protein. beta-carotene decreased colon cancer risk among younger men (odds ratio [OR] = 0.4, CI = 0.1-1.2) and women (OR = 0.1, CI = 0.1-0.5), although not among older men (OR = 1.2, CI = 0.3-4.9) and women (OR = 1.9, CI = 0.6-64). Calcium decreased risk of colon cancer among older men (OR = 0.1, CI = < 0.1-0.8) and younger women (OR = 0.2, CI = < 0.1-0.7).(ABSTRACT TRUNCATED AT 250 WORDS)

To test the hypothesis that a high intake of dietary cholesterol and fat is associated with elevated risks of lung cancer, we analyzed data from a population-based, prospective, cohort study conducted among 41,837 postmenopausal Iowa (United States) women who completed, in 1986, a comprehensive mailed questionnaire including information on usual intake of 127 food items. All cohort members were followed for cancer incidence through the statewide cancer registry. By 1991, after six years of follow-up, 272 incident lung-cancer cases were identified. After controlling for total energy intake and other confounding factors, dietary cholesterol, total fat, and animal fat were unrelated to lung cancer risk. Intake in the upper three quartiles of plant-derived fat, however, was related to a 30 to 40 percent lower incidence of lung cancer, comparative with those in the lowest quartile, with more pronounced reduction in risk observed among smokers (relative risk = 0.6, 95 percent confidence interval = 0.4-0.9). This prospective cohort study suggests that high intake of fat of plant origin may be associated with reduced risk of lung cancer, while dietary cholesterol and animal fat intake is unrelated to the etiology of this malignancy in postmenopausal women.

To investigate the relation of dietary intakes of sucrose, meat, and fat, and anthropometric, lifestyle, hormonal, and reproductive factors to colon cancer incidence, data were analyzed from a prospective cohort study of 35,215 Iowa (United States) women, aged 55-69 years and without a history of cancer, who completed mailed dietary and other questionnaires in 1986. Through 1990, 212 incident cases of colon cancer were documented. Proportional hazards regression was used to adjust for age and other risk factors. Risk factors found to be associated significantly with colon cancer included: (i) sucrose-containing foods and beverages other than ice cream/milk; relative risks (RR) across the quintiles = 1.00, 1.73, 1.56, 1.54, and 2.00 (95% confidence intervals [CI] for quintiles two and five exclude 1.0); (ii) sucrose; RR across the quintiles = 1.00, 1.70, 1.81, 1.82, and 1.45 (CI for quintiles two through four exclude 1.0); (iii) height; RR = 1.23 for highest to lowest quintile (P for trend = 0.02); (iv) body mass index; RR = 1.41 for highest to lowest quintile (P for trend = 0.03); and (v) number of livebirths, RR = 1.59 for having had one to two livebirths and 1.80 for having had three or more livebirths compared with having had none (P for trend = 0.04). These data support hypotheses that sucrose intake or being tall or obese increases colon cancer risk; run contrary to the hypothesis that increased parity decreases risk; support previous findings of no association with demographic factors other than age, cigarette smoking, or use of oral contraceptives or estrogen replacement therapy; and raise questions regarding previous associations with meat, fat, protein, and physical activity.

At least three case-control studies have examined the association between alcohol consumption and endometrial cancer; two studies showed inverse associations, and a third a positive association. To our knowledge, no prospective studies of this association have been reported. The association between alcohol and endometrial cancer was examined in the Iowa Women's Health Study (United States), a prospective study of postmenopausal women. Information on alcohol consumption and other variables was obtained through a mailed questionnaire in January 1986. Through December 1990, 167 incident endometrial cancer cases occurred in the at-risk cohort of 25,170 women. Multivariate-adjusted relative risks (RR) and 95 percent confidence intervals (CI) were computed using Cox proportional hazards regression controlling for age, body mass index (BMI), parity, age at menopause, and noncontraceptive estrogen use, and to determine multiplicative interactions. The RRs of endometrial cancer associated with < 4.0 and > or = 4.0 g of alcohol per day compared with abstainers were 0.7 (CI = 0.5-1.1) and 1.0 (CI = 0.7-1.6), respectively. No statistically significant association between endometrial cancer and consumption of either beer, wine, or liquor was observed. There was no interaction between alcohol and any other endometrial cancer risk factors, including BMI or noncontraceptive estrogen use. These data do not support an association between alcohol and endometrial cancer among postmenopausal women.

We recently provided data from a prospective cohort study of postmenopausal women which suggested that a first livebirth at age 30 or older (cf before age 20) was associated with a twofold increased risk of breast cancer in women without a family history, but a 5.8-fold higher risk in women with a positive family history. To address the question of whether these observations reflect difficulty becoming pregnant or maintaining a pregnancy, we performed additional analyses in which the outcome of each pregnancy was considered. During five years of follow-up, 620 incident cases of breast cancer were identified in the 37,105 women at risk. There was little evidence for an increased risk associated with a history of spontaneous abortion (relative risk [RR] = 1.1; 95 percent confidence interval [CI] = 0.9-1.4), nor was the risk higher among women who reported two or more spontaneous abortions in consecutive pregnancies (RR = 1.0, CI = 0.7-1.4). Although women who reported that they had tried unsuccessfully to become pregnant had only slightly and nonsignificantly elevated risks of breast cancer (RR = 1.1, CI = 0.9-1.3), a more pronounced and statistically significant association was noted in women with a positive family history (RR = 2.1, CI = 1.4-3.2). There was a strong inverse association between failure to become pregnant and parity (P < 0.0001); nearly 50 percent of the nulliparous married women reported having tried and failed to become pregnant, whereas the frequency was only 6.8 percent among married women with five or more livebirths.(ABSTRACT TRUNCATED AT 250 WORDS)

The epidemiologic literature on the relationship between vegetable and fruit consumption and human cancer at a variety of sites was reviewed systematically in Part I. It was concluded that consumption of higher levels of vegetables and fruit is associated consistently, although not universally, with a reduced risk of cancer at most sites, and particularly with epithelial cancers of the alimentary and respiratory tracts. Possible mechanisms by which vegetable and fruit intake might alter risk of cancer are addressed here. A large number of potentially anticarcinogenic agents are found in these food sources, including carotenoids, vitamins C and E, selenium, dietary fiber, dithiolthiones, glucosinolates and indoles, isothiocyanates, flavonoids, phenols, protease inhibitors, plant sterols, allium compounds, and limonene. These agents have both complementary and overlapping mechanisms of action, including the induction of detoxification enzymes, inhibition of nitrosamine formation, provision of substrate for formation of antineoplastic agents, dilution and binding of carcinogens in the digestive tract, alteration of hormone metabolism, antioxidant effects, and others. It appears extremely unlikely that any one substance is responsible for all the associations seen. Possible adverse effects of vegetable and fruit consumption are also examined. One way to consider the relationships reviewed here is to hypothesize that humans are adapted to a high intake of plant foods that supply substances crucial to the maintenance of the organism, but only some of which are currently called 'essential nutrients.' Cancer may be the result of reducing the level of intake of foods that are metabolically necessary--it may be a disease of maladaptation.

The epidemiologic literature on the relationship between vegetable and fruit consumption and human cancer at a variety of sites is reviewed systematically. A total of 13 ecologic studies, nine cohort studies, and 115 case-control studies are included. Cancer of all sites, cancers of lung, breast, colon, rectum, esophagus, larynx, oral cavity and pharynx, stomach, pancreas, prostate, bladder, ovary, endometrium, cervix, and thyroid, as well as mesothelioma and gestational trophoblastic disease, are considered. Relevant data from clinical trials, animal, and in vitro studies are included. It is concluded that consumption of higher levels of vegetables and fruit is associated consistently, although not universally, with a reduced risk of cancer at most sites. The association is most marked for epithelial cancers--particularly those of the alimentary and respiratory tracts--and, currently, is weak to nonexistent for hormone-related cancers. The association exists for a wide variety of vegetables and fruit with some suggestion that raw forms are associated most consistently with lower risk. Possible mechanisms by which vegetable and fruit intake might alter risk of cancer and possible adverse effects of vegetable and fruit consumption will be considered in Part II of this review.