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BACKGROUND: Efficacy of vitamin D supplementation may vary by dosing strategies and adiposity. To address such heterogeneity, we performed a meta-analysis of randomised controlled trials of vitamin D supplementation and total cancer outcomes. METHODS: PubMed and Embase were searched through January 2022. Summary relative risk (SRR) and 95% confidence interval (CI) were estimated using the DerSimonian–Laird random-effects model. RESULTS: For total cancer incidence (12 trials), the SRR for vitamin D supplementation vs. control group was 0.99 (95% CI, 0.94–1.03; P = 0.54; I(2) = 0%). No significant association was observed regardless of whether the supplement was given daily or infrequently in a large-bolus. Yet, among trials testing daily supplementation, a significant inverse association was observed among normal-weight individuals (SRR, 0.76; 95% CI, 0.64–0.90; P = 0.001, I(2) = 0%), but not among overweight or obese individuals (P(heterogeneity) = 0.02). For total cancer mortality (six trials), the SRR was 0.92 (95% CI, 0.82–1.03; P = 0.17; I(2) = 33%). A significant inverse association emerged (SRR, 0.87; 95% CI, 0.78–0.96; P = 0.007; I(2) = 0%) among studies testing daily supplementations but not among studies that testing infrequent large-bolus supplementations (P(heterogeneity) = 0.09). CONCLUSIONS: For vitamin D supplementation, daily dosing, but not infrequent large-bolus dosing, reduced total cancer mortality. For total cancer incidence, bolus dosing did not reduce the risk and the benefits of daily dosing were limited to normal-weight individuals.

The Sarajevo Red Line venerates the dead through both a physical memorial and performance. The artistic choices made by Haris Pašovic in creating the temporary memorial provide a way for both survivors and the world at large to unite in empathy, trying to come to terms with the tragedy, and assured that those who were forced to give the ultimate sacrifice would be remembered. The use of multiple mediums enhances the ability of an audience to connect, thus giving people an opportunity to relate to the tragedy whether it directly affected them or not. The seeming paradox inherent in the term trauma art is made more dramatic in memorials, but especially so in the Sarajevo Red Line. The overall idea of the Sarajevo Red Line is to commemorate the thousands of people (both adults and children) who lost their lives in the siege of Sarajevo that continued for nearly four years. That particular battle was bloody and tragic, yet the memorial itself is beautiful in both its simplicity and its complexity. DOI: 10.5901/mjss.2013.v4n9p449

BACKGROUND The strong correlation between national consumption of fat and national rate of mortality from prostate cancer has raised the hypothesis that dietary fat increases the risk of this malignancy. Case-control and cohort studies have not consistently supported this hypothesis. PURPOSE We examined prospectively the relationship between prostate cancer and dietary fat, including specific fatty acids and dietary sources of fat. We examined the relationship of fat consumption to the incidence of advanced prostate cancer (stages C, D, or fatal cases) and to the total incidence of prostate cancer. METHODS We used data from the Health Professionals Follow-up Study, which is a prospective cohort of 51529 U.S. men, aged 40 through 75, who completed a validated food-frequency questionnaire in 1986. We sent follow-up questionnaires to the entire cohort in 1988 and 1990 to document new cases of a variety of diseases and to update exposure information. As of January 31, 1990, 300 new cases of prostate cancer, including 126 advanced cases, were documented in 47855 participants initially free of diagnosed cancer. The Mantel-Haenszel summary estimator was used to adjust for age and other potentially confounding variables. Multiple logistic regression was used to estimate relative risks (RRs) when controlling simultaneously for more than two covariates. RESULTS Total fat consumption was directly related to risk of advanced prostate cancer (age- and energy-adjusted RR = 1.79, with 95% confidence interval [CI] = 1.04-3.07, for high versus low quintile of intake; P [trend] = .06). This association was due primarily to animal fat (RR = 1.63; 95% CI = 0.95-2.78; P [trend] = .08), but not vegetable fat. Red meat represented the food group with the strongest positive association with advanced cancer (RR = 2.64; 95% CI = 1.21-5.77; P = .02). Fat from dairy products (with the exception of butter) or fish was unrelated to risk. Saturated fat, monounsaturated fat, and alpha-linolenic acid, but not linoleic acid, were associated with advanced prostate cancer risk; only the association with alpha-linolenic acid persisted when saturated fat, monounsaturated fat, linoleic acid, and alpha-linolenic acid were modeled simultaneously (multivariate RR = 3.43; 95% CI = 1.67-7.04; P [trend] = .002). CONCLUSION The results support the hypothesis that animal fat, especially fat from red meat, is associated with an elevated risk of advanced prostate cancer. IMPLICATIONS These findings support recommendations to lower intake of meat to reduce the risk of prostate cancer. The potential roles of carcinogens formed in cooking animal fat and of alpha-linolenic acid in the progression of prostate cancer need to be explored.

Most cases of breast and prostate cancer are not associated with mutations in known high-penetrance genes, indicating the involvement of multiple low-penetrance risk alleles. Studies that have attempted to identify these genes have met with limited success. The National Cancer Institute Breast and Prostate Cancer Cohort Consortium--a pooled analysis of multiple large cohort studies with a total of more than 5,000 cases of breast cancer and 8,000 cases of prostate cancer--was therefore initiated. The goal of this consortium is to characterize variations in approximately 50 genes that mediate two pathways that are associated with these cancers--the steroid-hormone metabolism pathway and the insulin-like growth factor signalling pathway--and to associate these variations with cancer risk.

Association between animal products and prostate cancer have been observed in numerous observational studies, but it is not clear whether the high fat content of these foods or some other component accounts for these associations. We examine these associations among 51,529 men who contributed detailed dietary data.Participants of the Health Professionals Follow-Up Study completed a semiquantitative food-frequency questionnaire in 1986, and subsequently in 1990 and 1994. Other data on potential risk factors were collected at baseline and in subsequent questionnaires during follow-up. Between 1986 and 1996, 1897 total cases of prostate cancer (excluding stage A1) and 249 metastatic cancers were identified. We used pooled logistic regression for analyses of diet and prostate cancer.Intakes of total meat, red meat, and dairy products were not associated with risk of total or advanced prostate cancer. An elevated risk for metastatic prostate cancer was observed with intake of red meat (relative risk (RR)= 1.6 for top vs. bottom quintile comparison, 95% confidence interval (CI) = 1.0-2.5); this association was slightly attenuated after controlling for saturated and alpha-linolenic fatty acids (RR = 1.5, 95% CI = 0.88-2.5). Processed meats, bacon and beef, pork or lamb as a main dish each contributed to an elevated risk of metastatic prostate cancer. Dairy product intake increased risk of metastatic prostate cancer (RR = 1.4, 95% CI = 0.91-2.2 for top vs. bottom quintile comparison), but no association remained after controlling for calcium and other fatty acids. A high intake in both red meat and dairy product was associated with a statistically significant two-fold elevation in risk of metastatic prostate cancer, compared to low intake of both products; however, most of the excess risk could be explained by known nutritional components of these foods.Intakes of red meat and dairy products appear to be related to increased risk of metastatic prostate cancer. While known nutrients, such as calcium and fatty acids, may explain most of the dairy association observed, it appears that a portion of the risk of metastatic prostate cancer associated with red meat intake remains unexplained.

The A2 allele of the CYP17 gene has been thought to be associated with increased functional activity of this steroidogenic enzyme. Consequently, the A2 allele has been examined as a biomarker of individual susceptibility to hormone-related diseases among men and women. We prospectively assessed the association between the A2 allele of CYP17 and prostate cancer risk among 590 cases and 782 controls in a case-control study nested within the Physicians' Health Study cohort. We also evaluated associations between CYP17 genotype and plasma steroid hormones among controls and the potential interaction between CYP17 and SRD5A2 V89L polymorphisms in relationship with prostate cancer risk and circulating steroid hormone levels. We observed a borderline significant association between the A2 allele and prostate cancer risk (odds ratio, 1.23; 95% confidence interval, 0.99-1.54), however, we did not observe evidence of a gene-dosage effect (versus A1/A1 genotype: A1/A2 genotype; odds ratio, 1.26; 95% confidence interval, 0.99-1.59; A2/A2 genotype: odds ratio, 1.17; 95% confidence interval, 0.85-1.61). The A2 allele was not overrepresented among cases with advanced prostate cancer. Among controls, carriers of the A2 allele had steroid hormone levels similar to noncarriers. We also found no evidence of a gene-gene interaction between CYP17 and SRD5A2 V89L polymorphisms on prostate cancer risk or endogenous steroid hormone levels. These results suggest that CYP17 genotype may possibly confer a small increased susceptibility to prostate cancer but is not a strong predictor of endogenous steroid hormone levels in men.

Carcinogens from tobacco reach the colorectal mucosa through either the alimentary tract or the circulatory system and could possibly damage or alter expression of important cancer-related genes. Twenty-one of 22 studies found that long-term, heavy cigarette smokers have a 2-3-fold elevated risk of colorectal adenoma. Risk of large adenomas, immediate cancer precursors, was elevated in smokers in 12 of 12 studies. The studies of smoking and colorectal cancer risk conducted earlier in the twentieth century consistently did not show any association. However, 27 studies in various countries, including the vast majority of those that have been analyzed in the past several years, now show an association between tobacco use and colorectal cancer. In the United States, 15 of 16 studies conducted after 1970 in middle-age men and elderly men and, in the 1990s, in women demonstrate an association. This temporal pattern is consistent with an induction period of three to four decades between genotoxic exposure and the diagnosis of colorectal cancer and with men as a group having begun smoking several decades earlier than women. Overall, accumulating evidence, much within the past decade, strongly supports the addition of colorectal cancer to the list of tobacco-associated malignancies and the possibility that up to one in five colorectal cancers in the United States may be potentially attributable to tobacco use.

Although most prospective cohort studies do not support an association between coffee consumption and pancreatic cancer, the findings for alcohol are inconsistent. Recently, a large prospective cohort study of women reported statistically significant elevations in risk of pancreatic cancer for both coffee and alcoholic beverage consumption. We obtained data on coffee, alcohol, and other dietary factors using semiquantitative food frequency questionnaires administered at baseline (1986 in the Health Professionals Follow-Up Study and 1980 in the Nurses' Health Study) and in subsequent follow-up questionnaires. Data on other risk factors for pancreatic cancer, including cigarette smoking, were also available. Individuals with a history of cancer at study initiation were excluded from all of the analyses. During the 1,907,222 person-years of follow-up, 288 incident cases of pancreatic cancer were diagnosed. The data were analyzed separately for each cohort, and results were pooled to compute overall relative risks (RR). Neither coffee nor alcohol intakes were associated with an increased risk of pancreatic cancer in either cohort or after pooling the results (pooled RR, 0.62; 95% confidence interval, 0.27-1.43, for3 cups of coffee/day versus none; and pooled RR, 1.00; 95% confidence interval, 0.57-1.76, foror = 30 grams of alcohol/day versus none). The associations did not change with analyses examining different latency periods for coffee and alcohol. Similarly, no statistically significant associations were observed for intakes of tea, decaffeinated coffee, total caffeine, or alcoholic beverages. Data from these two large cohorts do not support any overall association between coffee intake or alcohol intake and risk of pancreatic cancer.

1,25-dihydroxyvitamin D [1,25(OH)2D] inhibits proliferation and promotes differentiation of human colon cancer cell lines. Epidemiological findings, although not entirely consistent, suggest an inverse relationship between vitamin D intake and colorectal cancer and adenoma, colorectal cancer precursor lesions. We evaluated the relationship of plasma 1,25(OH)2D and 25-hydroxyvitamin D [25(OH)D] with distal colorectal adenoma among 326 matched case and control pairs (nested in the prospective Nurses' Health Study), who provided blood in 1989-1990 and who underwent endoscopy in 1989-1996. Plasma vitamin D metabolite concentrations were determined blindly by RIA. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated from multiple conditional logistic regression models. Mean plasma 1,25(OH)2D and 25(OH)D levels did not significantly differ (P = 0.3 and 0.7, respectively) between cases (31.6 +/- 8.4 pg/ml and 26.4 +/- 10.6 ng/ml, respectively) and controls (32.2 +/- 8.6 pg/ml and 26.8 +/-10.2 ng/ml, respectively). However, women whose plasma 1,25(OH)2D concentration was below 26.0 pg/ml (a level typically considered to be below normal) were at increased risk of distal colorectal adenoma (OR, 1.58; 95% CI, 1.03-2.40). Compared with the lowest 1,25(OH)2D quartile, women in the second (OR, 0.64; 95% CI, 0.41-1.02), third (OR, 0.80; 95% CI, 0.50-1.30), or upper (OR, 0.71; 95% CI, 0.43-1.15) quartiles were at a statistically nonsignificant lower risk of adenoma. The relationship was stronger for large/villous adenoma and among those with consistent vitamin D intake over the 10 years prior to blood draw. Compared with women in the lowest quartile, for plasma 25(OH)D, women in the second (OR, 0.64; 95% CI, 0.41-1.00) and third (OR, 0.58; 95% CI, 0.36-0.95) quartiles were at a statistically significantly lower risk of distal colorectal adenoma, but there was no difference in risk in the top quartile (OR, 1.04; 95% CI, 0.66-1.66). We conclude that women who have low levels of circulating 1,25(OH)2D may be at higher risk of distal colorectal adenomas, but additional study is warranted.

Diet and lifestyle likely play major roles in colon cancer incidence; however, the proportion of colon cancer risk that might be preventable is unknown. Thus, we estimated the proportion of colon cancer risk among men in the prospective Health Professionals Follow-up Study that might be attributable to a constellation of modifiable risk factors, and thus might be preventable.We included 47,927 men aged 40-75 years in 1986, among whom we confirmed 411 colon cancer cases from 1986 to 1996. Risk factors considered were obesity, physical inactivity, alcohol consumption, early adulthood cigarette smoking, red meat consumption, and low intake of folic acid from supplements. We calculated a risk score that was the sum across the six risk factors of the values of 1 (better exposure) to 5 (worse exposure) corresponding to the exposure category. We entered the risk score into a logistic regression model and estimated the population attributable risk percent (PAR%) using the method of Bruzzi et al.After adjusting for age and family history of colorectal cancer and comparing the risk score for the combined six modifiable colon cancer risk factors at or above the approximate 20th, 10th, or 5th percentiles vs. below, the PAR% increased from 39% (95% confidence interval (CI) = 23-58%), to 48% (95% CI = 25-71%), to 55% (95% CI = 27-80%), respectively. Using a second method in which we used cut-points consistent with general-good health behaviors for each risk factor, comparing men with at least one risk factor to men without any risk factors (3.1% of the men), the PAR% was 71% (95% CI = 33-92%).The findings from this analysis suggest that, if all the members of this cohort of middle-aged US men had a modifiable exposure distribution comparable to the men with low risk scores, a large proportion of colon cancer risk might be avoidable. Additional study is required to determine whether making changes in these six risk factors now would reduce the risk of colorectal neoplasia, or whether the proportion of colon neoplasia that might be avoidable would be similar in populations with different characteristics.

A recent report suggested that men with vertex balding have higher levels of plasma insulin-like growth factor 1 (IGF-1). The association of its major carrier protein, insulin-like growth factor binding protein 3 (IGFBP-3), with male pattern hair loss has not been examined.We evaluated the relations of plasma concentrations of IGF-1 and IGFBP-3 with vertex balding in middle-aged and elderly men.Participants were 431 male members of the Health Professionals Follow-up Study who responded to a question in 1992 on their hair pattern at 45 years of age and who were 47 to 81 years old when they provided a blood specimen in 1993-1994. Odds ratios (ORs) of vertex balding associated with IGF-1 and IGFBP-3 were estimated from logistic regression models mutually adjusting for each other and controlling for age at blood draw.Of the 431 men, 128 had vertex balding at age 45. Compared with men who were not balding, for a 1 standard deviation increase in plasma IGF-1 level (72.4 ng/mL), the OR for vertex balding was 1. 31 (95% CI, 0.95-1.81). For a 1 standard deviation increase in plasma IGFBP-3 (957 ng/mL), the OR for vertex balding was 0.62 (95% CI, 0.44-0.88).Older men with vertex balding have lower circulating levels of IGFBP-3 and higher levels of IGF-1 when controlling for IGFBP-3 level.

Insulin-like growth factor-1 (IGF-1) is an important mitogen, and IGF binding protein-3 (IGFBP-3) has opposing effects. Acromegalics, who have abnormally elevated levels of IGF-1, are at increased risk of colorectal tumors. Recent studies have found that IGF-1 levels correlate with risk of prostate cancer and colorectal cancer in men, premenopausal breast cancer in women, and lung cancer in men and women. We examined whether prediagnostic plasma levels of IGF-1 and IGFBP-3 influence risk of colorectal cancer and adenoma in women. From 1989 to 1990, a total of 32,826 women from the Nurses' Health Study provided blood specimens that were archived in liquid nitrogen. During 6 years of follow-up from 1989 to 1994, we documented 79 new cases of colorectal cancer, 90 cases of intermediate/late-stage adenoma (or =1 cm or tubulovillous/villous histology), and 107 cases of early-stage adenoma (1 cm and tubular histology). After matching controls (2:1 for cancers and 1:1 for adenomas) to cases by age, month of blood draw, fasting status, and indication for endoscopy (for adenoma controls), plasma IGF-1 and IGFBP-3 levels were measured. Controlling for IGFBP-3 level, relative to women in the low tertile of IGF-1, those in the high tertile were at elevated risk of intermediate/late-stage colorectal neoplasia adenoma [multivariate relative risk (RR), 2.78; 95% confidence interval (CI), 0.76-9.76] and cancer (RR, 2.18; 95% CI, 0.94-5.08). Controlling for IGF-1 level, relative to women in the low tertile of IGFBP-3, women in the high tertile of IGFBP-3 were at lower risk of intermediate/late-stage colorectal adenoma (RR, 0.28; 95% CI, 0.09-0.85) and cancer (RR, 0.28; 95% CI, 0.10-0.83). Neither IGF-1 nor IGFBP-3 had any appreciable relation with early-stage adenoma. These analyses indicate that high levels of circulating IGF-1 and particularly low levels of IGFBP-3 are associated independently with an elevated risk of large or tubulovillous/villous colorectal adenoma and cancer.

A variety of external factors interacting with genetic susceptibility influence the carcinogenesis process. External factors including oxidative compounds, electrophilic agents, and chronic infections may enhance genetic damage. In addition, various hormonal factors which influence growth and differentiation are critically important in the carcinogenic process. Diet and nutrition can influence these processes directly in the gastrointestinal tract by providing bioactive compounds to specific tissues via the circulatory system, or by modulating hormone levels. Differences in certain dietary patterns among populations explain a substantial proportion of cancers of the colon, prostate and breast. These malignancies are largely influenced by a combination of factors related to diet and nutrition. Their causes are multifactorial and complex, but a major influence is the widespread availability of energy-dense, highly processed and refined foods that are also deplete in fiber. These dietary patterns in combination with physical inactivity contribute to obesity and metabolic consequences such as increased levels of IGF-1, insulin, estrogen, and possibly testosterone. These hormones tend to promote cellular growth. For prostate cancer, epidemiologic studies consistently show a positive association with high consumption of milk, dairy products, and meats. These dietary factors tend to decrease 1.25(OH)2 vitamin D, a cell differentiator, and low levels of this hormone may enhance prostate carcinogenesis. While the nutritional modulation of growth-enhancing and differentiating hormones is likely to contribute to the high prevalence of breast, colorectal, prostate, and several other cancers in the Western world, these cancers are relatively rare in less economically developed countries, where malignancies of the upper gastrointestinal tract are quite common. The major causes of upper gastrointestinal tract cancers are likely related to various food practices or preservation methods other than refrigeration, which increase mucosal exposure to irritants or carcinogens.

We examined whether the prevalence of benign prostatic hyperplasia (BPH) varies by racial or ethnic origin in a large cohort of American male health professionals.Included in our study were 1,508 men who underwent surgery for BPH between 1986 and 1994, and 1,837 with high moderate to severe lower urinary tract symptoms assessed by the American Urological Association symptom index in 1992 or 1994. "Noncases" comprised 23,246 asymptomatic participants. Self-reported major ancestry was black in 201 men, Asian in 413, other origin in 604 and white in 25,373. White heritage was further classified as southern European in 6,408 men, Scandinavian in 2,951 and other white in 16,014. The relative risk of BPH and 95% confidence intervals (CI) adjusted for age, body mass index, alcohol consumption, smoking and physical activity were calculated by logistic regression.Black men were not at increased risk for BPH (relative risk 0.85, 95% CI 0.55 to 1.31) compared with white men. Asian men were less likely to have undergone BPH surgery (relative risk 0.41, 95% CI 0.21 to 0.82), although the relative risk for symptoms was similar to that of white men. White men whose major ancestry was southern European were at modestly higher risk for BPH surgery (relative risk 1.28, 95% CI 1.12 to 1.46) and symptoms (relative risk 1.34, 95% CI 1.20 to 1.50), whereas men of Scandinavian heritage were at slightly decreased risk for symptoms than those of other white heritages.Racial and ethnic variation is evident in the incidence of BPH surgery and symptom severity. Whether this observed variation reflects underlying biological phenomena rather than differences in symptom tolerance requires further exploration.

African-American men have the highest and Asian-American men have the lowest prostate cancer incidence rates in the United States; internationally, rates for the Asian continent are among the lowest. Higher insulin-like growth factor (IGF)-1, which participates in the control of cellular growth and differentiation and is modulated by IGF-binding protein-3 (IGFBP-3), was associated with an increased prostate cancer risk in three recent studies. We, therefore, investigated whether plasma levels of IGF-1 and IGFBP-3 vary by race in United States men selected from among members of the Health Professionals Follow-up Study who were 47-78 years old in 1993-1995 when they provided blood (n = 18,000). All of the men who described their major ancestry as African American (n = 63) and a random sample of 75 Asians and 75 Caucasians were invited to provide a second blood sample in 1997, of whom 42, 52, and 55, respectively, did so. IGF-1 and IGFBP-3 concentrations were determined by ELISA. We used nonparametric methods to assess racial variation in age-adjusted levels. Caucasians had the highest median IGF-1 level (224 ng/ml), followed by Asians (208 ng/ml) and African Americans (205 ng/ml). Median IGFBP-3 concentration was similar between Caucasians and Asians but was more than 13% lower in African Americans. Median molar IGF-1:IGFBP-3 ratio was greatest in Caucasians and lowest in Asians. The lower IGF-1 blood levels relative to IGFBP-3 levels among Asian men are consistent with their lower prostate cancer incidence. Although differences in circulating IGF-1 do not seem to account for the greater prostate cancer risk among African-American men, their absolute lower levels of IGFBP-3 may be contributory.

5alpha-Reductase type 2, the predominant prostatic isozyme of this protein, converts testosterone to dihydrotestosterone. It has been hypothesized that individuals with greater 5alpha-reductase activity are at increased risk for prostate cancer (CaP). A single nucleotide polymorphism of the 5alpha-reductase type 2 gene (SRD5A2) gives rise to a substitution of leucine (leu) for valine (val) at codon 89 (V89L), the presence of which may affect serum androstanediol glucuronide (AAG) levels. We studied the effect of this polymorphism on the risk of prostate cancer in a prospective, nested, case-control design within the Physicians' Health Study. In all controls (n = 799), the leu allele frequency was 0.30. Among the 386 controls with plasma AAG levels available, there was no significant association between AAG levels and V89L genotype. We also detected no significant association between risk for CaP and genotype [odds ratio: val/val = 1.0 (reference), leu/val = 0.96 (95% confidence interval, 0.76-1.20), and leu/ leu = 0.84 (95% confidence interval, 0.57-1.24)]. These data do not support a moderate to large effect of the SRD5A2 V89L polymorphism on plasma AAG levels or CaP risk in this predominantly Caucasian cohort, although a small effect cannot be completely excluded.

The consistently observed epidemiologic associations of obesity and physical activity with colorectal cancer and precursor adenoma risk suggest that insulin and glucose control may be contributory. We evaluated the association of glycosylated hemoglobin (HbA1c), a clinical indicator of average glycemia over the previous 2 months, and possibly, indirectly, a marker of average blood insulin level, with colorectal carcinogenesis.Among women in the Nurses' Health Study, who provided blood in 1989-90 and were diagnosed subsequently in 1989-94, we included 79 colorectal cancer cases and 156 matched controls, and 201 distal colorectal adenoma cases and 201 matched controls. HbA1c concentrations in red blood cells were determined blindly by turbidometric immunoinhibition. Odds ratios (OR) and 95% confidence intervals (CI) were estimated from conditional logistic regression models.HbA1c level did not significantly differ between colorectal cancer cases (median 5.5%) and controls (5.5%, p = 0.5), although a small difference between adenoma cases (5.6%) and controls (5.5%, p = 0.06) was noted. Compared to the lowest tertile of HbA1c (median 5.2%), women in the middle (median 5.5%, OR = 1.2, CI = 0.6-2.5) and upper (5.8%, OR = 1.2, CI = 0.6-2.7) tertiles were not at an increased risk for colorectal cancer. A modestly elevated risk of distal colorectal adenoma in the upper (median 5.8%, OR = 1.4, CI = 0.9-2.3) versus lower (median 5.3%) tertile could not be excluded. These associations were not appreciably altered after adjusting for known and suspected colorectal cancer risk factors.Over the range of levels observed in this relatively small sample of middle-aged women, prediagnostic HbA1c does not clearly predict colorectal cancer and adenoma risk.

We define incidence rates and risk factors for acute urinary retention.In 1992, 41,276 United States male health professionals 45 to 83 years old self-reported baseline health data and American Urological Association symptom index scores. In 1995 a subset reported the year of any episode of acute urinary retention requiring catheterization. Of 8,418 respondents 6,100 without a history of prostate cancer, prostatectomy or acute urinary retention before 1992 provided data. Incidence rates from 1992 to 1995 were calculated and risk factors were assessed using logistic regression.During 15,851 person-years of followup 82 men reported an episode of acute urinary retention (sampling weighted incidence 4.5/1,000 person-years, 95% confidence intervals 3.1 to 6.2). Rates increased with age and baseline symptom severity. In men with symptom score 0 to 7 (none or mild lower urinary tract symptoms) the incidence of acute urinary retention increased from 0.4/1,000 person-years for those 45 to 49 years old to 7.9/1,000 person-years for those 70 to 83 years old. In men with symptom score 8 to 35 (moderate or severe lower urinary tract symptoms) rates increased from 3.3/1,000 person-years for those 45 to 49 years old to 11.3/1,000 person-years for those 70 to 83 years old. Men with a clinical diagnosis of benign prostatic hyperplasia and a symptom score 8 or greater had the highest rates (age adjusted incidence 13.7/1,000 person-years). All 7 lower urinary tract symptoms comprising the American Urological Association symptom index individually predicted acute urinary retention (age adjusted odds ratio 1.8 to 2.9 for symptoms occurring more than 25% of the time during the last month). The sensation of incomplete bladder emptying, having to void again after less than 2 hours and a weak urinary stream were the best independent symptom predictors. Use of medications with adrenergic or anticholinergic side effects also predicted acute urinary retention.Acute urinary retention occurred relatively infrequently but older age, moderate or severe lower urinary tract symptoms, a diagnosis of benign prostatic hyperplasia and specific drug therapies significantly increased the risk of occurrence.

CAG repeat length in exon 1 of the androgen receptor (AR) gene correlates inversely with transcriptional transactivation activity of the AR. Men with shorter AR CAG repeat lengths are at higher risk of prostate cancer. Because benign prostatic hyperplasia (BPH) is an androgen-dependent condition, we examined the hypothesis that a shorter AR gene CAG repeat length increases the risk of developing of BPH.Among 14,916 men of the Physicians' Health Study who had provided a blood sample in 1982, we measured AR gene CAG repeat lengths for 310 men who had surgery for BPH up to 7.5 years of follow-up and 1,041 controls.Risk of surgery for BPH increased linearly with decreasing AR CAG repeat length (P (trend) = 0.03). Relative to men with a CAG repeat lengthor = 25, men with a repeat lengthor = 19 had an odds ratio of BPH surgery of 1.76 (95% confidence interval, 1.16-2.65).Variability in the AR gene CAG repeat influences the development of symptomatic BPH.

Studies that have examined the relationship between cigarette use and prostate cancer incidence have yielded inconsistent results, although most studies have suggested that smoking is related to the occurrence of fatal prostate cancer. We evaluated prospectively the relationship between cigarette smoking and total, distant metastatic, and fatal prostate cancer in 47,781 male health professionals throughout the United States followed with questionnaires. From 1986 to 1994, we documented 1369 men with prostate cancer (excluding stage A1). One hundred fifty-two of the men had distant metastatic disease at diagnosis, and 103 fatal cases occurred from 1986 to 1994. Early (before age 30), late (within recent 10 years), and lifetime cumulative smoking history were unrelated to risk of total prostate cancer. However, men who had smoked 15 or more pack-years of cigarettes within the preceding 10 years were at higher risk of distant metastatic prostate cancer [multivariate relative risk (RR), 1.81; 95% confidence interval (CI), 1.05-3.11; P (trend), 0.03] and fatal prostate cancer [RR, 2.06; CI, 1.08-3.90; P (trend), 0.02] relative to nonsmokers. Within 10 years after quitting, the excess risk among smokers is eliminated. The higher rate of fatal prostate cancer among smokers did not appear to result from confounding by diet or other lifestyle factors, different screening behavior between smokers and nonsmokers, or from other smoking-related comorbidities. Our results indicate that although smoking was unrelated to prostate cancer incidence, recent tobacco use had a substantial impact on the occurrence of fatal prostate cancer.

Dietary consumption of the carotenoid lycopene (mostly from tomato products) has been associated with a lower risk of prostate cancer. Evidence relating other carotenoids, tocopherols, and retinol to prostate cancer risk has been equivocal. This prospective study was designed to examine the relationship between plasma concentrations of several major antioxidants and risk of prostate cancer. We conducted a nested case-control study using plasma samples obtained in 1982 from healthy men enrolled in the Physicians' Health Study, a randomized, placebo-controlled trial of aspirin and beta-carotene. Subjects included 578 men who developed prostate cancer within 13 years of follow-up and 1294 age- and smoking status-matched controls. We quantified the five major plasma carotenoid peaks (alpha- and beta-carotene, beta-cryptoxanthin, lutein, and lycopene) plus alpha- and gamma-tocopherol and retinol using high-performance liquid chromatography. Results for plasma beta-carotene are reported separately. Odds ratios (ORs), 95% confidence intervals (Cls), and Ps for trend were calculated for each quintile of plasma antioxidant using logistic regression models that allowed for adjustment of potential confounders and estimation of effect modification by assignment to either active beta-carotene or placebo in the trial. Lycopene was the only antioxidant found at significantly lower mean levels in cases than in matched controls (P = 0.04 for all cases). The ORs for all prostate cancers declined slightly with increasing quintile of plasma lycopene (5th quintile OR = 0.75, 95% CI = 0.54-1.06; P, trend = 0.12); there was a stronger inverse association for aggressive prostate cancers (5th quintile OR = 0.56, 95% CI = 0.34-0.91; P, trend = 0.05). In the placebo group, plasma lycopene was very strongly related to lower prostate cancer risk (5th quintile OR = 0.40; P, trend = 0.006 for aggressive cancer), whereas there was no evidence for a trend among those assigned to beta-carotene supplements. However, in the beta-carotene group, prostate cancer risk was reduced in each lycopene quintile relative to men with low lycopene and placebo. The only other notable association was a reduced risk of aggressive cancer with higher alpha-tocopherol levels that was not statistically significant. None of the associations for lycopene were confounded by age, smoking, body mass index, exercise, alcohol, multivitamin use, or plasma total cholesterol level. These results concur with a recent prospective dietary analysis, which identified lycopene as the carotenoid with the clearest inverse relation to the development of prostate cancer. The inverse association was particularly apparent for aggressive cancer and for men not consuming beta-carotene supplements. For men with low lycopene, beta-carotene supplements were associated with risk reductions comparable to those observed with high lycopene. These data provide further evidence that increased consumption of tomato products and other lycopene-containing foods might reduce the occurrence or progression of prostate cancer.

The p450 hepatic microsomal enzyme system metabolizes exogenous drugs and carcinogens. Debrisoquine hydroxylase (CYP2D6), one member of the p450 hemoproteins, has polymorphic expression leading to poor metabolism of debrisoquine and similar compounds in approximately 7% of Caucasians. The genetic locus for this enzyme has been characterized, and the mutations responsible for the slowed metabolism have been identified. Epidemiological studies of the CYP2D6 phenotype suggest an association between the normal or rapid metabolism phenotype and increased risk of lung and bladder cancer. Preliminary data have also suggested an association with prostate cancer (CaP). We used a PCR-based assay to investigate possible associations between the CYP2D6 B allele, the most common genetic mutation responsible for the poor metabolism phenotype, and CaP. Using genomic DNA isolated from peripheral blood, we genetically typed 571 men with CaP and 767 matched controls, all participants in the Physician's Health Study. Relative to men homozygous for the wild-type allele, heterozygotes for the B allele have an odds ratio of 1.19 (95% confidence interval, 0.94-1.51) for CaP, and men homozygous for the B allele have an odds ratio of 1.37 (95% confidence interval, 0.86-2.20). When analyzed as a trend over zero, one, or two copies of the B allele, there emerges a possible association between the B allele and an increased risk of CaP of borderline statistical significance (P = 0.07).

Because the role of exercise in prostate cancer is unclear, we examined the relationship between leisure time physical activity and risk of prostate cancer in the Health Professionals Follow-up Study, a prospective cohort study of male health professionals in the United States. In 1986, 47,542 men 40-75 years of age and free of cancer responded to a mailed questionnaire that included an assessment of physical activity. The reported average time per week spent on each of a variety of nonoccupational activities was multiplied by its typical energy expenditure requirements expressed in metabolic equivalents (METs) and summed to yield a total weekly MET-hour score. We also examined MET-hours from all vigorous activities, defined as those requiring energy expenditures of six or more METs, and nonvigorous activities. From 1986 until January 31, 1994, we identified 1362 incident cases of total prostate cancer (excluding stage A1), 419 advanced (extraprostatic) cases, and 200 metastatic cases. No relationship with total or advanced prostate cancer was evident for total, vigorous, and nonvigorous physical activity. For metastatic prostate cancer, we also found no linear trends for these activities, but did observe a significantly lower risk in the highest category of vigorous activity (multivariate relative risk = 0.46; 95% confidence interval = 0.24-0.89 for25 versus 0 MET-hours), controlling for age, vasectomy, history of diabetes, height, smoking, and dietary factors. This highest category included 15% of the population and reflects at least 3 h/week of participation in vigorous activities. Differences in disease surveillance according to activity level could not account for our findings. The results from this cohort indicate that physical activity is unlikely to influence the incidence of total prostate cancer appreciably; however, the suggestion of a lower risk of metastatic prostate cancer in men engaging in high levels of vigorous activities warrants further study.

Cooking meat creates heterocyclic amines (HCAs) through pyrolysis of amino acids and creatinine. Although recognized as mutagenic, the etiological role of HCA in human cancer is unclear, due to the lack of information on the effect of typical food cooking methods on HCA concentrations and on variation in HCA exposure in populations. We estimated overall daily dietary HCA intake and variation in intake between individuals, using recent data on HCA concentrations in various meats prepared by cooking methods, temperatures, and times common in United States in the 1990s. Random samples of 250 participants from each of three large prospective cohorts were mailed a questionnaire to assess frequency of consumption, cooking method, and typical outside appearance of pan-fried, broiled, and grilled or barbecued chicken, fish, hamburger, and steak; fried, microwaved, and broiled bacon; fried sausage; roast beef; and homemade gravy. The 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), and 2-amino-3,4,8-trimethylimidazo[4,5,f]quinoxaline (DiMeIQx) concentrations, measured in composite samples by solid-phase extraction and high-performance liquid chromatography, were assigned to each food, cooking method, and doneness level. The dietary reports showed approximately 30-fold relative variation in 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline intake, 20-fold for 2-amino- -methyl-6-phenylimidazo[4,5-b]pyridine, and over 110-fold for 2-amino-3,4,8-trimethylimidazo[4,5,f]quinoxaline, when the 10th and 90th percentiles of HCA intake were compared (90th/10th percentile value). These reported variations in HCA exposure among participants in these three large cohorts indicates that estimation of HCA intake and determination of association with disease risk are feasible, if additional information on meat cooking methods is obtained.

The androgen receptor (AR) gene contains a polymorphic GGN microsatellite in exon 1, which encodes polyglycine in the amino terminus of the AR. Previous work has shown that a polymorphic region of CAG repeats also in exon 1 is inversely related to the ability of the AR to transactivate other genes and to prostate cancer risk. We investigated whether AR gene GGN repeat length is related to prostate cancer in a nested study of 582 cases and 794 controls matched on age and smoking status in the Physicians' Health Study. DNA was prepared from archived blood. Using PCR, the region surrounding the GGN repeat was amplified. Fluorescence-labeled primers were used such that the fragment produced could be sized using polyacrylamide gels and Genescan software. We estimated odds ratios and 95% confidence intervals from logistic models controlling for the matching variables for the relation between GGN repeat length and total prostate cancer and by stage/grade and by age at diagnosis. Among controls, the most frequent GGN repeat lengths were 23 (53.5%) and 24 (34.0%), with a range of 10-29. There was no statistically significant difference in the mean GGN repeat length between cases (23.13) and controls (23.05). However, cases had a narrower spread of repeats lengths (parametric test, P = 0.03; nonparametric test, P = 0.07) than controls, with fewer extreme lengths in either direction. The risk of total prostate cancer was slightly increased for a GGN repeat length of 23 compared to all others (odds ratio, 1.20; 95% confidence interval 0.97-1.49); risk did not vary by tumor stage/grade. For every one repeat deviation in either direction from 23, the risk of prostate cancer decreased by 8% (P = 0.04). Although the AR gene GGN repeat probably plays only a modest role in prostate cancer, the observed relation of this repeat with prostate cancer risk supports the evaluation of the effect of GGN repeat length on AR transactivation.

Prostatic cells express vitamin D receptor (VDR), which mediates the functions of 1,25-dihydroxyvitamin D. Two recent case-control studies suggested strong inverse associations between two VDR polymorphisms, TaqI and poly(A), and risk of prostate cancer. These two and a third polymorphism, BsmI, are closely linked. In a case-control study nested in the Physicians' Health Study, a randomized double-blind trial of aspirin and beta-carotene among 22,071 United States male physicians, we examined the associations between BsmI and TaqI and prostate cancer risk and whether the associations varied according to age and vitamin D metabolite levels among 372 incident cases and 591 controls. Among controls, the BB genotype was significantly associated with higher 1,25-dihydroxyvitamin D (median = 36.2 pg/ml for the BB versus 33.9 pg/ml for the bb genotype; P = 0.02), suggesting an association of the VDR polymorphisms with VDR function. Overall, we observed no significant associations of these VDR polymorphisms with prostate cancer risk: relative risk (RR) = 0.86 [95% confidence interval (CI) = 0.57-1.29] for the BB genotype and RR = 0.92 (95% CI = 0.69-1.22) for the Bb genotype, compared with the bb genotype (results were similar for the TaqI polymorphism). Stratification by age (or = 61 and61 years) and tumor aggressiveness showed no significant associations. However, in an analysis restricted to men with plasma 25-hydroxyvitamin D below the median, we observed a 57% reduction (RR = 0.43, 95% CI = 0.19-0.98) in risk for those with the BB versus the bb genotype; the risk reduction was particularly marked among older men (RR = 0.18, 95% CI = 0.05-0.68). We did not observe this inverse association among men with 25-hydroxyvitamin D levels above the median, nor did we observe it among younger men.

A lower risk of prostate cancer among diabetics has been suggested by several but not all studies. However, the studies have not always accounted for time since diagnosis of diabetes mellitus, or have not examined confounding factors such as diet and diagnostic bias. We thus examined this relationship in the Health Professionals Follow-Up Study from 1986 and 1994, in which 1,369 new cases of non-stage A1 prostate cancer were documented in 47,781 men. A prior history of a diagnosis of diabetes (mostly adult-onset) was associated with a reduced risk of prostate cancer (multivariate relative risk [RR] = 0.75; 95 percent confidence interval [CI] = 0.59-0.95) controlling for age, body mass index (wt/ht2) at age 21, and, in 1986, race, vasectomy, and intakes of total energy, total fat, calcium, fructose, and lycopene. After excluding the first year of follow-up after the diagnosis of diabetes, the RR was 0.63 (CI = 0.54-0.89). Prostate cancer was not reduced in the first five years after diagnosis (RR = 1.24, CI = 0.87-1.77), but was lower in the next five years (RR = 0.66, CI = 0.39-1.10) and lowest after 10 years (RR = 0.54, CI = 0.37-0.78); P-value for trend across time = 0.004. Similar associations were noted for advanced cases. Detection bias was unlikely to account for our findings. The basis of this relationship is unclear but may reflect hormonal changes related to diabetes, perhaps low testosterone levels.

Laboratory and clinical data indicate an antitumor effect of 1,25(OH)2 vitamin D (1,25(OH)2D) on prostate cancer. High calcium intake suppresses formation of 1,25(OH)2D from 25(OH)D, thereby decreasing the 1,25(OH)2D level. Ingestion of fructose reduces plasma phosphate transiently, and hypophosphatemia stimulates 1,25(OH)2D production. We thus conducted a prospective study among 47,781 men of the Health Professionals Follow-Up Study free of cancer in 1986 to examine whether calcium and fructose intake influenced risk of prostate cancer. Between 1986 and 1994, 1369 non-stage A1 and 423 advanced (extraprostatic) cases of prostate cancer were diagnosed. Higher consumption of calcium was related to advanced prostate cancer [multivariate relative risk (RR), 2.97; 95% confidence interval (CI), 1.61-5.50 for intakesor = 2000 mg/day versus500 mg/day; P, trend, 0.002] and metastatic prostate cancer (RR, 4.57; CI, 1.88-11.1; P, trend,0.001). Calcium from food sources and from supplements independently increased risk. High fructose intake was related to a lower risk of advanced prostate cancer (multivariate RR, 0.51; CI, 0.33-0.80, for intakes70 versusor = 40 g/day; P, trend, 0.007). Fruit intake was inversely associated with risk of advanced prostate cancer (RR, 0.63; 95% CI, 0.43-0.93; for5 versusor = 1 serving per day), and this association was accounted for by fructose intake. Non-fruit sources of fructose similarly predicted lower risk of advanced prostate cancer. A moderate positive association between energy-adjusted fat intake and advanced prostate cancer was attenuated and no longer statistically significant when controlled for calcium and fructose. Our findings provide indirect evidence for a protective influence of high 1,25(OH)2D levels on prostate cancer and support increased fruit consumption and avoidance of high calcium intake to reduce the risk of advanced prostate cancer.

Cancer ranks as the second-leading cause of death in developed countries and diet has long been suspected as playing a prominent role in its etiology. As a result, a substantial amount of research has been devoted to this field of study. Given the epidemiologic and biologic credibility, it is reasonable to attempt to identify specific nutrients, foods, or combination of these that are causally related to the development of cancer. Various study designs have been employed to generate and test specific hypotheses. In this review, we approach the dietary prevention of cancer primarily from an epidemiologic perspective. We examine the growing body of evidence on dietary etiologic factors and explore the practical prospects for prevention of cancer overall. An attempt is also made to explain inconsistencies in the findings and provide ideas for future research efforts in this field.

Evidence for an effect of reproductive factors on colorectal carcinogenesis is inconsistent and little is known about their role in development of precursor adenomatous polyps. We evaluated the relation between reproductive factors and distal colorectal adenomas (n = 982) during 14 years of follow up of 26,983 participants in the Nurses' Health Study (United States). The women were free of diagnosed cancer or polyps in 1980, underwent endoscopy 1980-94, and had reported on their parity, oral contraceptive (OC) use, and ages at menarche, first term-pregnancy, and menopause. We calculated relative risks (RR) and 95 percent confidence intervals (CI) using multiple logistic regression. Women with higher parity had an increased risk of adenomas of the distal colorectum (P trend = 0.004; 6+ cf 0 parity: RR = 1.3, CI = 0.9-1.8) or distal colon (P trend = 0.002, RR = 1.7, CI = 1.2-2.6). This association was significantly stronger among women with a family history of colorectal cancer (P interaction = 0.03); comparing 6+ term-pregnancies with nulliparity, among those with a family history, the RR for distal colon adenoma was 3.2 (CI = 1.4-7.2), while among those without a family history, the RR was 1.3 (CI = 0.8-2.2). We observed no association for distal colorectal adenoma and age at menarche, age at first term-pregnancy, ever use of OCs, or menopausal status. Further work is needed to clarify the relation of parity with colon adenoma risk.

We evaluated the relation of specific sources and components of fiber with diagnosis of distal colon (n = 531) or rectal (n = 159) adenomatous polyps or hyperplastic (n = 327) polyps in the Health Professionals Follow-up Study. We studied 16,448 men free of cancer or polyps in 1986, who underwent endoscopy in 1986-1994, and who provided diet and medical history. Relative risks (RRs) and 95% confidence intervals (CIs) adjusted using multiple logistic regression were calculated. We observed a modest reduced risk of distal colon adenoma with increasing intake of fiber from fruit (P-trend = 0.03) but not cereals or vegetables. The RR comparing the highest (median, 8.4 g/day) to lowest (1.3 g/day) quintile of fruit fiber intake was 0.81 (95% CI, 0.59-1.11). Soluble fiber, but not insoluble fiber, appeared to be inversely associated with distal colon adenoma (P-trend = 0.007). Comparing extreme quintiles (9.4 versus 3.4 g/day soluble fiber), the RR was 0.69 (95% CI, 0.46-1.03). Polyps detected in 1986 or later among men also with a negative endoscopy before 1986 may be considered to be "incident," with diet report corresponding more closely to time of polyp development. For "incident" cases (n = 130), the relation between soluble fiber and distal colon adenoma was strengthened (extreme quintiles RR, 0.27; 95% CI, 0.11-0.66; P-trend = 0.003), whereas for "prevalent" cases (n = 401), we found no association. No consistent relation between fiber and rectal adenomas or hyperplastic polyps was observed. These results suggest that soluble fiber may be particularly important in reducing risk of adenomatous polyps of the distal colon and support national dietary guidelines of increasing fruit consumption.

Physical inactivity and high body mass index (weight in kilograms divided by height in square meters) have been linked to increased risk of colon cancer. However, none of the few prospective studies in women has shown a statistically significant reduction in colon cancer incidence or mortality associated with increased leisure-time physical activity.In this prospective study, we asked whether leisure-time physical activity, body mass index, or body fat distribution could significantly influence the risk of colon cancer in women.The participants in this study were enrolled in the Nurses' Health Study, which began in 1976. Every 2 years, the women provided additional personal information and information on medical risk factors and major medical events. The time spent per week at a variety of leisure-time physical activities was determined, and the time spent at each activity was multiplied by its typical energy expenditure, expressed in terms of metabolic equivalents or METs. The resulting values for each woman were added to yield an MET-hours-per-week score. Reported diagnoses of colon cancer were confirmed by review of hospital records and pathology reports. Relative risks and associated 95% confidence intervals were calculated.In multivariate analyses that included body mass index, women who expended more than 21 MET-hours per week on leisure-time physical activity had a relative risk of colon cancer of 0.54 (95% confidence interval [CI] = 0.33-0.90) in comparison with women who expended less than 2 MET-hours per week. Women who had a body mass index greater than 29 kg/m2 had a relative risk of colon cancer of 1.45 (95% CI = 1.02-2.07) in comparison with women who had a body mass index less than 21 kg/m2. A tendency toward higher colon cancer risk was observed for increasing waist-to-hip ratio (relative risk = 1.48 [95% CI = 0.88-2.49] for comparison of the highest quintile ratio [0.833] to the lowest [0.728]).The significant inverse association between leisure-time physical activity and incidence of colon cancer in women in this study is consistent with what has been found in men. Recommendations to increase physical activity and maintain lean body weight should receive greater emphasis as part of a feasible approach to the prevention of colon cancer.

Folate derivatives are important in experimental colorectal carcinogenesis; low folate intake, particularly with substantial alcohol intake, is associated with increased risk. The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of 5,10-methylenetetrahydrofolate, required for purine and thymidine syntheses, to 5-methyltetrahydrofolate, the primary circulatory form of folate necessary for methionine synthesis. A common mutation (677C--T) in MTHFR reduces enzyme activity, leading to lower levels of 5-methyltetrahydrofolate. To evaluate the role of folate metabolism in human carcinogenesis, we examined the associations of MTHFR mutation, plasma folate levels, and their interaction with risk of colon cancer. We also examined the interaction between genotype and alcohol intake. We used a nested case-control design within the Physicians' Health Study. Participants were ages 40-84 at baseline when alcohol intake was ascertained and blood samples were drawn. During 12 years of follow-up, we identified 202 colorectal cancer cases and matched them to 326 cancer-free controls by age and smoking status. We genotyped for the MTHFR polymorphism and measured plasma folate levels. Men with the homozygous mutation (15% in controls) had half the risk of colorectal cancer [odds ratio (OR), 0.49; 95% confidence interval (CI), 0.27-0.87] compared with the homozygous normal or heterozygous genotypes. Overall, we observed a marginal significant increased risk of colorectal cancer (OR, 1.78; 95% CI, 0.93-3.42) among those whose plasma folate levels indicated deficiency (3 ng/ml) compared with men with adequate folate levels. Among men with adequate folate levels, we observed a 3-fold decrease in risk (OR, 0.32; 95% CI, 0.15-0.68) among men with the homozygous mutation compared with those with the homozygous normal or heterozygous genotypes. However, the protection due to the mutation was absent in men with folate deficiency. In men with the homozygous normal genotype who drank little or no alcohol as reference, those with the homozygous mutation who drank little or no alcohol had an 8-fold decrease in risk (OR, 0.12; 95% CI, 0.03-0.57), and for moderate drinkers, a 2-fold decrease in risk (OR, 0.42; 95% CI, 0.15-1.20); no decrease in risk was seen in those drinking 1 or more drinks/day. Our findings provide support for an important role of folate metabolism in colon carcinogenesis. In particular, these results suggest that the 677C--IT mutation in MTHFR reduces colon cancer risk, perhaps by increasing 5,10-methylenetetrahydrofolate levels for DNA synthesis, but that low folate intake or high alcohol consumption may negate some of the protective effect.

Prostate cancer (CaP) is the most commonly diagnosed, nondermatological cancer in the United States. The development and progression of CaP is influenced by androgens. 5 alpha-Reductase, type II, converts testosterone to dihydrotestosterone and is critical to the development of the prostate. A TA dinucleotide repeat polymorphism exists in the 3' untranslated region of the 5 alpha-reductase type II gene. 5 alpha-Reductase alleles with longer TA repeats are more common in African-Americans, the group with the highest incidence of CaP. It has been hypothesized that the longer TA repeat alleles might be associated with increased risk of CaP. We studied this potential association within the Physician's Health Study, a predominantly Caucasian cohort study. Using PCR we identified the TA genotype in 590 men with CaP and 802 age-matched controls. The frequency of each allele in the controls was TA(0), 0.87, TA(9), 0.13, and TA(18), 0.01. Homozygotes for the longer TA alleles, TA(9) and TA(18), were underrepresented among cases with an odds ratio of 0.47 (confidence interval, 0.20-1.12), but this was not statistically significant (P = 0.08, two tailed). Our analysis does not support the prior hypothesis that longer TA alleles confer an increased risk of CaP in a predominantly Caucasian population; in fact, longer TA alleles are more prevalent in men without CaP.

To explore the roles of reproductive factors and oral contraceptive use in the etiology of colorectal cancer, we examined incident cases of colorectal cancer (n = 501) that occurred during 1,012,280 person-years of follow-up between 1980 and 1992 in the Nurses' Health Study. The women completed mailed, self-administered questionnaires every 2 years to update information on the risk factors and major medical events. In multivariate analysis, the relative risk (RR) of colorectal cancer among women who experienced menarche at age 14 or older was 0.83 (95% confidence interval (CI) = 0.64-1.08) compared with women who had menarche at age 13; women whose menarche occurred under age 12 were at higher risk (RR = 1.22; 95% CI = 0.96-1.55, P for trend = 0.01). Compared with women whose first pregnancy was before age 24, the risk for colorectal cancer was significantly increased among women whose first pregnancy was at age 30 or older (RR = 1.57; 95% CI = 1.15-2.14; P for trend = 0.02). No important associations were seen for parity or age at menopause. Women who used oral contraceptives for 96 months or longer had a 40% lower risk of developing colorectal cancer (RR = 0.60; 95% CI = 0.40-0.89; P for trend = 0.02) compared with women who never used oral contraceptives. These prospective data suggest that a later age of menarche and use of oral contraceptives may reduce risk of colorectal cancer, whereas women with a later age at first pregnancy may have a higher risk.

The role of diet in the etiology of prostate cancer remains unclear, because results from several case-control and cohort studies on fat intake and risk of prostate cancer have been inconsistent; few of the studies have adjusted the results for caloric intake. To examine the relationship between energy, intake of several nutrients and risk of prostate cancer (all stages combined and advanced stages separately), we conducted a population-based case-control study in Orebro County, Sweden, from 1989 through 1994. A total of 526 patients with newly diagnosed prostate cancer and 536 controls, randomly selected from the population register and frequency-matched by age, were included in the analyses. Information about dietary intake was obtained from a self-administered semi-quantitative food frequency questionnaire. Odds ratios with 95% confidence intervals were estimated by unconditional logistic regression. In age-adjusted analyses, there were positive associations of prostate cancer (all stages combined) risk with total energy intake as well as intake of total fat (saturated and monounsaturated), protein, retinol and zinc. The positive association with energy intake was stronger for advanced cancer, with an excess risk of 70% for the highest quartile vs. the lowest. After adjustment for energy intake, there was no apparent association of prostate cancers (all stages combined) with any of the investigated nutrients. However, a weak positive association between intake of retinol and advanced cancer was observed. We conclude that our results provide some evidence that total energy intake is a risk factor for prostate cancer.

We examined the relationship of a common polymorphism (667C--T) of the methylenetetrahydrofolate reductase (MTHFR) gene with the risk of colorectal cancer in a case-control study conducted in the Health Professionals Follow-up Study. MTHFR genotypes were ascertained from blood samples among 144 men previously diagnosed with colorectal cancer and 627 controls. The adjusted odds ratio (OR) for the MTHFR variant homozygous (val/val) genotype was 0.57 [95% confidence interval (CI), 0.30-1.06]. High dietary intake of methionine (OR, 0.27; 95% CI, 0.06-1.20) and low consumption of alcohol (OR, 0.11; 95% CI, 0.01-0.85) were associated with reduced incidence of colorectal cancer. Alcohol intake was a stronger risk factor among men with the val/val genotype (P, trend = 0.01), and consumption of five or more alcoholic drinks per week abolished the reduced risk of colorectal cancer among val/val individuals (P, interaction = 0.02). The inverse association of methionine with colorectal cancer risk was slightly stronger among individuals with the MTHFR val/val genotype. These data suggest that dietary methyl supply is particularly critical among MTHFR val/val individuals. When dietary methyl supply is high, MTHFR val/val individuals may be at reduced risk of colorectal cancer probably because higher levels of 5,10-methylenetetrahydrofolate may prevent imbalances of nucleotide pools during DNA synthesis. In contrast, when 5-methyltetrahydrofolate is depleted by alcohol consumption, val/val individuals may be less able to compensate, leading to potentially oncogenic alterations in DNA methylation.