Kana Wu

Plasma and Dietary Carotenoids, and the Risk of Prostate Cancer: A Nested Case-Control Study

The association between plasma carotenoids and prostate cancer risk was investigated in a case-control study nested within the prospective Health Professionals Follow-up Study. We matched 450 incident prostate cancer cases diagnosed from 1993–1998 to 450 controls by age, time, month, and year of blood donation. Modest inverse, but not statistically significant, associations were observed among plasma α-carotene, β-carotene, and lycopene concentrations, and overall risk of prostate cancer diagnosis {odds ratio (highest versus lowest quintile; OR), α-carotene: OR, 0.67 [95% confidence interval (CI), −0.40–1.09]; β-carotene: OR, 0.78 (95% CI, 0.48–1.25); lycopene: OR, 0.66 (95% CI, 0.38–1.13)}. The inverse association between plasma lycopene concentrations and prostate cancer risk was limited to participants who were 65 years or older (OR, 0.47; 95% CI, 0.23–0.98) and without a family history of prostate cancer (OR, 0.48; 95% CI, 0.26–0.89). Combining, older age and a negative family history provided similar results (OR, 0.43; 95% CI, 0.18–1.02). Inverse associations between β-carotene and prostate cancer risk were also found among younger participants (<65 years of age; OR, 0.36; 95% CI, 0.14–0.91; Ptrend = 0.03). Combining dietary intake and plasma data confirmed our results. We found a statistically significant inverse association between higher plasma lycopene concentrations and lower risk of prostate cancer, which was restricted to older participants and those without a family history of prostate cancer. This observation suggests that tomato products may exhibit more potent protection against sporadic prostate cancer rather than those with a stronger familial or hereditary component. In addition, our findings also suggest that among younger men, diets rich in β-carotene may also play a protective role in prostate carcinogenesis.

Insulin, the Insulin-Like Growth Factor Axis, and Mortality in Patients With Nonmetastatic Colorectal Cancer

PURPOSE Obesity, sedentary lifestyle, and Western dietary pattern have been linked to increased risk of cancer recurrence and mortality among patients with surgically resected colorectal cancer. Excess energy balance leads to increased circulating insulin and depressed levels of circulating insulin-like growth factor binding protein (IGFBP) -1, which promote cancer cell growth in preclinical models. PATIENTS AND METHODS Among 373 patients diagnosed with nonmetastatic colorectal cancer between 1991 and 2004, we performed a prospective observational study nested within two large US cohorts to evaluate the association between mortality and prediagnosis circulating C-peptide (a marker of insulin secretion), IGFBP-1, insulin-like growth factor-I (IGF-I), and IGFBP-3. RESULTS Compared with patients in the bottom quartile, patients in the top quartile of plasma C-peptide had an age-adjusted hazard ratio (HR) for death of 1.87 (95% CI, 1.04 to 3.36; P = .03 for trend), whereas those in the top quartile of circulating IGFBP-1 had a significant reduction in mortality (HR = 0.48; 95% CI, 0.28 to 0.84; P = .02 for trend). Little change in these estimates was noted after adjusting for other covariates known or suspected to influence survival. No associations were noted between mortality and IGF-I or IGFBP-3, which are two components of the IGF axis not closely correlated with lifestyle factors. CONCLUSION Among patients with surgically resected colorectal cancer, higher levels of prediagnosis plasma C-peptide and lower levels of prediagnosis plasma IGFBP-1 were associated with increased mortality. Circulating insulin and IGFBP-1 are potential mediators of the association between lifestyle factors and mortality after colorectal cancer resection.

The Mediterranean and Dietary Approaches to Stop Hypertension (DASH) diets and colorectal cancer

BACKGROUND Although the Mediterranean diet has been studied for cancer mortality and the Dietary Approaches to Stop Hypertension (DASH) diet shares similarities with the Mediterranean diet, few studies have specifically examined these 2 diets and incident colorectal cancer. OBJECTIVE The objective was to prospectively assess the association between the Alternate Mediterranean Diet (aMed) and the DASH-style diet scores and risk of colorectal cancer in middle-aged men and women. DESIGN A total of 87,256 women and 45,490 men (age 30-55 y for women and 40-75 y for men at baseline) without a history of cancer were followed for ≤ 26 y. The aMed and DASH scores were calculated for each participant by using dietary information that was assessed ≤ 7 times during follow-up. Relative risks (RRs) for colorectal cancer were computed with adjustment for potential confounders. RESULTS We documented 1432 cases of incident colorectal cancer among women and 1032 cases in men. Comparing top with bottom quintiles of the DASH score, the pooled RR for total colorectal cancer was 0.80 (95% CI: 0.70, 0.91; P for trend = 0.0001). The corresponding RR for DASH score and colon cancer was 0.81 (95% CI: 0.69, 0.95; P for trend = 0.002). There was a suggestion of an inverse association with rectal cancer with a pooled RR of 0.73 (95% CI: 0.55, 0.98; P for trend = 0.31) when comparing top with bottom quintiles of DASH score. No association was observed with aMed score. CONCLUSION Adherence to the DASH diet (which involves higher intakes of whole grains, fruit, and vegetables; moderate amounts of low-fat dairy; and lower amounts of red or processed meats, desserts, and sweetened beverages) was associated with a lower risk of colorectal cancer.

Dietary Patterns and Risk of Prostate Cancer in U.S. Men

We prospectively investigated the associations between dietary patterns and risk of prostate cancer in the Health Professionals Follow-up Study. Between 1986 and 2000, 3,002 incident prostate cancer cases were identified in our cohort. Using factor analysis, two major dietary patterns were identified, a prudent and a western dietary pattern. Dietary patterns were not appreciably associated with risk of total prostate cancer. For the highest versus the lowest quintiles, the multivariable relative risk (RR) for the prudent pattern was 0.94 [95% confidence interval (CI), 0.83-1.06], and for the western pattern, the multivariable RR was 1.03 (95% CI, 0.92-1.17). Neither were these associated with risk of advanced prostate cancer [highest versus lowest quintile, prudent pattern (RR, 1.01; 95% CI, 0.68-1.49); western pattern (RR, 1.13; 95% CI, 0.77-1.67)]. Higher western pattern scores were suggestively associated with a greater risk of advanced prostate cancer among older men [highest versus lowest quintile (RR, 1.35; 95% CI, 0.97-1.90)], but not after adding processed meat to the model [highest versus lowest quintile (RR, 1.11; 95% CI, 0.75-1.65)]. We did not find any evidence for a protective association between prudent pattern and risk of prostate cancer. The lack of association between a western dietary pattern as identified by factor analysis in our cohort and prostate cancer risk suggests that dietary risk factors for prostate cancer are likely to differ from those for other conditions, such as cardiovascular disease and type 2 diabetes, that have been associated with a western dietary pattern in this cohort. (Cancer Epidemiol Biomarkers Prev 2006;15(1):167–71)

Manganese superoxide dismutase (MnSOD) gene polymorphism, interactions with carotenoid levels and prostate cancer risk

BACKGROUND The manganese superoxide dismutase (MnSOD) gene encodes an antioxidant enzyme (SOD2) that may protect cells from oxidative damage. The MnSOD allele with Val as amino acid 16 encodes a protein that has 30-40% lower activity compared with the MnSOD Ala variant, hence possibly increasing susceptibility to oxidative stress. On the other hand, some epidemiologic studies suggest that the Ala allele is associated with a higher risk of cancer, including prostate cancer. METHODS We conducted a nested case-control study in the Health Professionals Follow-up Study with 612 incident prostate cancer cases and 612 matched controls to investigate the role of the MnSOD gene Ala16Val polymorphism and its joint association with plasma carotenoid concentrations in relation to risk of total prostate cancer and aggressive prostate cancer (advanced stage or Gleason sum > or =7). RESULTS The allele frequencies in the controls were 49.8% for Ala and 50.2% for Val. No association was found between the MnSOD genotype and risk of total and aggressive prostate cancer. Furthermore, no statistically significant interaction was observed between the MnSOD genotype and any of the plasma carotenoids in relation to risk of total and aggressive prostate cancer. In analyses in which we combined data from plasma and dietary carotenoids and created a quintile score to reflect long-term carotenoid status, a 3-fold [95% confidence interval: 1.37-7.02] increased risk of aggressive prostate cancer was observed among men with the Ala/Ala genotype in the presence of low long-term lycopene status (P-value, test for interaction = 0.02) as compared with men with the Ala/Val+Val/Val genotypes with low long-term lycopene status. CONCLUSION In this cohort of mainly white men, the MnSOD gene Ala16Val polymorphism was not associated with total or aggressive prostate cancer risk. However, men with the MnSOD Ala/Ala genotype who had low long-term lycopene status had a higher risk of aggressive prostate cancer compared with individuals with the other genotypes. These results are consistent with findings from earlier studies that reported when antioxidant status is low, the MnSOD Ala/Ala genotype may be associated with an increased risk of aggressive prostate cancer.

Dietary patterns and risk of colon cancer and adenoma in a cohort of men (United States)

BackgroundExamining the effects of dietary patterns on cancer risk may provide insights beyond the assessment of individual foods or nutrients. Design: In the health professionals follow-up cohort, associations between the ‘prudent’ and the ‘western’ dietary pattern and risk of colon cancer and adenomas were examined in 561 colon cancer cases and 1207 distal colon adenoma cases. Results: Higher prudent pattern scores were only weakly and non-significantly associated with decreased risk of colon cancer or distal colon adenoma (highest versus lowest quintile: colon cancer: multivariate adjusted relative risk (RR)=0.84 (95 confidence interval (CI)=0.64–1.10); ptrend=0.37; distal adenoma: multivariate odds ratio (OR)=0.88 (95 CI=0.73–1.08); ptrend=0.12). Our findings suggest a moderately increased risk of colon cancer and distal adenoma with higher western pattern scores (colon cancer: RR=1.27 (95 CI=0.96–1.69), ptrend=0.05; distal adenoma: OR=1.28 (95 CI=1.05–1.56), ptrend=0.01). Adding body mass index, which is positively related to western pattern and thus may be considered an intermediate endpoint between western pattern and colon cancer, attenuated associations somewhat but not substantially. Conclusion: Our data do not provide evidence for an appreciable inverse association between higher prudent pattern scores and risk of colon cancer or distal colon adenomas, but do support a moderate positive association between higher western pattern scores and risk of colon cancer or distal colon adenomas.

Meat mutagens and risk of distal colon adenoma in a cohort of U.S. men.

Cooking meats at high temperatures and for long duration produces heterocyclic amines and other mutagens. These meat-derived mutagenic compounds have been hypothesized to increase risk of colorectal neoplasia, but prospective data are unavailable. We examined the association between intakes of the heterocyclic amines 2-amino-3,8-dimethylimidazo[4,5,-f]quinoxaline (MeIQx), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3,4,8-trimethylimidazo[4,5,-f]quinoxaline (DiMeIQx), and meat-derived mutagenicity (MDM) and risk of distal colon adenoma using a cooking method questionnaire administered in 1996 in the Health Professionals Follow-up Study cohort. Between 1996 and 2002, 581 distal colon adenoma cases were identified. Higher intake of MDM was marginally associated with increased risk of distal adenoma [fourth versus lowest quintile: odds ratio (OR), 1.39; 95% confidence interval (95% CI), 1.05-1.84; highest versus lowest quintile: OR, 1.29; 95% CI, 0.97-1.72; Ptrend = 0.08]. Adjusting for total red meat or processed meat intake did not explain those associations. Our data also suggested a positive association between higher MeIQx (highest versus lowest quintile: OR, 1.28; 95% CI, 0.95-1.71; Ptrend = 0.22) and risk of adenoma, but this association was attenuated after adjusting for processed meat intake. DiMeIQx and PhIP did not seem to be associated with risk of adenoma. In conclusion, higher consumption of mutagens from meats cooked at higher temperature and longer duration may be associated with higher risk of distal colon adenoma independent of overall meat intake. Because mutagens other than heterocyclic amines also contribute to MDM, our results suggest that mutagens other than heterocyclic amines in cooked meats may also play a role in increasing the risk of distal adenoma. (Cancer Epidemiol Biomarkers Prev 2006;15(6):1120–5)

Review Article: The Role of Molecular Pathological Epidemiology in the Study of Neoplastic and Non-neoplastic Diseases in the Era of Precision Medicine.

Molecular pathology diagnostics to subclassify diseases based on pathogenesis are increasingly common in clinical translational medicine. Molecular pathological epidemiology (MPE) is an integrative transdisciplinary science based on the unique disease principle and the disease continuum theory. While it has been most commonly applied to research on breast, lung, and colorectal cancers, MPE can investigate etiologic heterogeneity in non-neoplastic diseases, such as cardiovascular diseases, obesity, diabetes mellitus, drug toxicity, and immunity-related and infectious diseases. This science can enhance causal inference by linking putative etiologic factors to specific molecular biomarkers as outcomes. Technological advances increasingly enable analyses of various -omics, including genomics, epigenomics, transcriptomics, proteomics, metabolomics, metagenomics, microbiome, immunomics, interactomics, etc. Challenges in MPE include sample size limitations (depending on availability of biospecimens or biomedical/radiological imaging), need for rigorous validation of molecular assays and study findings, and paucities of interdisciplinary experts, education programs, international forums, and standardized guidelines. To address these challenges, there are ongoing efforts such as multidisciplinary consortium pooling projects, the International Molecular Pathological Epidemiology Meeting Series, and the Strengthening the Reporting of Observational Studies in Epidemiology-MPE guideline project. Efforts should be made to build biorepository and biobank networks, and worldwide population-based MPE databases. These activities match with the purposes of the Big Data to Knowledge (BD2K), Genetic Associations and Mechanisms in Oncology (GAME-ON), and Precision Medicine Initiatives of the United States National Institute of Health. Given advances in biotechnology, bioinformatics, and computational/systems biology, there are wide open opportunities in MPE to contribute to public health.

Aspirin and the Risk of Colorectal Cancer in Relation to the Expression of 15-Hydroxyprostaglandin Dehydrogenase (HPGD)

Aspirin use is associated with a lower risk of colorectal cancer arising in association with high expression of 15-PGDH (HPGD) in normal colon mucosa. An Aspirin a Day May Keep Colon Cancer Away Aspirin, the ubiquitous drug that people use for everything, ranging from fever and headache to prevention of heart disease and colon cancer, is not without its drawbacks. Especially at high doses, aspirin increases the risk of gastrointestinal problems, such as bleeding and ulcers, in addition to other side effects such as bruising. Thus, it would be nice to know which patients are most likely to derive a benefit from aspirin treatment, and to avoid exposing everyone else to unnecessary adverse effects. Fink and coauthors analyzed two large studies totaling more than 100,000 participants and discovered that patients who used aspirin for colon cancer prevention were less likely to develop colon cancer with a high expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH). Conversely, colon cancers expressing low amounts of 15-PGDH were equally common in patients who used aspirin and those who didn’t. The applicability of these results for preventative medicine will still need to be confirmed in prospective trials, to determine whether the concentration of 15-PGDH (determined in advance, perhaps during routine colonoscopy) can predict which patients would benefit from using aspirin to prevent colon cancer. The current paper lays the groundwork for such studies and provides hope that we may someday be able to maximize the benefits of aspirin and use it for targeted efforts at cancer prevention. Aspirin use reduces the risk of colorectal neoplasia, at least in part, through inhibition of prostaglandin-endoperoxide synthase 2 (PTGS2, cyclooxygenase 2)–related pathways. Hydroxyprostaglandin dehydrogenase 15-(nicotinamide adenine dinucleotide) (15-PGDH, HPGD) is down-regulated in colorectal cancers and functions as a metabolic antagonist of PTGS2. We hypothesized that the effect of aspirin may be antagonized by low 15-PGDH expression in the normal colon. In the Nurses’ Health Study and the Health Professionals Follow-Up Study, we collected data on aspirin use every 2 years and followed up participants for diagnoses of colorectal cancer. Duplication-method Cox proportional, multivariable-adjusted, cause-specific hazards regression for competing risks data was used to compute hazard ratios (HRs) for incident colorectal cancer according to 15-PGDH mRNA expression level measured in normal mucosa from colorectal cancer resections. Among 127,865 participants, we documented 270 colorectal cancer cases from which we could assess 15-PGDH expression. Compared with nonuse, regular aspirin use was associated with lower risk of colorectal cancer that developed within a background of colonic mucosa with high 15-PGDH expression [multivariable HR, 0.49; 95% confidence interval (CI), 0.34 to 0.71], but not with low 15-PGDH expression (multivariable HR, 0.90; 95% CI, 0.63 to 1.27) (P for heterogeneity = 0.018). Regular aspirin use was associated with lower incidence of colorectal cancers arising in association with high 15-PGDH expression, but not with low 15-PGDH expression in normal colon mucosa. This suggests that 15-PGDH expression level in normal colon mucosa may serve as a biomarker that may predict stronger benefit from aspirin chemoprevention.

Folic acid and prevention of colorectal adenomas: A combined analysis of randomized clinical trials

Observational data suggest that lower folate status is associated with an increased risk of colorectal neoplasia, implying that folate may be useful as a chemopreventive agent. We conducted a combined analysis of three large randomized trials of folic acid supplementation for the prevention of metachronous adenomas in patients with an adenoma history. Participants included 2,632 men and women who had a history of adenomas randomized to either 0.5 or 1.0 mg/day of folic acid or placebo and who had a follow‐up endoscopy 6 to 42 months after randomization [mean = 30.6 (standard deviation = 8.1) months]. We used random‐effects meta‐analysis to estimate risk ratios (RRs) and 95% confidence intervals (CIs). The RR comparing folic acid versus placebo was 0.98 (95% CI = 0.82–1.17) for all adenomas and 1.06 (95% CI = 0.81–1.39) for advanced lesions. Folic acid was associated with a nonsignificant decreased risk of any adenoma among subjects in the lowest quartile of baseline plasma folate (≤11 nmol/L) and no effect among individuals in the highest quartile (>29 nmol/L, p for trend = 0.17). There was a nonsignificant trend of decreasing risk of any adenoma associated with folic acid supplements with increasing alcohol intake. During the early follow‐up reported here, more deaths occurred in the placebo group than in the folic acid group (1.7% vs. 0.5%, p = 0.002). In conclusion, after up to 3.5 years of folic acid use, there is no clear decrease or increase in the occurrence of new adenomas in patients with a history of adenoma.