New Insights into Genetic Variation and Cancer

Cancer has become the leading cause of death in women, surpassing heart diseases. In males it takes a second place. The disease burden is large and grows as a result of aging of the population, especially in western countries. Cancer research in the past has led to a better understanding of treatment and prognosis. Nevertheless, despite substantial efforts in this research field, the pathogenesis of cancer is still largely unclear. Since long it has been recognized, that cancer is not merely one disease, but ha

Protective Effect of NSAIDs on Cancer and Influence of COX-2 C(-765)G Genotype

Purpose: Inhibition of COX-2 enzymes is a frequently suggested mechanism for the beneficial effects of NSAIDs on carcinogenesis. The aim of this study was to explore the role of cumulative NSAID use on four common non-skin related cancers and modification by COX-2 G(-765)C genotype. Patients and methods: 7621 participants of The Rotterdam Study were included. In a mean follow up period of 10 years, 720 colorectal, lung, breast or prostate cancers occurred. Cumulative NSAID use was calculated per NSAID class. Individual associations of NSAID use and COX-2 G(-765)C genotype on cancer risk were explored with Cox' proportional hazard models. Next, the association of NSAIDs and cancer stratified by COX-2 genotype was studied. Finally, the effect of combinations of NSAID use and COX-2 genotype on survival times was investigated. Results: All NSAID classes were associated with a reduced risk of colorectal cancer but not of other cancers. No associations between COX-2 genotype and incident cancer, overall or cancer specific mortality were observed. COX-selective NSAIDs showed modest further risk reduction. Survival times were more than twice as long for carriers of a COX-2 C-765 allele with colorectal cancer who used NSAIDs in the five years prior to diagnosis than for patients homozygous for the wild type (G(-765)) without NSAID use (p = 0.007). Conclusion: Our results confirm the protective effect of NSAID use on colorectal cancer. Individuals diagnosed with colorectal cancer who carry a COX-2 C-765 allele and are on NSAIDs have an increased survival in comparison to non-users with the wild type (G(-765))

Renin-anglotensin system inhibitors, angiotensin I-converting enzyme gene insertion/deletion polymorphism, and cancer

BACKGROUND. Angiotensin I-converting enzyme (ACE) inhibitors, angiotensin II antagonists, and the ACE insertion/ deletion (I/D) gene polymorphism all influence serum angiotensin II action. Because angiotensin II levels have been associated with cancer, the objective of the current epidermiologic study was to investigate whether renin-angiotensin system inhibitors and/or ACE genotypes were associated with an altered risk of colorectal, lung, breast, and prostate cancer. METHODS. Data were obtained from the Rotterdam Study, a population-based, prospective cohort study with 7983 participants. Participants who had a history of 1 of the cancers of interest (n = 216) or who had a medication history <6 months (n 88) were excluded, leaving 7679 participants, of whom the ACE genotypes could be assessed in 6670 individuals. The mean follow-up was 9.6 years, during which 730 incident cancers occurred. The effect of medication, ACE I/D genotypes, and their interaction on cancer risk and progression was studied by using Cox proportional hazard models. RESULTS. Carriers of the high-activity genotype DD had an increased risk of breast cancer compared with low-activity II/ID) genotype carriers (hazard ratio [HR], 1.47; 95% confidence interval [95% CI], 1.05-2.04), but no association was demonstrated for other cancers. DD carriers who were exposed to long-term and high-dose medication were at lower risk for cancer (HR, 0.28; 95% CI, 0.10-0.79). Short-term, high-dose users were at risk for colorectal cancer progression in the II/ID stratum (HR, 3.83; 95% CI, 1.67-8.79). CONCLUSIONS. Renin-angiotensin system-inhibiting drugs seemed to protect against cancer in individuals with the DD genotype, which was associated with high levels of ACE

Cytochrome P450 3A gene variation, steroid hormone serum levels and prostate cancer-The Rotterdam Study

Purpose: To study if polymorphisms in genes encoding for CYP3A enzymes, that play a role in steroid hormone metabolism, affect steroid hormone serum levels and prostate cancer incidence or mortality. Methods: 3048 male participants of The Rotterdam Study were included. Prostate cancer cases and non-cases were studied for differences in baseline hormone levels with Student's r-test. General linear models were performed on different random subsets of hormone levels to study associations with genotype. Cox' proportional hazard models were used to study prostate cancer incidence and mortality among genotypes. Results: Both DHEAS sulphate as free-testosterone were significantly increased at baseline in males who developed a prostate cancer within the study period. CYP3A4 G-allele carriage was associated with lower levels of estrone sulphate (p=0.005) and higher levels of estradiol (p=0.04) compared to non-carriers. CYP3A5 A-allele carriage was associated with increased levels of estrone sulphate (p=0.02). CYP3A7 Gallele carriage was associated with the highest number of significant differences in steroid hormone levels. Carriers of the allele resulting in continued enzyme expression during adulthood had decreased levels of dehydroepiandrosterone (DHEA) sulphate (p=0.05), androstenedione (p=0.006), estrone (p=0.0001) and estrone sulphate (p=0.003) compared to mean levels of these hormones in homozygous wild type carriers. CYP3A43 genotype was not associated with any of the studied hormone levels. However, carriers of the CYP3A43 G-allele showed a significant 5-fold increase in mortality among early onset diagnosed prostate cancers. Conclusion: Increased levels of free testosterone and DHEA sulphate were associated with prostate cancer incidence along the study period. Primarily the amount of CYP3A7 expression seemed to affect steroid hormone levels. Nevertheless, testosterone, a precursor of the prostate growth and differentiation stimulating dehydrotestosterone, was not influenced by CYP3A genotype. In line with this, no significant associations were observed for CYP3A genotypes and prostate cancer incidence. (C) 2010 Elsevier Inc. All rights reserved