Sonja I. Berndt

Genetic Polymorphisms of Interleukin-1B (IL-1B), IL-6, IL-8, and IL-10 and Risk of Prostate Cancer

Chronic intraprostatic inflammation is suspected to play a role in the pathogenesis of prostate cancer. Polymorphisms in cytokine genes can influence inflammation and immune response and may be related to the risk of prostate cancer. Four common single nucleotide polymorphisms (SNPs) in the genes encoding interleukin-1B (IL-1B), IL-6, and IL-8 were assessed in 503 prostate cancer cases and 652 controls, and three SNPs in IL-10 were assessed in an additional 817 prostate cancer cases and 1,190 controls (for a total of 1,320 prostate cancer cases and 1,255 controls). Cases and controls were selected from the on-going Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial and were frequency matched on age, ethnicity, time-period since initial screening, and date of blood draw. Single-locus analyses were conducted using conditional logistic regression. In addition, we did a haplotype analysis for the three IL-10 SNPs tested. Overall, no associations were detected between the seven polymorphisms in the four cytokine genes examined in this study and prostate cancer risk. Further stratifying by use of nonsteroidal anti-inflammatory drugs did not modify the associations. Findings were similar for early or advanced prostate cancers. Similarly, we observed no association between the major IL-10 haplotypes and the risk of prostate cancer. At least seven common polymorphisms in genes of inflammatory cytokines IL-1B, IL-6, IL-8, and IL-10 do not seem to play a role in the risk of prostate cancer.

Calcium intake and prostate cancer risk in a long-term aging study: the Baltimore Longitudinal Study of Aging.

OBJECTIVE To investigate the association between prostate cancer and calcium and other nutrients thought to influence the synthesis of 1,25-dihydroxyvitamin D [1,25(OH)2D]. METHODS We included in the analysis 454 male participants in the Baltimore Longitudinal Study of Aging who were 46 to 92 years old at the time of completion of a food frequency questionnaire. Among them, 69 men were diagnosed with prostate cancer during their lifetime. In 68% of the cases, the food frequency questionnaire was completed after the diagnosis of cancer. Multiple logistic regression analysis was used to calculate the odds ratio and 95% confidence interval of prostate cancer. RESULTS The median calcium intake was 788 mg/day. The adjusted odds ratio of prostate cancer for the highest tertile compared with the lowest tertile of calcium intake was 0.92 (95% confidence interval 0.48 to 1.77; P(trend) = 0.89). Likewise, no significant trends were found for phosphorus, vitamin D, fructose, or animal protein intake. Dairy products, including milk, were not associated with an increased risk of prostate cancer. The adjusted odds ratio of prostate cancer was 1.26 (95% confidence interval 0.57 to 2.79; P(trend) = 0.73) for men with high dairy intakes compared with those with low dairy intakes. CONCLUSIONS The results of this study suggest that calcium intake within moderate limits is not associated with a notably increased risk of prostate cancer.

Disparities in Treatment and Outcome for Renal Cell Cancer Among Older Black and White Patients

PURPOSE Black patients with renal cell cancer have shorter survival compared with their white counterparts, but the causes for this disparity are unclear. To elucidate reasons for this inequality, we examined differences in treatment and survival between black and white patients. PATIENTS AND METHODS A retrospective cohort study was conducted using data from the linked Surveillance, Epidemiology and End Results (SEER) cancer registry and Medicare databases. Participants included 964 black and 10,482 white patients age >or= 65 years who were enrolled into Medicare and diagnosed with renal cell cancer between 1986 and 1999. Information on surgical treatment was ascertained from both databases, whereas data regarding coexisting illness and survival was obtained from the Medicare database. RESULTS The percentage of black patients receiving nephrectomy treatment was significantly lower compared with whites (61.2% v 70.4%; P < .0001). After adjustment for age, sex, median income, cancer stage, tumor size, and comorbidity index, blacks were less likely to undergo nephrectomy treatment compared with whites (risk ratio = 0.93; 95% CI, 0.90 to 0.96). Overall survival was worse for blacks than whites even after adjustment for demographic and cancer prognostic factors (hazard ratio [HR] = 1.16; 95% CI, 1.07 to 1.25); however, additional adjustment for comorbidity index and nephrectomy treatment reduced the disparity substantially (HR = 1.00; 95% CI, 0.93 to 1.09). CONCLUSION This study indicates that the lower survival rate among blacks compared with whites with renal cell cancer can be explained largely by the increased number of comorbid health conditions and the lower rate of surgical treatment among black patients.

Genetic Variation in Base Excision Repair Genes and the Prevalence of Advanced Colorectal Adenoma

Base excision repair (BER) corrects DNA damage caused by oxidative stress and low folate intake, which are putative risk factors for colorectal neoplasia. To examine the relationship between genetic variation in BER genes and colorectal adenoma risk, we conducted a case-control study of 767 cases of advanced colorectal adenoma and 773 controls from the baseline screening exam of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cases included participants diagnosed with advanced left-sided adenoma, and controls were subjects without evidence of a left-sided polyp by sigmoidoscopy, frequency-matched to cases on race and gender. Twenty single nucleotide polymorphisms were genotyped in four BER genes (APEX1, PARP1, POLB, and XRCC1), and conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for the association with colorectal adenoma. Two variants with possible functional significance were associated with risk. The APEX1 51H variant was associated with a borderline significant decreased risk of colorectal adenoma (OR, 0.66; 95% CI, 0.44-1.00), and the XRCC1 399Q variant was inversely associated with risk among Caucasians (OR, 0.80; 95% CI, 0.64-0.99). Homozygotes at two PARP1 loci (A284A and IVS13+118G>A) were also associated with a decreased risk of colorectal adenoma compared with wild-type carriers (OR, 0.70; 95% CI, 0.49-0.98 for both), which was restricted to advanced adenomas displaying histologically aggressive characteristics (OR, 0.51; 95% CI, 0.33-0.78, P = 0.002 for PARP1 A284A). This study suggests that polymorphisms in APEX1, XRCC1, and PARP1 may be associated with advanced colorectal adenoma.

Genetic variation in the nucleotide excision repair pathway and colorectal cancer risk.

Nucleotide excision repair (NER) enzymes are critical for the removal of bulky DNA adducts caused by environmental carcinogens, such as heterocyclic amines and polycyclic aromatic hydrocarbons, which are found in two putative risk factors for colorectal cancer, tobacco smoke and meat cooked at high temperature. To examine the association between common genetic variants in NER genes and the risk of colorectal cancer, we conducted a case-cohort study within the CLUE II cohort. Twenty-two single nucleotide polymorphisms in 11 NER genes were genotyped in 250 colorectal cancer cases and a subcohort of 2,224 participants. Incidence rate ratios (RR) and 95% confidence intervals (95% CI) were estimated using a modified Cox regression model and robust variance estimate. The ERCC6 1213G variant, which is thought to reduce NER capacity, was associated with an increased risk of colorectal cancer compared with the homozygous wild type (RR, 1.36; 95% CI, 1.00-1.86 and RR, 2.64; 95% CI, 1.53-4.58 for the RG and GG genotypes respectively with Ptrend = 0.0006). Having at least one XPC 492H allele was also associated with an increased risk of colorectal cancer (RR, 1.75; 95% CI, 1.20-2.57). When the combined effects of ERCC6 R1213G and XPC R492H were examined, the risk of colorectal cancer significantly increased with increasing number of variant alleles (Ptrend = 0.00003). Our study suggests that genetic polymorphisms in the NER genes, ERCC6 and XPC, may be associated with an increased risk of colorectal cancer. (Cancer Epidemiol Biomarkers Prev 2006;15(11):2263–9)

Mismatch repair polymorphisms and the risk of colorectal cancer

Rare germline variants in mismatch repair genes have been linked to hereditary nonpolyposis colorectal cancer; however, it is unknown whether common polymorphisms in these genes alter the risk of colorectal cancer. To examine the association between common variants in mismatch repair genes and colorectal cancer, we conducted a case‐cohort study within the CLUE II cohort. Four single nucleotide polymorphisms in 3 mismatch repair genes (MSH3 R940Q, MSH3 T1036A, MSH6 G39E and MLH1 I219V) were genotyped in 237 colorectal cancer cases and a subcohort of 2,189 participants. Incidence rate ratios (RRs) and 95% confidence intervals (95% CIs) for each polymorphism were estimated. The MSH3 1036A variant was found to be associated with an increased risk of colorectal cancer (RR = 1.28, 95% CI: 0.94–1.74 and RR = 1.65, 95% CI: 1.01–2.70 for the AT and TT genotypes, respectively, with ptrend = 0.02), particularly proximal colon cancer. Although the MSH3 940Q variant was only weakly associated with colorectal cancer overall (ptrend = 0.07), it was associated with a significant increased risk of proximal colon cancer (RR = 1.69, 95% CI: 1.10–2.61 and RR = 2.68, 95% CI: 0.96–7.47 for the RQ and QQ genotypes, respectively with ptrend = 0.005). Processed meat intake appeared to modify the association between the MSH3 polymorphisms and colorectal cancer (pinteraction < 0.10 for both). No association was observed with the MSH6 and MLH1 polymorphisms overall. This study suggests that common polymorphisms in the mismatch repair gene, MSH3, may increase the risk of colorectal cancer, especially proximal colon cancer.

A Systematic Review of Vitamin D Receptor Gene Polymorphisms and Prostate Cancer Risk

PURPOSE Polymorphisms in the vitamin D receptor gene have been hypothesized to alter the risk of prostate cancer. However, studies investigating the associations between specific vitamin D receptor polymorphisms and prostate cancer risk have yielded inconsistent results. MATERIALS AND METHODS We performed a meta-analysis of 26 studies evaluating the association between vitamin D receptor TaqI, poly(A), BsmI, ApaI, and/or FokI polymorphisms, and prostate cancer risk. RESULTS The studies were heterogeneous in terms of study design, selection of cases and controls, and racial composition. Random effects models were used to estimate the pooled OR and 95% CI of each vitamin D receptor polymorphism under codominant, additive, dominant and recessive genetic models. Overall we did not find evidence to support an association between any of the vitamin D receptor polymorphisms and the risk of prostate cancer. For TaqI, which is the most studied vitamin D receptor polymorphism with 18 studies (total of 2,727 cases and 3,685 controls), the pooled OR was 1.00 (95% CI 0.85 to 1.18) for the Tt vs TT genotypes, 0.94 (95% CI 0.78 to 1.13) for the tt vs TT genotypes and 0.89 (95% CI 0.71 to 1.10) for the recessive model (tt vs Tt plus TT). ORs for the poly(A) microsatellite, BsmI, ApaI and FokI polymorphisms were similar. CONCLUSIONS The results of this meta-analysis suggest that the vitamin D receptor TaqI, poly(A), BsmI, ApaI and FokI polymorphisms are not related to prostate cancer risk.

Polymorphisms in estrogen-metabolizing and estrogen receptor genes and the risk of developing breast cancer among a cohort of women with benign breast disease

BackgroundA cohort study was conducted to examine the role of genetic polymorphisms in three estrogen metabolizing enzymes (COMT, CYP1A1, CYP1B1) and the two estrogen receptors (ESR1, ESR2) in the progression of benign breast disease (BBD) to breast cancer.MethodsAmong participants in an ongoing cohort study, 1438 Caucasian women had a breast biopsy for BBD and were successfully genotyped for at least one of the polymorphisms examined in this study. Genotypes were determined using DNA extracted from blood specimens collected in 1989. Incident cases of breast cancer occurring subsequent to BBD diagnosis up to 2003 were identified through cancer registries.ResultsAmong all participants, the ESR2 *5772G allele was associated with a significant decrease in the risk of breast cancer among women with BBD (Odds Ratio (OR) 0.38; 95% Confidence Interval (CI) 0.15, 0.96). Compared to the reference wild-type genotypes, marginally significant associations with the development of breast cancer were observed between carriers of the variant ESR1 – 104062T allele (OR 0.70, 95% CI 0.45, 1.09), the variant ESR2 *38A allele (OR 1.40; 95% CI 0.88, 2.25), and the variant CYP1B1 453Ser allele (OR 1.48, 95% CI 0.95, 2.32).ConclusionThe results indicate that specific polymorphisms in the CYP1B1, ESR1, and ESR2 genes may play a role in progression of BBD to breast cancer among Caucasian women. Although additional studies are needed to confirm or refute our findings, these results suggest that genetic markers may aid in the identification of women who are at risk for progression of BBD to cancer.

Vitamin E as a Cancer Chemopreventive Agent

Vitamin E, considered the most important lipid soluble antioxidant in humans, plays a role in cancer chemoprevention that is substantiated by evidence from in vitro studies since the mid-1980s on its antioxidant effects, and more recent studies of effects beyond an antioxidant mechanism, such as antiinflammation, inhibition of cancer-cell proliferation and growth, apoptosis, and angiogenesis. To date, most studies have focused predominantly on a specific form of vitamin E—e.g., α-tocopherol. In recent years, in vitro studies increasingly suggest that other forms of vitamin E also exert potent cancer-chemopreventive effects.

Abstract 51: Prospective study of LINE-1 hypomethylation in peripheral leukocyte DNA and colorectal cancer risk.

Abstract Background: The family of long interspersed nuclear elements (LINE-1) retrotransposons is reportedly hypomethylated in many cancers and reflects global methylation status in the genome. Global hypomethylation in peripheral blood leukocyte DNA has been increasingly studied and associated with increased risk of cancer, including colorectal cancer and adenoma in cross-sectional studies. Methods: To minimize disease- and/or treatment-related effects, we studied LINE-1 methylation levels in prospectively collected blood specimens from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial in relation to subsequent colorectal cancer risk. In a nested study of 398 cases and 519 controls who were cancer-free at blood collection, the extent of LINE-1 hypomethylation was measured by using the McrBC methylation specific restriction enzyme to cut methylated but not unmethylated DNA, followed by real-time PCR of the undigested/unmethylated LINE1 promoter sequences. We estimated the association between colorectal cancer risk and LINE-1 methylation categories by computing odds ratios (ORs) and 95% confidence intervals (CIs) through multivariable logistic regression modeling. Results: Overall, we observed no clear association between colorectal cancer and LINE-1 methylation categories (lowest tertile vs. highest: OR=1.06, 95% CI=0.74-1.52; P trend=0.72). However, we observed a nearly significant trend of decreasing LINE-1 methylation (hypomethylation) associated with increasing colorectal cancer risk, after excluding cases diagnosed within 1 year (lowest tertile vs. highest: OR=1.40, 95% CI=0.87-2.27; P trend=0.14) and 5 years (OR=2.65, 95% CI=0.96-7.36; P trend=0.07) following the blood collection. We noted no significant risk modification by folate intake or other suspected risk factors of colorectal cancer, such as smoking, obesity, and aspirin/ ibuprofen use in analyses including all subjects or excluding cases diagnosed within 5 years following blood collection (P interaction ranged between = 0.12 to 0.98). Conclusion: Findings from this prospective investigation offer further support for a potential dose-dependent relationship between LINE-1 hypomethylation in leukocyte DNA and subsequent colorectal cancer risk. Citation Format: Wen-Yi Huang, L. Joseph Su, Sonja I. Berndt, Lee E. Moore, Hormuzd A. Katki, Srinivasan Yegnasubramanian, Mark P. Purdue. Prospective study of LINE-1 hypomethylation in peripheral leukocyte DNA and colorectal cancer risk. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 51.