Luke D. Ratnasinghe

Associations between Catalase Phenotype and Genotype: Modification by Epidemiologic Factors

Catalase is an endogenous antioxidant enzyme that neutralizes hydrogen peroxide and is induced by oxidative challenge. A −262C → T polymorphism in the promoter region of the gene (CAT) is associated with risk of several conditions related to oxidative stress. We sought to determine the functional effects of the CAT polymorphism on enzyme activity in erythrocytes and the potential modifying effects of demographic and lifestyle factors on genotype/phenotype relationships, using specimens and data from controls from breast and prostate cancer studies in Arkansas (n = 420). There was a dose-response reduction in catalase activity by genotype, with geometric means of 115.4 units/mg hemoglobin for those with CC genotypes, 82.1 units/mg for those with CT genotypes, and 73.5 units/mg for those with TT genotypes. Associations were only observed among Caucasians (P < 0.0001), with no effects among African Americans (P = 0.91), and were stronger among women than men, although numbers in stratified analyses were small. Differences in catalase activity by genotype were most pronounced among those in the highest tertiles of consumption of fruits and vegetables (−35%, P = 0.003), with weaker relationships among those who were lower consumers (−21.8%, P = 0.16). Among those with CC genotypes, there was no change in activity by consumption, but there were notable decreases in activity by tertiles of consumption for those with at least one T allele. These data indicate that the CAT −262C → T polymorphism predicts a portion of catalase phenotype, which may be limited to Caucasians. Associations between genotype and phenotype were modified by dietary factors, illustrating the biochemical complexity of studies of genetic polymorphisms and disease risk. (Cancer Epidemiol Biomarkers Prev 2006;15(6):1217-22)

CYP3A43 Pro340Ala Polymorphism and Prostate Cancer Risk in African Americans and Caucasians

The human cytochrome P450 3A subfamily of enzymes is involved in the metabolism of steroid hormones, carcinogens, and many drugs. A cytosine-to-guanine polymorphism in CYP3A43 results in a proline-to-alanine substitution at codon 340. Although the functional significance of this polymorphism is unknown, we postulate that the substitution of proline, an α-imino acid, with alanine, an amino acid, could be of biochemical significance. In a case-control study with 490 incident prostate cancer cases (124 African Americans and 358 Caucasians) and 494 controls (167 African Americans and 319 Caucasians), we examined the association between CYP3A43 Pro340Ala polymorphism and prostate cancer risk. When all subjects were considered, there was a 3-fold increase in risk of prostate cancer among individuals with the CYP3A43-Ala/Ala genotype (odds ratio, 3.0; 95% confidence interval, 1.2-7.2) compared with those with the CYP3A43-Pro/Pro genotype after adjusting for age, race, and smoking. The prevalence of the polymorphism was significantly higher in African Americans than Caucasians (45% versus 13%). In African Americans, there was a 2.6-fold increase in prostate cancer risk among individuals with the CYP3A43-Ala/Ala genotype (odds ratio, 2.6; 95% confidence interval, 1.0-7.0) compared with those with the CYP3A43-Pro/Pro genotype. Among Caucasians, the small number of homozygotes precluded computing risk estimates; there were only three individuals with the CYP3A43-Ala/Ala genotype. Our results suggest that the CYP3A43-Pro340Ala polymorphism contributes to prostate cancer risk.

Physical Activity and Reduced Breast Cancer Risk: A Multinational Study

We evaluated the association between physical activity and breast cancer risk among 1,463 breast cancer cases and 4,862 controls in a multinational study. All subjects were asked how many times and for how long they exercised or engaged in strenuous physical labor per week. We used multivariate logistic regression to assess the association between physical activity and breast cancer risk. For all subjects combined, the multivariate-adjusted odds ratio was 50% lower (95% confidence interval = 0.4–0.6) for women who reported physical activity once per week or more after adjusting for age, race, body mass index, and pack years of smoking compared to those who reported physical activity less than once per week. Women who reported physical activity 3 times/wk or more did not gain any additional reduced risk. The amount of time spent in physical activity per session was also significantly associated with reduced risk. All ethnic groups examined including Caucasian-Americans, African-Americans, Hispanic-Americans, Tunisian-Arabs, and Polish-Caucasians were at 35% or greater reduced risk for breast cancer if they were physically active for more than 30 minutes per week. Our study shows that physical activity may reduce breast cancer risk regardless of race, weight category, or family history of breast cancer.

A prospective study of polymorphisms of DNA repair genes XRCC1, XPD23 and APE/ref-1 and risk of stroke in Linxian, China

Background: Stroke is the leading cause of death in Linxian, China. Although there is evidence of DNA damage in experimental stroke, no data exist on DNA repair and stroke in human populations. Aim: To assess the risk of stroke conferred by polymorphisms in the DNA repair genes, XRCC1, XPD23 and APE/ref-1 in a cohort of individuals originally assembled as subjects in two cancer prevention trials in Linxian, China. Methods: The subjects for this prospective study were sampled from a cohort of 4005 eligible subjects who were alive and cancer free in 1991 and had blood samples available for DNA extraction. Using real-time Taqman analyses, all incident cases of stroke (n = 118) that developed from May 1996, and an age- and a sex-stratified random sample (n = 454) drawn from all eligible subjects were genotyped. Cox proportional hazards models were used to estimate relative risks (RRs) and 95% CIs. Results: No association was observed between polymorphisms in APE/ref-1 codon 148 and XRCC1*6 codon 194, and stroke. Polymorphisms in XRCC1*10 codon 399 were associated with a significantly reduced risk of stroke (RR 0.59, 95% CI 0.36 to 0.96, p = 0.033), whereas XPD23 codon 312 was associated with a significantly increased risk of stroke (RR 2.18, 95% CI 1.14 to 4.17, p = 0.010). Conclusions: Polymorphisms in DNA repair genes may be important in the aetiology of stroke. These data should stimulate research on DNA damage and repair in stroke.

Abstract 3426: Recurrent breast cancer risk and physical activity

Introduction: Physical activity reduces the risk of breast cancer. However, the potential role of physical activity in recurrence of breast cancer is not well established. The aim of our study is to examine the association between physical activity and risk of recurrent breast cancer. Methods: Data was obtained from the Global Epidemiological Study (GES). The GES is an IRB approved multinational biorepository and database to assess cancer and other disease risk factors and biomarkers. In-person interviews of all subjects provided demographics, family-history and other disease related information including age, BMI, diet and physical activity. For statistical analyses, t-tests were used for continuous variables and chi-square tests for categorical variables. The association between recurrent breast cancer and physical activity was assessed using logistic regression in univariate and multivariate analyses. Results: From a total of 2435 breast cancer subjects 215 had recurrent breast cancer. The average age of subjects without recurrence was 55.62 years and those with breast cancer recurrence was 58.35 years. In univariate analysis, subjects in the highest tertile of physical activity were 39% less likely to have recurrent breast cancer compared to those who reported no physical activity [Odds Ratio: 0.61, 95% Confidence Interval: 0.40-0.93]. In multivariate analysis, subjects in the highest tertile of physical activity were 45% less likely to have recurrent breast cancer compared to those who reported no physical activity [Odds Ratio: 0.55, 95% Confidence Interval: 0.34-0.89] after adjusting for age, BMI and cancer-stage. A statistically significant dose-response for physical-activity and reduced risk of recurrent breast cancer was observed with a P-value for trend of 0.05. Conclusion: Our study suggests that physical activity reduces the risk of recurrence of breast cancer. Further studies with larger sample size are needed to confirm our findings. Citation Format: Teresa A. Lehman, Ramakrishna V. Modali, Luke D. Ratnasinghe. Recurrent breast cancer risk and physical activity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3426.

Abstract 870: Physical activity, diet and ovarian cancer risk

Physical activity and diet are modifiable risk factors for most cancers. Previous studies of the association between physical activity, diet and ovarian cancer risk have yielded mixed results. We evaluated the association between physical activity, diet and ovarian cancer risk among 578 ovarian cancer cases and 7188 non-cancer controls in the Global Epidemiology Study (GES). The GES is linked to the Global Repository that houses biomaterial. For ovarian cancer, newly diagnosed subjects provided informed consent and were asked about physical activity and diet during in-person interviews. The multivariate-adjusted odds ratio (OR) was 0.6 (95% confidence interval (95% CI): 0.5-0.8) for women who reported physical activity greater than 160 minutes per week after adjusting for age, race, BMI and pack-years of smoking compared to women who reported less than 30 minutes of physical activity. Women who were in the highest tertile of vegetables consumers were at 20% reduced risk for ovarian cancer compared to the lowest tertile [OR:0.8, 95% CI: 0.6-0.9]. Individuals who were in the highest tertile of dairy consumers were at 40% reduced risk for ovarian cancer compared to the lowest tertile [OR: 0.6, 95% CI: 0.5-0.8]. For meat consumption, individuals who were in the highest tertile were at 60% increased risk for ovarian cancer compared to the lowest tertile [OR: 1.6, 95% CI: 1.3-2.0]. Results from our study suggest that physical activity and diet are modifiable risk factors for ovarian cancer. Citation Format: Teresa A. Lehman, Ramakrishna V. Modali, Luke Ratnasinghe. Physical activity, diet and ovarian cancer risk. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 870. doi:10.1158/1538-7445.AM2015-870

Abstract 2765: Evaluation of family history of cancer in first-degree relatives and increased cancer risk: A multinational study

Family history of cancer is a known risk factor for several of the more prevalent cancer types. However, familial aggregation of cancer may not follow the genetic linkage pattern seen with most inherited cancer syndromes. In these instances, clustering may be due to unknown hereditary genetic mutations or to an aggregation of environmental risk factors and such clustering may still confer a significant risk. We assessed the association between family history of cancer in first-degree relatives and cancer risk among 9,122 cancer cases and 76,537 controls in a multinational study. Analyses also included evaluation of breast, colon and prostate cancer risk associated with family history of these respective cancer types. Cases were verified by physician diagnosis and all study participants were administered an in-depth survey to ascertain various demographic and lifestyle factors as well as a complete family history of cancer among first-degree relatives. Multivariable logistic regression was used to assess the association between family history of cancer and cancer risk. Among all subjects, the odds ratio (OR) for individuals with a family history of cancer was 1.79 [95% confidence interval = 1.7-1.9] after adjusting for age, gender, BMI, smoking pack years and ethnicity. Additionally, a greater cancer risk was associated with increasing number of first-degree relatives with a history of cancer. Ethnic groups studied included Caucasian-Americans, African-Americans, Hispanic/Latinas and Caucasian-Polish. All ethnic groups showed a significant association between family history of cancer and cancer risk with the highest adjusted OR of 2.65 [95% confidence interval = 2.0-3.6] among the Hispanic/Latina group. Further analyses indicated that family history of colon, breast and prostate cancer was significantly associated with an increased risk of these respective cancer types across studied ethnic groups. In particular, the adjusted ORs for breast, colon and prostate cancer risk in the Caucasian-Polish group were at least double the overall adjusted ORs for each cancer type. Our study shows that family history of cancer is a significant predictor of cancer risk especially among certain ethnic groups. In addition, family history of cancer can represent both a genetic predisposition and/or environmental exposure and risk associated with familial clustering of cancer. Citation Format: Laxmi Modali, Teresa A. Lehman, Ramakrishna Modali, Luke D. Ratnasinghe. Evaluation of family history of cancer in first-degree relatives and increased cancer risk: A multinational study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2765. doi:10.1158/1538-7445.AM2015-2765