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Angstadt A.Y.,Penn State College of Medicine | Hartman T.J.,Emory University | Lesko S.M.,Northeast Regional Cancer Institute | Muscat J.E.,Penn State College of Medicine | And 3 more authors.
Genes Chromosomes and Cancer | Year: 2014

UDP-glucuronosyltransferases (UGTs) play an important role in the phase II metabolism of exogenous and endogenous compounds. As colorectal cancer (CRC) etiology is thought to involve the biotransformation of dietary factors, UGT polymorphisms may affect CRC risk by altering levels of exposure. Genotyping of over 1800 Caucasian subjects was completed to identify the role of genetic variation in nine UGT1A and five UGT2B genes on CRC risk. Unconditional logistic regression and haplotype analyses were conducted to identify associations with CRC risk and potential gene-environment interactions. UGT1A haplotype analysis found that the T-G haplotype in UGT1A10 exon 1 (block 2: rs17864678, rs10929251) decreased cancer risk for the colon [proximal (OR=0.28, 95% CI=0.11-0.69) and for the distal colon (OR=0.32, 95% CI=0.12-0.91)], and that the C-T-G haplotype in the 3′ region flanking the UGT1A shared exons (block 11: rs7578153, rs10203853, rs6728940) increased CRC risk in males (OR=2.56, 95% CI=1.10-5.95). A haplotype in UGT2B15 containing a functional variant (rs4148269, K523T) and an intronic SNP (rs6837575) was found to affect rectal cancer risk overall (OR=2.57, 95% CI=1.21-5.04) and in females (OR=3.08, 95% CI=1.08-8.74). An interaction was found between high NSAID use and the A-G-T haplotype (block 10: rs6717546, rs1500482, rs7586006) in the UGT1A shared exons that decreased CRC risk. This suggests that UGT genetic variation alters CRC risk differently by anatomical sub-site and gender and that polymorphisms in the UGT1A shared exons may have a regulatory effect on gene expression that allows for the protective effect of NSAIDs on CRC risk. © 2014 Wiley Periodicals, Inc.

Ashmore J.H.,Washington State University | Rogers C.J.,Pennsylvania State University | Kelleher S.L.,Pennsylvania State University | Lesko S.M.,Northeast Regional Cancer Institute | And 2 more authors.
Critical Reviews in Food Science and Nutrition | Year: 2016

Iron is an essential micronutrient that is involved in many redox processes and serves as an integral component in various physiological functions. However, excess iron can cause tissue damage through its pro-oxidative effects, potentiating the development of many diseases such as cancer through the generation of reactive oxidative species. The two major forms of iron in the diet are heme and nonheme iron, both of which are found in several different foods. In addition to natural food sources, intake of nonheme iron may also come from fortified foods or in supplement form. This review summarizes the results of human population studies that have examined the role of dietary iron (heme and nonheme), heme iron alone, and iron from supplements in colorectal carcinogenesis. © 2016, Copyright © Taylor and Francis Group, LLC.

Churilla T.M.,Commonwealth Medical College | Lesko S.L.,Commonwealth Medical College | Lesko S.L.,Northeast Regional Cancer Institute | Brereton H.D.,Commonwealth Medical College | And 5 more authors.
BMJ Open | Year: 2011

Objectives: Low serum vitamin D levels have been associated with risk for certain malignancies, but studies have not directly analysed levels between community oncology and primary care practices. The purpose of this study was to compare serum vitamin D levels in patients at a community oncology practice with non-cancer patients at a primary care practice. Design: Retrospective case-control study. 25-Hydroxyvitamin D levels were ordered for screening in both cancer and non-cancer patients. Levels were compared in univariate and multivariate analyses adjusted for age, body mass index and season of blood draw. Setting: A community-based radiation oncology centre and a community-based primary care practice: both located in Northeastern Pennsylvania, USA. Participants: 170 newly diagnosed cancer patients referred for initial consultation at the community oncology centre from 21 November 2008 to 18 May 2010, and 170 non-cancer patients of the primary care practice who underwent screening for hypovitaminosis D for the first time from 1 January 2009 to 31 December 2009. Primary and secondary outcome measures: The primary outcome measure was mean serum vitamin D level, and the secondary outcome measures were frequencies of patients with vitamin D levels <20 ng/ml and levels <30 ng/ml. Results: The oncology patients had a significantly lower mean serum vitamin D level (24.9 ng/ml) relative to a cohort of non-cancer primary care patients (30.6 ng/ml, p<0.001) from the same geographical region. The relationship retained significance after adjustment for age, body mass index and season of blood draw in multivariate analysis (p=0.001). Levels <20 and <30 ng/ml were more frequent in the oncology patients (OR (95% CI)=2.59 (1.44 to 4.67) and 2.04 (1.20 to 3.46), respectively) in multivariate analysis. Conclusions: Cancer patients were found to have low vitamin D levels relative to a similar cohort of noncancer primary care patients from the same geographical region.

Angstadt A.Y.,Penn State College of Medicine | Berg A.,Penn State College of Medicine | Zhu J.,Penn State College of Medicine | Miller P.,U.S. National Cancer Institute | And 5 more authors.
Cancer | Year: 2013

BACKGROUND Genetic polymorphisms in combination with the Western-style diet, physical inactivity, smoking, excessive alcohol consumption, and obesity have been hypothesized to affect colorectal cancer (CRC) risk. Metabolizers of environmental carcinogenic and endogenous compounds affecting CRC risk include the phase II detoxification UDP-glucuronosyltransferase (UGT) enzymes UGT2B17 and UGT2B28, which are 2 of the most commonly deleted genes in the genome. METHODS To study the effect of UGT2B17 and UGT2B28 copy number variation (CNV) on CRC risk, 665 Caucasian CRC cases and 621 Caucasian controls were genotyped who had completed extensive demographics and lifestyle questionnaires. RESULTS A significant association between the UGT2B17 deletion genotype (0/0) and decreased CRC risk was found when the entire population was analyzed (P =.044). Stratification by sex yielded a decreased risk (P =.020) in men with the UGT2B17 deletion (0/0), but no association was observed in women (P =.724). A significant association between UGT2B17 (0/0) and decreased risk for rectal (P =.0065) but not colon cancer was found. No significant association was found between UGT2B28 CNV and CRC risk. CONCLUSIONS The UGT2B17 deletion genotype (0/0) was associated with a decreased CRC risk in a Caucasian population. After sex stratification, the association was observed in men but not in women, which is consistent with previous findings that men have higher UGT2B17 expression and activity than women. Because UGT2B17 metabolizes certain nonsteroidal anti-inflammatory drugs and flavonoids with antioxidative properties, individuals with a gene deletion may have higher levels of these protective dietary components. © 2013 American Cancer Society.

Ashmore J.H.,Pennsylvania State University | Lesko S.M.,Northeast Regional Cancer Institute | Muscat J.E.,Pennsylvania State University | Gallagher C.J.,Pennsylvania State University | And 4 more authors.
Genes Chromosomes and Cancer | Year: 2013

Previous research has shown that greater intakes of dietary folate are associated with reduced risk for colorectal cancer (CRC) and that single nucleotide polymorphisms (SNPs) in genes involved in folate-mediated one-carbon metabolism (FOCM) also may be involved in altering CRC risk. The objective of this study was to evaluate the role of folate intake (and intakes of related dietary components such as methionine), 35 SNPs in three FOCM pathway genes (MTHFD1, MTHFR, and TYMS), and their interactions on CRC risk in a population-based case-control study in Pennsylvania (686 cases, 740 controls). Diet and supplement use was assessed for the year before diagnosis or interview for cases and controls, respectively, with a modified Diet History Questionnaire from the National Cancer Institute. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using unconditional logistic regression. Using a dominant model for the variant allele, several SNPs were significantly associated with CRC including MTHFD1 rs8003379 (OR=1.65; 95% CI=1.00-2.73) and rs17824591 (OR=1.98; 95% CI=1.14-3.41) and the TYMS rs2853533 SNP (OR=1.38; 95% CI=1.05-1.80). Using a nondominant model, the AA genotype for MTHFR rs1476413 exhibited a marginally significant (OR=1.56; 95% CI=1.00-2.44) association with CRC. Two TYMS SNPs (rs16948305 and rs495139) exhibited significant (P=0.024 and P=0.040, respectively) gene-diet interactions with folate intake. One MTHFD1 (P=0.019) and one MTHFR (P=0.042) SNP exhibited gene-diet interactions with methionine intake. These findings suggest that allelic variants in genes involved in FOCM interact with dietary factors including folate and methionine to modify risk for CRC. © 2013 Wiley Periodicals, Inc.

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