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. Author manuscript; available in PMC: 2014 Jul 1.
Published in final edited form as: Cancer. 2013 Apr 10;119(13):2477–2485. doi: 10.1002/cncr.28009

The effect of copy number variation (CNV) in the phase II detoxification genes, UGT2B17 and UGT2B28, on colorectal cancer risk

Andrea Y Angstadt a, Arthur Berg a, Junjia Zhu a, Paige Miller b, Terryl J Hartman c, Samuel M Lesko d, Joshua E Muscat a, Philip Lazarus a,e, Carla J Gallagher a,e
PMCID: PMC3686841  NIHMSID: NIHMS442498  PMID: 23575887

Abstract

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 phase II detoxification enzymes, UGT2B17 and UGT2B28, which are two 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 we genotyped 665 Caucasian CRC cases and 621 Caucasian controls that 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 analyzing the entire population (p = 0.044). Stratification by sex yielded a decreased risk (p = 0.020) in men with the UGT2B17 (0/0), but no association was observed in women (p = 0.724). A significant association between UGT2B17 (0/0) and decreased risk for rectal (p = 0.0065) 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 not women, which is consistent with previous findings that men have higher UGT2B17 expression and activity than women. As UGT2B17 metabolizes certain NSAIDs and flavonoids with antioxidative properties, individuals with a gene deletion may have higher levels of these protective dietary components.

Introduction

Worldwide, colorectal cancer (CRC) is the third most commonly diagnosed cancer in males and the second in females in developed countries 1. While physical inactivity, obesity, red and processed meat consumption, smoking, and excessive alcohol consumption are factors that have been shown to increase the risk for CRC, genetic polymorphisms may also play a role 1-3. The UDP-glucuronosyltransferase (UGT) family of enzymes play an important role in the phase II detoxification of many exogenous and endogenous compounds including drugs, dietary compounds, environmental carcinogens, and hormones 4, 5. UGT2B17 and UGT2B28 are the only UGT genes that exhibit common whole gene deletion polymorphisms 6, with the prevalence of these deletions in Caucasians at ~30% and ~13%, respectively 6. In addition, only 43% of Caucasians have two copies of both genes and 57% contain at least one deletion 7. Copy Number Variation (CNV) in UGT2B17 is associated with decreased urine testosterone levels 8, increased male fat mass 9, and increased lung cancer risk 4. Levels of UGT2B17 expression was shown to be directly proportional to UGT2B17 CNV in both lymphoblastoid cell lines 6 and in human liver samples 10, suggesting that the UGT2B17-associated phenotype effect is likely mediated by variation in UGT2B17 expression level 6. Interestingly, among individuals who have two copies of the gene, men have been shown to have higher levels of hepatic expression and activity of UGT2B17 than women 10.

The UGT2B28 gene lies ~500 kb downstream from UGT2B17 on chromosome 4q13 but is much less studied. Similar to UGT2B17, UGT2B28 is involved in androgen metabolism, but it is also responsible for the metabolism of estrogen and some bile acids 11. Altered expression of the UGT2B28 gene was associated with progression of esophageal dysplasia in a Chinese chemoprevention trial 12, indicating that UGT2B28 may be important in carcinogenesis. In Japanese CRC patients, copy number aberration of UGT2B28 resulted in reduced gene expression in neoplastic cells, suggesting that this CNV causes altered expression in CRC tumors 13. The combined effect of UGT2B17 and UGT2B28 CNV only recently has been studied. While Setlur et al. 14 did not find an association with the UGT2B17 and UGT2B28 gene deletions and prostate cancer risk 14, Nadeau et al. concluded that both Caucasian and Asian prostate cancer patients with the UGT2B17 and UGT2B28 gene deletions have an increased risk of biochemical recurrence after surgical treatment 15.

In the present study, the UGT2B17 and UGT2B28 CNVs were evaluated in 665 Caucasian CRC cases and 621 Caucasian controls from central and northeast Pennsylvania, deemed at high-risk since colorectal cancer incidence rates were higher in this region compared to the U.S. as a whole 16. An evaluation of dietary data from a similar central and northeast Pennsylvania study population 17 revealed that red and processed meat intake—a risk factor for colorectal cancer—was higher in this population compared to a nationally representative sample 18. Using extensive demographic and dietary data collected from all recruited subjects, a possible gene-environment relationship was demonstrated with the UGT2B17 CNV and CRC risk.

Materials and Methods

Subjects

Copy number variance (CNV) analysis was conducted on individuals from a population-based case-control study designed to investigate CRC risk factors conducted from 2006-2011 in a contiguous 19-county area in central and northeast Pennsylvania. Random digit dialing was used to identify controls, and they were screened to ensure they had no previous history of CRC. All cases were recruited within 24 months of their CRC diagnosis. Of those contacted, 57% of eligible cases and 51% of eligible controls participated in the study. The tumors were classified by anatomical site and the histological code of the International Classification of Diseases for Oncology 19 and coded as follows; proximal colon (C180-C184), distal colon (C185-C187), and rectum (C199, C209).

Written consent was obtained from cases and controls, a personal interview was scheduled at the home of the participant, and a self-administered food frequency questionnaire was mailed with instructions to complete before the interview 20. Questions on preferred meat cooking methods, doneness levels for individual meat subtypes, and intake of processed meat items were used to generate estimated exposure to meat-derived mutagens with the NCI’s Computerized Heterocyclic Amines Resource for Research in Epidemiology of Disease (CHARRED) software application 21.

Copy Number Variance (CNV) detection

Oral buccal cell swabs, saliva, and blood samples were collected for genomic DNA isolation. DNA was isolated from oral buccal cell swabs using standard phenol: chloroform isolation, saliva using an Oragene DNA Kit (DNA Genotek Inc, Ontario Canada), and blood using QIAamp DNA Blood mini kit (Qiagen Valencia, CA). Picogreen analysis was used to quantify the amount of double stranded DNA for each genomic sample (Life Technologies, Grand Island, NY).

TaqMan Copy Number Assays were used to detect UGT2B28 and UGT2B17 CNV. The UGT2B17 assay, ID# hs03185327_cn, was predesigned while the UGT2B28 assay, ID#UGT2B28_CCGJPDF, was custom designed. Assay locations and gene deletion sites are shown in Figure 1. The quantitative assays were performed using the 7900-HT real-time PCR machine in quadruplicate in 384 well plates with a 10μl reaction volume containing 10ng DNA, 5μl TaqMan Universal PCR Master Mix (Applied Biosystems Carlsbad, California), 0.5μl of the CNV assay, and 0.5μl of the reference RNase P assay (part #4403328). The reaction was completed using the following cycling conditions: 95°C for 15sec and 60°C for 1 min for 40 cycles. Control DNA samples purchased from the Coriell Institute Cell Repositories with a known copy number for each CNV were selected using data from McCarroll et al. 2006 6. Six control samples for each CNV (2 for each genotype) were run on every 384 well assay plate. Data was analyzed using the SDS 2.2 software (Applied Biosystems Carlsbad, California) to quantify the amplification cycle and then the data was imported into the Copy Caller v1.0 software (Applied Biosystems Carlsbad, California).

Figure 1.

Figure 1

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Schematic representation of the UGT2B17 and UGT2B28 genes. Arrows represent transcription direction of each gene and red boxes above exon I/intron I of the respective genes indicate location of TaqMan assays. Blue tick marks demonstrate the extent of the gene deletion(s) as it includes the entire gene for both UGT2B17 and UGT2B28.

Statistical Analysis

Unconditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between CNV and CRC risk. An additive model was used for logistic regression analysis: wildtype CNV (+/+) > (0/+) > (0/0). Dietary characteristics and Hardy Weinberg equilibrium between cases and controls were compared using the χ2-test for categorical variables and non-parametric Wilcoxon rank sum test for continuous variables. Likelihood ratio tests were used to evaluate the fit of each model. In order to control for implausible dietary data, individuals who reported < 500 or >5000 kcal/day (n = 42) were excluded along with individuals ≤ 35 years of age (n = 10). All logistic regression models were controlled for age (years), total energy intake (kcal/day), and sex. The association between known or suspected CRC risk factors; alcohol (grams/day), BMI (kg/m2), smoking status (never, current, or past smoker), pack-years smoking, family history of CRC in a first degree relative (yes, no), regular nonsteroidal anti-inflammatory drug (NSAID) use (defined as high [> 3 times/week] or low [≤ 3 times/week] for at least 1 year prior to the interview for controls or diagnosis for cases), and physical activity (defined as low [<1 hour] and high [≥ 1 hour/week] of vigorous activity), were tested individually for potential confounding. The numbers of individuals that lacked information for select covariates are as follows; BMI (n = 65), pack-years (n = 20/684 individuals that smoked), family history of CRC, NSAID use, and physical activity (n = 256), total energy intake and alcohol intake (n = 238), and information related to carcinogens produced from cooking meat (n = 239). According to a 10% change-in-estimate criterion 22, meaning that the covariates changed the UGT2B17/UGT2B28 genotype OR estimate by more than 10%, BMI, family history, NSAID use, and physical activity were included in the final multivariate model. Dietary carcinogen levels (PhIP, MeIQx, DiMeIQx, and BaP) were adjusted for total energy intake (kcal/day) by the nutrient density method (grams per 1000 kcal) 23 and separated into quintiles of intake based on the distribution among the controls. Polytomous regression was used to evaluate the associations between CNV and CRC risk by anatomical subsite 24. Reported p-values are 2-sided and p < 0.05 was considered significant for all tests.

All statistical analyses were performed with SAS version 9.3 (SAS Institute, Inc., Cary, NC) and JMP version 8.0 (SAS Institute, Inc., Cary, NC)

Results

Case/Control Demographic and Dietary Differences

Recruited cases and controls were sex and age matched, but because select samples did not have DNA yield necessary for genotyping, these variables were assessed in all analyses. A total of 665 Caucasian CRC cases (368 males, 297 females) and 621 Caucasian controls (359males, 262 females) were analyzed for association of CNVs with CRC risk after sample exclusion for implausible dietary data. Table 1 summarizes the basic demographic characteristics of the cases and controls included in this study, stratified by sex. Cases were older than controls (females, p = 2.0e-6, males, p = 0.03). BMI was significantly higher in female cases versus controls (p = 0.04). Smoking status or pack-years did not differ between cases or controls. The number of individuals with a first degree family history of CRC among male cases was greater than among controls (p = 4e-4). In men a higher percentage of NSAID use was significant (p = 0.04). The opposite was true for physical activity in which only women (p = 0.002) demonstrated a significant difference. Alcohol intake was significantly different between female cases and controls (p = 2e-8). PhIP, DiMeIQx, and MeIQx intakes did not differ. While no difference in BaP intake was found for males, female controls had a higher average intake than cases (p = 0.03).

Table 1.

Population demographics and dietary characteristics.
Female Male
Case
(n=297)		 Control
(n=262)		 P-
value		 Case
(n=368)		 Control
(n=359)		 P-
value
Age* 67.8 ± 12.3 63.0 ± 11.2 <.0001 66.5 ± 11.1 64.9 ± 10.2 0.0297
BMI* 29.8 ± 7.0 28.6 ± 6.4 0.0373 29.7 ± 5.8 29.5 ± 5.4 0.7724
Smoking Status 0.1454 0.1503
 Never Smokers 168 (56.6%) 144 (55%) 134 (36.4%) 156 (43.5%)
 Formers Smokers 108 (36.4%) 87 (33.2 %) 191 (51.9%) 167 (46.5%)
 Current Smokers 21 (7.1%) 31 (11.8%) 43 (11.7%) 36 (10%)
Pack-years* 24.4 ± 22.6 20.3 ± 21.3 0.1208 32.0 ± 28.4 32.1 ± 28.3 0.9388
History of CRC in 1st Degree Family 47 (19.9%) 31 (14.4%) 0.1789 58 (19.5%) 25 (9%) 0.0004
NSAID use 0.4025 0.038
 High > 3x/week 106 (43.1%) 101 (47.0%) 159 (53.5%) 169 (62.0%)
 Low < 3x/week 140 (56.9%) 114 (53.0%) 138 (46.5%) 103 (37.9%)
Physical Activity 0.002 0.1632
 High > 1hr/day vigorous
exercise		 61 (24.8%) 82 (38.1%) 98 (33.0%) 105 (38.6%)
 Low < 1hr/day vigorous
exercise		 185 (75.2%) 133 (61.9%) 199 (67.0%) 167 (61.4%)
Total energy (kcal/day)* 1622.6 ± 788.8 1614.5 ± 708.7 0.5591 2075.8 ± 874.1 1931.6 ± 762.4 0.0943
Alcohol (grams)* 3.1 ± 7.4 6.3 ± 21.7 <.0001 12.5 ± 33.7 13.6 ± 34.4 0.4193
Carcinogens produced from cooking meat
ng/kcal/day
 PhiP* 40.1 ± 61 45.2 ± 72.8 0.2366 55 ± 85.8 46.8 ± 62.6 0.2393
 MeIQx* 16.7 ± 17.9 14.3 ± 16.5 0.1017 20.9 ± 25.0 20.0 ± 21.3 0.9693
 DiMeIQx* 1.5 ± 1.69 1.3 ± 1.73 0.1063 1.76 ± 2.24 1.58 ± 1.95 0.4425
 BAP* 7.8 ± 14.2 10.3 ± 16.3 0.0269 13.3± 22.2 13.7± 21.9 0.6978
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*

Mean ± SD

UGT2B17 and UGT2B28 CNV associations with CRC risk

The UGT2B17 and UGT2B28 CNV frequencies are shown in Table 2 for all samples. The success rate of genotyping for UGT2B17 and UGT2B28 was 92% and 91%, respectively. The UGT2B17 polymorphism was in Hardy-Weinberg Equilibrium for both cases and controls, whereas the UGT2B28 polymorphism was not in equilibrium in controls (p = 0.027) and in equilibrium in cases. The frequencies of the null (0/0) variants in the control population for UGT2B17 and UGT2B28 were 15% and 4%, respectively. Example CNV calls for select cases and controls in our sample set are shown in Figure 2. The Coriell controls for both genes were called correctly using the calibrator sample [2 gene copies (+/+), NA10855 for UGT2B17 and NA10835 for UGT2B28, validating our sample calls (Figure 2)].

Table 2.

Genotype frequencies of copy number variants in UGT2B17 and UGT2B28: (+/+) is the wildtype and represents 2 copies of the gene, (0/+) represents 1 copy of the gene, and (0/0) represents 0 copies of the gene.

UGT2B17 UGT2B28
Controls
(%)		 All CRC
(%)		 Proximal
Colon (%)		 Distal
Colon
(%)		 Rectum
(%)		 Controls
(%)		 All CRC
(%)		 Proximal
Colon (%)		 Distal
Colon
(%)		 Rectum
(%)
Overall
(0/0) 86 (15) 79 (13) 32 (13) 25 (15) 21 (12) 21 (4) 17 (3) 6 (2) 5 (3) 5 (3)
(+/0) 286 (50) 278 (46) 111 (47) 76 (46) 78(43) 136 (24) 148 (24) 61 (25) 40 (25) 41 (23)
(+/+) 201 (35) 249 (41) 94 (40) 65 (39) 81 (45) 408 (72) 442 (73) 178 (73) 118 (72) 130 (74)
Male
(0/0) 52 (16) 45 (14) 17 (14) 14 (14) 13 (12) 13 (4) 12 (4) 3 (3) 4 (4) 5 (5)
(+/0) 173 (53) 148 (44) 52 (44) 46 (47) 42 (40) 79 (24) 82 (25) 28 (23) 24 (24) 25 (25)
(+/+) 102 (31) 142 (42) 49 (42) 37 (48) 51 (48) 231 (72) 240 (72) 88 (74) 72 (72) 71 (70)
Female
(0/0) 34 (14) 34 (13) 15 (13) 11 (16) 8 (11) 8 (3) 5 (2) 3 (2) 1 (2) 0 (0)
(+/0) 113 (46) 130 (48) 59 (49) 30 (43) 36 (49) 57 (24) 66 (24) 33 (26) 16 (25) 16 (21)
(+/+) 99 (40) 107 (39) 45 (38) 28 (41) 30 (40) 177 (73) 202 (74) 90 (72) 46 (75) 59 (79)
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Figure 2.

Figure 2

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Graphical representation of the calculated copy number produced by CopyCaller v1.0 for select cases and controls in our CRC cohort. Samples IDs in red are the Coriell controls used as calibrators and the red line on each bar graph indicates the standard deviation between the four replicates.

Unconditional logistic regression was used to assess the separate effect of UGT2B17 and UGT2B28 CNV on CRC risk, adjusting for age, sex, BMI, first degree family history, NSAID use, and physical activity. The combined effect of both gene CNVs was evaluated but the sample size was too small to detect any significant associations with CRC risk. A 10% change-in-estimate in genotype was not found after addition of any of the carcinogens in the statistical regression models. However, similar to previous reports 25, high PhIP consumption was associated with CRC risk (1.78 OR, 1.14-2.77 95% CI, p = 0.012) and with rectal cancer risk (1.95 OR, 1.26-3.02 95% CI, p = 0.0029) in males. PhIP consumption in males was also associated with distal colon (1.92 OR, 1.06-3.49 95% CI, p = 0.032) and rectal cancer risk (2.33 OR, 95% CI 1.30-4.18, p = 0.0047). High consumption of DiMeIQx increased the risk of distal colon (1.57 OR, 95% CI 1.02-2.44, p = 0.043) and rectal cancer (1.58 OR, 1.03-2.43, p = 0.038) overall as well as rectal cancer risk in females (2.18 OR, 1.12-4.22 95% CI, p = 0.021). Intake of high levels of BaP consumption increased overall risk for rectal cancer (1.66 OR, 1.07-2.58 95% CI, p = 0.025), an association observed primarily in males (2.10 OR, 1.19-3.70 95% CI, p = 0.017).

The odds ratio (OR) and 95% confidence intervals are shown by forest plots in Figure 3. A significant association (Figure 3) between the UGT2B17 deletion (0/0) and decreased CRC risk was found when analyzing the entire population (0.82 OR, 0.67-0.99 95% CI, p = 0.044), adjusting for age, sex, BMI, kcal/day, past regular NSAID use, family history of CRC, and physical activity. This association was observed in men with UGT2B17 (0/0) (0.72 OR, 0.55-0.95 95% CI, p = 0.020), but not in women (0.95 OR, 0.70-1.27 95% CI, p = 0.724; Figure 3). Polytomous regression analysis by anatomical sub-site [proximal colon (194 cases), distal colon (145 cases), and rectum (151 cases)] showed that the significant association between UGT2B17 (0/0) and decreased cancer risk was only found for rectal cancer (0.67 OR, 0.50-0.89 95% CI, p = 0.0065) and not for proximal (0.90 OR, 0.69-1.17 95% CI, p = 0.44) or distal colon cancer (0.89 OR, 0.67-1.182 95% CI, p = 0.42; Figure 3). After sex stratification, only male rectal cancer cases with UGT2B17 (0/0) exhibited decreased risk for CRC (0.57 OR, 0.38-0.85 95% CI, p = 0.0056). No differences were observed between UGT2B17 CNV and female CRC cases by anatomical sub-site. No significant association was found between the UGT2B28 polymorphism and CRC risk before or after stratification by sex or anatomical sub-site (Figure 3).

Figure 3.

Figure 3

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Effect of gene copy number variance on colorectal cancer risk. Unconditional logistic regression analysis was used to calculate odds ratios and 95% confidence intervals and polytomous regression analysis was used to evaluate the associations between CNV and CRC risk by anatomical subsite. *significant result.

Discussion

In this study, an association between the UGT2B17 (0/0) genotype and decreased risk for CRC was found using a Caucasian case-control population that consumes a diet high in red and processed meat 17. No association between the UGT2B28 CNV and CRC risk were observed when analyzed alone or in combination with the UGT2B17 CNV. This lack of significance may be a result of a limited sample size when the UGT2B28/UGT2B17 polymorphisms were combined for analysis. A novel aspect of this study was the fact that the analysis was adjusted with a variety of dietary and demographic CRC risk factors using data generated by an extensive dietary questionnaire given to the study cohort. As the risk for sporadic CRC is thought to be largely due to lifestyle choices, particularly dietary factors 26, it was hypothesized that consumption of certain dietary components and the UGT CNVs were jointly affecting CRC risk, because these genes are known to glucuronidate a variety of endogenous and exogenous agents 11, 27-30. The UGT2B17 and UGT2B28 polymorphisms have not been previously studied for associations with CRC risk. The copy number loss and corresponding gene expression loss of UGT2B28 has been previously identified as aberrant in CRC tumor cells 13. The present data suggests that the UGT2B28 genotype is not involved in altering CRC risk, but loss of the UGT2B28 gene and expression in neoplastic colon cells may be associated with tumor progression as previously defined 13.

The UGT2B17 deletion polymorphism (0/0) has been previously associated with an increased risk for lung adenocarcinoma 10 and, in some studies, prostate cancer 31, 32. In contrast to these previous studies, a protective affect for UGT2B17 (0/0) was found in the present study with CRC risk. Although the overall protective affect is weakened if a two gene Bonferroni correction is applied (p <0.025), the association between UGT2B17 and decreased CRC risk remains in males (p = 0.020) and in rectal cancer (p = 0.0065) upon multiple testing correction. Due to the fact that UGT2B17 (0/+) individuals did not have a significant decrease in CRC risk (data not shown), the overall protective affect for UGT2B17 (0/0) needs additional independent validations in order to rule out any false positive possibility. The overall frequency of the UGT2B17 deletion in the Caucasian control (0.4) and case (0.36) population was slightly higher than previously published studies (0.193-0.321) 4, 6, 7, 9, 31, but this may simply reflect local selection 33 as our population comes from a contiguous 19-county area in Pennsylvania. Among the components glucuronidated by UGT2B17 that may be linked to a protective effect for CRC cancer are NSAIDs and flavonoids 30. NSAID use is known to be associated with a reduction of risk in both colorectal adenomas and carcinomas 34 and a protective effect was even found with the lowest dose of aspirin (75 mg per day) after only 5 years 35. Flavonoids have antioxidative properties and can serve as free-radical scavengers that aid in the detoxification of meat-derived mutagens such as the heterocyclic amine PhIP 36. Studies have found that intake of specific dietary flavonoids may be linked with reduced CRC risk and concluded that flavonoids reduced oxidative stress caused by food mutagens in vitro in lymphocytes of healthy individuals and colon cancer patients 36, 37. Individuals with UGT2B17 (+/+) may be excreting these protective components faster than individuals with (0/+) or (0/0) genotypes. Therefore, without the UGT2B17 gene, NSAIDs and flavonoids are not excreted as quickly and can aid in detoxifying carcinogens which could result in the observed decreased CRC risk in UGT2B17 (0/0) individuals. In the present study, the analysis was adjusted for NSAID use, but a significant interaction between high NSAID use and UGT2B17 CNV (p= 0.22) was not found. This could be explained by the fact that NSAIDs are glucuronidated at different rates by UGT2B17 38, and it would be better to analyze this interaction on a drug by drug basis. The specific NSAID drugs taken by each individual were identified within the demographic and dietary questionnaire, but the sample numbers were not high enough to statistically identify interactions with any single NSAID. Also, as the original questionnaire was not predesigned to quantify intake of specific flavonoids, the ability to assess the combined effect of UGT2B17 CNV and flavonoid intake on CRC risk was limited.

The association between decreased CRC risk and UGT2B17 (0/0) was most prominent in men. UGT2B17 is expressed in a variety of human tissues including the colon and liver 39, but recent studies indicated that in human liver specimens, men exhibited a four-fold higher UGT2B17 expression level than women, and consistent with this increase in expression was a higher level of hepatic glucuronidation activity of UGT2B17 substrates in men 4. Since UGT2B17 exhibits higher levels of expression and contributes to higher levels of hepatic glucuronidation in men than women, the gene may play a greater role in metabolism of protective dietary compounds in men and could explain the observed decreased risk for CRC in men with UGT2B17 (0/0). Interestingly, the decreased risk associated with UGT2B17 (0/0) was observed among men for rectal cancer but not proximal or distal colon cancers. The interaction between the UGT2B17 genotype and dietary components may be more important in rectal cancer due to the specific carcinogens associated with risk for rectal cancer. Previous studies demonstrated that elevated levels of DiMeIQx and PhIP were associated with increased rectal cancer risk 25. The specific flavonoids quercetin and rutin have been found to reduce DNA damage from high PhIP doses in vitro to levels comparable to a 7.5 times lower PhIP dose 36.

Together, the present study suggests that the CNV status of UGT2B17 affects an individual’s risk for CRC, with the effect most prominent in men with rectal cancer. Results from this analysis also support previous studies demonstrating that increased exposure to HCAs and PAHs from red and processed meat increase CRC risk. Additional investigations examining the gene-environment interaction between UGT2B17 polymorphisms and exposure to dietary flavonoids will be important to determine the exact mechanisms underlying the protective effect of UGT2B17 on risk for CRC.

Supplementary Material

Supp Table S1

Acknowledgements

We thank Jennifer Engle and Ruth Jarbadan for aid in DNA extraction and sample preparation.

Funding Sources: NIH R00 CA 131477 and PA Department of Health CURE

Footnotes

The authors of this manuscript have no conflicts of interest to disclose.

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