Risk Of Advanced Colorectal Adenoma Research Articles

Exogenous Insulin Therapy Is Associated with the Risk of Advanced Colorectal Adenoma in Patients with Diabetes Mellitus.

Exogenous insulin therapy increases systemic exposure to insulin which may promote the development of colorectal neoplasia. We sought to evaluate the association between exogenous insulin therapy and the incidence of advanced adenoma in type 2 diabetes mellitus. A retrospective cohort study was conducted from January 1, 2007, to January 1, 2018, in a regional health system serving the United States Philadelphia metropolitan area, Central New Jersey, and South Central Pennsylvania. Study patients consisted of a random sample of patients with type 2 diabetes mellitus aged 40-80years who had undergone two rounds of colonoscopy examinations. The exposure was cumulative duration of insulin therapy (i.e., no use, 1-365days and > 365days). The outcome was time to incident advanced adenoma. Of the 975 eligible patients, 184 patients accumulated > 365days of insulin therapy before the follow-up colonoscopy. The mean (standard deviation) duration between the two rounds of colonoscopy examination was 5.1 (2.9) years among the insulin users and 5.3 (3.9) years among non-users. Compared to no insulin exposure, receiving > 365days of insulin therapy was associated with an increased incidence of advanced adenoma (adjusted hazard ratio [aHR] 4.84, 95% confidence interval [CI] 2.82-8.30), right-sided advanced adenoma (aHR 5.48, 95% CI 2.90-10.35), and 3 or more adenomas (aHR 2.61, 95% CI 1.46-4.69) at the follow-up colonoscopy examination. Insulin therapy is associated with an increased risk of advanced adenoma and may serve as a novel risk-stratification factor to enhance the efficiency of existing colorectal cancer screening and surveillance programs.

Association between serum γ-glutamyl transferase and advanced colorectal adenoma among inpatients: a case-control study.

Emerging evidence suggests a link between γ-glutamyl transferase (GGT) and various malignancies. However, the relationship between GGT and advanced colorectal adenoma, a critical precursor to colorectal cancer, remains unclear. This study aimed to elucidate this relationship. We conducted a single-center retrospective study from April 2015 to June 2022, enrolling 3534 inpatients including 525 cases and 3009 controls. Data were extracted from the electronic medical records, encompassing clinicodemographic characteristics, co-morbidities, and several blood biochemical indicators. Utilizing logistic regression and curve fitting, we explored the relationship between GGT and advanced colorectal adenoma. After adjustment for confounding factors, we found that for each 20-unit increase in GGT, the risk of advanced colorectal adenoma increased by 6% (OR= 1.06 [1.01-1.12]). Moreover, individuals with high GGT levels (≥50 U/L) had a 61% higher risk of advanced colorectal adenoma compared to those with low GGT levels (<50 U/L) (OR=1.61 [1.13-2.31]). Subgroup analysis demonstrated the robustness of these findings across subjects with different characteristics. High GGT levels were associated with higher odds of advanced colorectal adenoma. Our findings suggest that elevated GGT levels may serve as a potential diagnostic marker for advanced colorectal adenoma, providing new insights into its screening strategies.

Gender difference in metabolic syndrome and incident colorectal adenoma: A prospective observational study (KCIS No.42).

This community-based study aimed to elucidate whether there is a gender difference in the effect of metabolic syndrome (MetS) and its individual components on an elevated risk for incident colorectal adenoma.A prospective cohort study was conducted by enrolling 59,767 subjects aged 40 years or older between 2001 and 2009 in Keelung, Taiwan, to test this hypothesis, excluding those with a prior history of colorectal cancer and those with colorectal cancer diagnosed at the first screening. Cox proportional hazards regression models were used to assess the effect of MetS in terms of a dichotomous classification, each individual component and the number of components for males and females.Colorectal adenoma was present in 2.7% (n = 652) of male participants and 1.1% (n = 403) of female participants. The prevalence rate of MetS was 26.7% and 23.3% for males and females, respectively. The effect of MetS on colorectal adenoma was statistically significant and similar for the 2 genders, with an adjusted hazard ratio (aHR) of 1.33 (95% CI: 1.13–1.58) in males and 1.33 (95% CI: 1.06–1.66) in females after adjustment for confounders. However, MetS led to higher risk of advanced colorectal adenoma in men than in women. Regarding the effect of each component of MetS on colorectal adenoma, abnormal waist circumference and hypertriglyceridemia led to an elevated risk of colorectal adenoma in both genders. A rising risk of colorectal adenoma among females was noted in those with a moderately higher level of glycemia (100–125 mg/dL, aHR = 1.44, 95% CI: 1.12–1.85). Hypertriglyceridemia and high blood pressure were associated with an increased risk of advance colorectal adenoma in males.Both male and female subjects with MetS had a higher risk of colorectal adenoma. The contributions from individual components of MetS varied by gender. These findings suggest that the possible risk reduction of colorectal adenoma through metabolic syndrome-based lifestyle modifications may differ between genders.

Serum Levels of Lipopolysaccharides and Risk of Advanced Colorectal Adenoma

Production of lipopolysaccharides (LPS) from the outer membrane of Gram-negative bacteria promotes the survival of cancer cells. Systemic level of LPS is considered a biomarker for microbial translocation. The association between LPS and the risk of colorectal tumors is not well known. The goal of this study was to examine the association between LPS serum levels and risk of advanced colorectal adenoma (ACA).

Markers of systemic inflammation and colorectal adenoma risk: Meta-analysis of observational studies.

AIMTo perform a meta-analysis of observational studies on inflammatory markers levels and occurrence of colorectal adenoma.METHODSPubMed and EMBASE databases were searched until March 2016 for the articles reporting on the circulating levels of inflammatory markers, including: C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) and risk of colorectal adenoma. Random-effects models were used to calculate summary odds ratios (ORs) with 95%CIs for the highest vs lowest category of exposure. Heterogeneity was assessed by using the Q test and I2 statistic. Subgroup analyses were also performed to test for potential source of heterogeneity.RESULTSA total of 14 case-control studies were included. Ten studies on CRP including a total of 3350 cases and 4168 controls showed non-significant summary (OR = 1.23, 95%CI: 0.98-1.54; I2 = 54%, Pheterogeneity = 0.01) in the general analysis, but significant increased odds when considering only advanced adenoma (OR = 1.59, 95%CI: 1.09-2.32; I2 = 44%, Pheterogeneity = 0.15). Subgroup and stratified analyses revealed a potential influence of smoking status and aspirin use on the association between CRP levels and colorectal adenoma. Five studies examined the association between circulating levels of TNF-α and colorectal adenoma risk, including a total of 1,568 cases and 2,832 controls. The summary OR for the highest vs the lowest category of exposure was 1.00 (95%CI: 0.77-1.29). The relationship between circulating IL-6 levels and colorectal adenoma risk was investigated in 7 studies including a total of 1936 cases and 3611 controls. The summary OR for the highest vs the lowest category of exposure was 1.19 (95%CI: 0.92-1.55).CONCLUSIONSummary of current evidence suggests a positive association of CRP levels and advanced colorectal adenoma risk. The role of potential confounding factors should be further evaluated.

Plasma Inflammatory Markers and Risk of Advanced Colorectal Adenoma in Women

Evidence remains inconclusive about the association of systemic inflammatory markers with colorectal neoplasia. We investigated whether circulating inflammatory markers were associated with risk of advanced colorectal adenoma. We measured plasma macrophage inhibitory cytokine-1 (MIC-1), C-reactive protein (CRP), interleukin-6 (IL6), and soluble TNF receptor 2 (sTNFR-2) in blood samples drawn from 32,826 women in 1989 to 1990 in the Nurses' Health Study. Through 2008, we documented 757 cases of advanced colorectal adenomas (≥1 cm or any size with advanced histology); each case was matched by age and time of blood draw with one control randomly selected from participants who underwent lower endoscopy and did not have neoplasia. Plasma MIC-1 was associated with higher risk of advanced adenoma (Ptrend = 0.04), with an OR of 1.55 (95% confidence interval, 1.03-2.32) comparing extreme quintiles of MIC-1 after adjusting for colorectal cancer-risk factors and other inflammatory markers. Among cases, MIC-1 level was positively associated with the number of adenomas (P < 0.001) and gradually increased from adenomas located in the rectum, distal colon, and up to the proximal colon. There was a strong positive association between MIC-1 and risk of adenomas with multiplicity, ≥1 cm size and location in the proximal colon (all Ptrend < 0.05). CRP, IL6, or sTNFR-2 was not associated with adenoma risk. In conclusion, plasma MIC-1 was associated with higher risk of colorectal adenoma, especially multiple, large, and proximal adenomas. Our results provide further support for a role for MIC-1 in carcinogenesis and the potential for MIC-1 as an adjunctive biomarker for detection of advanced colorectal adenoma.

Dietary iron, iron homeostatic gene polymorphisms and the risk of advanced colorectal adenoma and cancer

Dietary iron intake and variation in iron homeostasis genes may affect colorectal neoplasia risk. We conducted two nested case-control studies within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial: one of advanced colorectal adenoma (1205 cases; 1387 controls) and one of colorectal cancer (370 cases; 401 controls). Iron intake was estimated with a food frequency questionnaire and genotyping was performed for 21 genes. Unconditional logistic regression was used to estimate odds ratio (OR) and 95% confidence intervals (95% CIs) for colorectal neoplasia risk within quartiles of intake. Several single nucleotide polymorphisms (SNPs) modified the association between iron intake and the risk of adenoma or cancer. Dietary iron was positively associated with colorectal adenoma among three SNPs of HEPHL1, including carriers of the AA genotype at rs7946162 (ORQ4-Q1 = 2.22, 95% CI 1.15-4.27, Ptrend = 0.03; Pinteraction = 0.10), the TT genotype at rs2460063 (ORQ4-Q1 = 2.39, 95% CI 1.26-4.54, Ptrend = 0.02; Pinteraction = 0.04) and the GG genotype at rs7127348 (ORQ4-Q1 = 2.40, 95% CI 1.23-4.67, Ptrend = 0.02; Pinteraction = 0.09). Heme iron was positively associated with colorectal cancer among those with GG genotypes for ACO1 rs10970985 (ORQ4-Q 1 = 2.45, 95% CI 3.40-8.06, Ptrend = 0.004; Pinteraction = 0.05). However, none of the associations were statistically significant after adjustment for multiple comparisons. Future studies should target the specific genes and SNPs for which the association was significant prior to multiple comparison correction.

Germline variation in NCF4, an innate immunity gene, is associated with an increased risk of colorectal cancer

Chronic inflammation has been implicated in the etiology of colorectal adenoma and cancer; however, few key inflammatory genes mediating this relationship have been identified. In this study, we investigated the association of germline variation in innate immunity genes in relation to the risk of colorectal neoplasia. Our study was based on the analysis of samples collected from the prostate, lung, colorectal and ovarian (PLCO) Cancer Screening Trial. We investigated the association between 196 tag single nucleotide polymorphisms (SNPs) in 20 key innate immunity genes with risk of advanced colorectal adenoma and cancer in 719 adenoma cases, 481 cancer cases and 719 controls. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs). After Bonferroni correction, the AG/GG genotype of rs5995355, which is upstream of NCF4, was associated with an increased risk of colorectal cancer (OR = 2.43, 95% CI = 1.73-3.39; p < 0.0001). NCF4 is part of the NAPDH complex, a key factor in biochemical pathways and the innate immune response. While not definitive, our analyses suggest that the variant allele does not affect expression of NCF4, but rather modulates activity of the NADPH complex. Additional studies on the functional consequences of rs5995355 in NCF4 may help to clarify the mechanistic link between inflammation and colorectal cancer.

Erythrocyte Membrane Phospholipid Fatty Acid Concentrations and Risk of Colorectal Adenomas: A Case–Control Nested in the French E3N-EPIC Cohort Study

Although dietary fatty acids may influence colorectal carcinogenesis, few studies have examined the association with adenoma risk. We assessed the association between biomarkers of dietary fatty acids or metabolism of fatty acids and the risk of colorectal adenomas in a nested case-control study from the French E3N-EPIC cohort. Among 13,106 women without prevalent cancer who completed the diet history questionnaire and who provided blood samples, 328 cases of adenomatous polyp were identified during an average of 6.6-year follow-up and randomly matched to 619 polyp-free colonoscopy controls. Erythrocyte membrane phospholipid fatty acid concentrations were determined by gas chromatography. Adjusted ORs for risk of colorectal adenomas with increasing concentrations of fatty acids were calculated using conditional logistic regression, separately for advanced and nonadvanced adenomas. Associations were stronger with advanced than nonadvanced adenomas. High concentration of pentadecanoate plus heptadecanoate acids were inversely associated with the risk of advanced adenomas [highest vs. lowest tertile: OR(T3vsT1) = 0.40 (95% confidence interval (CI) 0.20-0.79); P(trend) = 0.009]. Oleic acid was associated with an increased risk of advanced adenomas [OR(T3vsT1) = 2.32 (1.16-4.64); P(trend) = 0.018]. Some polyunsaturated fatty acids were associated with the risk of advanced adenomas, either positively for di-homo-γ-linolenate [OR(T3vsT1) = 2.07 (1.15-3.72); P(trend) = 0.013], or negatively for eicosapentaenoic and docosahexaenoic acids [OR(T3vsT1) = 0.50 (0.27-0.93); P(trend) = 0.044 and OR(T3vsT1) = 0.50 (0.26-0.96); P(trend) = 0.028, respectively]. A specific erythrocyte membrane phospholipid fatty acid profile, presumably reflecting both a complex dietary pattern and altered fatty acid metabolism, is associated with advanced colorectal adenoma risk. Adenomas could be a target for primary prevention of colorectal cancer, using interventional strategy based on lipidomic profile of patients.

Abstract 4832: High calcium reduces multiple or advanced colorectal adenoma risk by nearly 90% among those with variant alleles in two critical genes in calcium reabsorption.

Abstract Despite the rapidly increasing use of colonoscopy, colorectal cancer still remains the 2nd most common cause of cancer death in the United States. Most of these colorectal cancers arise from adenomas. High calcium consumption has been linked to reduced risks of colorectal adenoma and cancer. However, results from a large clinical trial conducted in the general population were not consistent from those conducted among colorectal adenoma patients. Adenoma patients have a lower intake of calcium than general population. Furthermore, previous studies indicate there is substantial inter-individual variation in the ability to (re)absorb calcium, which is mostly attributed to genetic variation. Thus, we hypothesized that some of the inconsistency in previous studies was due to interactions between calcium and genetic polymorphisms involved in calcium homeostasis. In an NIH R01 project, we conducted a two- phase study to evaluate whether polymorphisms in KCNJ1 and 13 other genes modified the associations between calcium intake and risk of colorectal adenoma. Included in the study were 1818 cases and 3992 controls identified from the Tennessee Colorectal Polyp Study (TCPS), a colonoscopy-based case control study conducted in Nashville, TN. We identified in Phase 1 and replicated in Phase 2 that two polymorphisms in two genes (i.e. one SNP in each gene) significantly modified the associations between calcium intake and colorectal adenoma risk. One gene is potassium inwardly-rectifying channel, subfamily J, member 1 (KCNJ1), which etiologically leads to hereditary familial diseases with impairments in reabsorption for calcium. The p for interaction with the SNP in the KCNJ1 gene remained statistically significant after Bonferroni correction for multiple comparisons (all SNPs in 14 genes). In the combined analysis of these two genes, we found 52% of the study population carry at least one variant allele in one of two genes while 13% of the population carry variant alleles in both genes. We found among those with zero variant alleles in two genes, the highest tertile of calcium intake was not associated with adenoma risk with an OR (95% CI) of 1.06(0.65-1.72). Highest calcium intake tertile was significantly associated with a 39% reduced adenoma risk among those who carry variant allele in one gene (p for trend, 0.046), and with a 69% reduced risk among those with alleles in both genes (p for trend, 0.039). The corresponding reduction in risk with advanced or multiple adenomas increased to 89% (95%CI: 41%-98%) among those with variant alleles in both genes (p for interaction, 5.5×10−5). In summary, high intake of calcium may only protect against colorectal carcinogenesis among those who carry variant alleles in two genes, particularly for those who carry variant alleles in both genes. Citation Format: Xiangzhu Zhu, Martha J. Shrubsole, Reid M. Ness, Qiuyin Cai, Jirong Long, Zhi Chen, Ji Liang, Guoliang Li, Walter E. Smalley, Todd L. Edwards, Edward Giovannucci, Wei Zheng, Qi Dai. High calcium reduces multiple or advanced colorectal adenoma risk by nearly 90% among those with variant alleles in two critical genes in calcium reabsorption. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4832. doi:10.1158/1538-7445.AM2013-4832

Dietary Iron, Iron Homeostatic Gene Polymorphisms and the Risk of Advanced Colorectal Adenoma and Cancer

Dietary iron intake and variation in iron homeostasis genes may affect colorectal neoplasia risk. We conducted two nested case–control studies within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial: one of advanced colorectal adenoma (1205 cases; 1387 controls) and one of colorectal cancer (370 cases; 401 controls). Iron intake was estimated with a food frequency questionnaire and genotyping was performed for 21 genes. Unconditional logistic regression was used to estimate odds ratio (OR) and 95% confidence intervals (95% CIs) for colorectal neoplasia risk within quartiles of intake. Several single nucleotide polymorphisms (SNPs) modified the association between iron intake and the risk of adenoma or cancer. Dietary iron was positively associated with colorectal adenoma among three SNPs of HEPHL1, including carriers of the AA genotype at rs7946162 (ORQ4– Q1 = 2.22, 95% CI 1.15–4.27, P trend = 0.03; P interaction = 0.10), the TT genotype at rs2460063 (ORQ4– Q1 = 2.39, 95% CI 1.26–4.54, P trend = 0.02; P interaction = 0.04) and the GG genotype at rs7127348 (ORQ4– Q1 = 2.40, 95% CI 1.23–4.67, P trend = 0.02; P interaction = 0.09). Heme iron was positively associated with colorectal cancer among those with GG genotypes for ACO1 rs10970985 (ORQ4– Q 1 = 2.45, 95% CI 3.40–8.06, P trend = 0.004; P interaction = 0.05). However, none of the associations were statistically significant after adjustment for multiple comparisons. Future studies should target the specific genes and SNPs for which the association was significant prior to multiple comparison correction.

Meat-related mutagen exposure, xenobiotic metabolizing gene polymorphisms and the risk of advanced colorectal adenoma and cancer

Meat mutagens, including heterocyclic amines (HCAs), polycyclic aromatic hydrocarbons (PAHs) and N-nitroso compounds (NOCs), may be involved in colorectal carcinogenesis depending on their activation or detoxification by phase I and II xenobiotic metabolizing enzymes (XME). Using unconditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI), we examined the intake of five meat mutagens and >300 single nucleotide polymorphisms (SNPs) in 18 XME genes in relation to advanced colorectal adenoma (1205 cases and 1387 controls) and colorectal cancer (370 cases and 401 controls) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Dietary intake of meat mutagens was assessed using a food frequency questionnaire with a detailed meat-cooking module. An interaction was observed between 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) intake and the NAT1 polymorphism rs6586714 in the adenoma study (P(interaction) = 0.001). Among individuals carrying a GG genotype, high MeIQx intake was associated with a 43% increased risk of adenoma (95% CI 1.11-1.85, P(trend) = 0.07), whereas the reverse was observed among carriers of the A variant (OR = 0.50, 95% CI 0.30-0.84, P(trend) = 0.01). In addition, we observed some suggestive (P < 0.05) modifying effects for SNPs in other XME genes (UGT1A, CYP2E1, EPHX1, AHR and GSTM3), but these were not significant after adjustment for multiple testing. This large and comprehensive study of XME genes, meat mutagens and the risk of colorectal tumours found that a NAT1 polymorphism modified the association between MeIQx intake and colorectal adenoma risk.

Associations between Genes in the One-Carbon Metabolism Pathway and Advanced Colorectal Adenoma Risk in Individuals with Low Folate Intake

Folate is essential for one-carbon metabolism, a pathway required by DNA synthesis, methylation, and repair. Low dietary and circulating folate and polymorphic variation in this pathway are associated with increased risk of colorectal adenoma and cancer. We genotyped 882 single nucleotide polymorphisms (SNP) in 82 one-carbon metabolism genes for 1,331 cases of advanced colorectal adenoma, identified by sigmoidoscopy at baseline, and 1,501 controls from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). We evaluated associations between one-carbon genes and adenoma risk in all subjects and stratified by folate intake. We applied the Adaptive Rank Truncated Product (ARTP) method to assess statistical significance at the gene and pathway levels. Folate intake was inversely associated with advanced colorectal adenoma risk [odds ratio (OR) by quartile = 0.85, P = 1.9 × 10(-5)]. We found no statistically significant associations between one-carbon genes and adenoma risk in all subjects. As hypothesized, we observed a statistically significant pathway-level association (P = 0.038) in the lowest quartile of folate; no significant associations were found in higher quartiles. Several genes including adenosine deaminase (ADA) and cysteine dioxygenase (CDO1) contributed to this signal (gene-level P = 0.001 and 0.0073, respectively). The most statistically significant SNP was rs244072 in ADA (P = 2.37 × 10(-5)). Stratification by dietary folate and application of the ARTP method revealed statistically significant pathway- and gene-level associations between one-carbon metabolism genes and risk of advanced colorectal adenoma, which were not apparent in analysis of the entire population. Folate intake may interact with associations between common variants in one-carbon metabolism genes and colorectal adenoma risk.

Highlights of This Issue

Data are conflicted about the efficacy of colonoscopy for reducing colon cancer risk. To address this question, Siegel and colleagues analyzed U.S. cancer surveillance data to gauge trends in population-based colorectal cancer incidence by tumor location. Data from cancer registries in the Surveillance, Epidemiology, and End Results (SEER) program were analyzed to quantify changes in rates by tumor location and disease stage. The authors report that, since 1999, incidence rates for both right- and left-sided colon tumors decreased annually in men and women. The authors suggest that increased colonoscopy utilization during the past decade may have contributed to a reduction in colon cancer incidence in the United States.Folate is essential for one-carbon metabolism, and low dietary and circulating folate levels are both associated with increased risks of colorectal adenoma and cancer. Han and colleagues genotyped single-nucleotide polymorphisms in 82 one-carbon metabolism genes in colorectal cancer cases from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). The authors report that, whereas folate intake was inversely associated with advanced colorectal adenoma risk, no statistically significant associations were evident between one-carbon metabolism genes and adenoma risk. However, a statistically significant association was observed in the lowest quartile of folate intake. These results indicate that stratification by dietary folate intake can reveal associations between one-carbon metabolism genes and the risk of advanced colorectal adenoma.It is not known if dairy intake after a prostate cancer diagnosis is associated with poor prognosis. To address this question, Pettersson and colleagues investigated post-diagnostic milk and dairy intake in relation to risk of lethal prostate cancer among participants in the Health Professionals Follow-Up Study. The authors found that total milk and dairy intake after diagnosis was not associated with a greater risk of lethal prostate cancer. The results of this study suggest that dairy intake after prostate cancer diagnosis is not associated with a greater risk of distant metastases and prostate cancer death.Lindström and colleagues used prostate cancer cases within the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3) to evaluate the performance of 25 independent single-nucleotide polymorphisms in prostate cancer risk models. The models combined genetic information with prostate cancer family history and age. The authors report that the best risk models included individual genetic markers along with family history of prostate cancer. These results indicate that incorporating genetic information and family history can be useful for identifying men that might benefit from prostate-specific antigen screening.

Serum IGF1, IGF2 and IGFBP3 and risk of advanced colorectal adenoma.

The insulin-like growth factor (IGF) signaling pathway is involved in cell proliferation and differentiation. Elevated serum IGF1 levels have been associated with increased colorectal cancer risk; however, studies of this association with colorectal adenoma are inconclusive. We examined serum IGF1, IGF2 and IGFBP3 levels in relation to risk of advanced colorectal adenoma in a case-control study within the prostate, lung, colorectal and ovarian cancer screening trial. A total of 764 advanced, left-sided colorectal adenoma cases and 775 controls frequency-matched on gender and ethnicity, without evidence of a left-sided polyp on sigmoidoscopy were included in the current study. Serum levels of IGF1, IGF2 and IGFBP3 were measured using an enzyme linked immunosorbent assay in serum samples collected at baseline. Logistic regression was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) for the associations adjusting for age, race, sex, year of blood draw, body mass index, smoking and education. Higher IGF1 levels were associated with increased adenoma risk: ORs = 1.58 (95% CI = 1.16-2.16), 1.42 (95% CI = 1.04-1.93), and 1.80 (95% CI = 1.30-2.47) for the second, third and fourth quartiles, respectively (p(trend) = 0.002). Elevated IGF2 levels were also associated with increased adenoma risk (OR = 1.43, 95% CI = 1.05-1.96 for the fourth vs. first quartile, p(trend) = 0.02), but the association was no longer significant after adjustment for IGF1 (p(trend) = 0.28). IGFBP3 levels were not associated with adenoma risk. Our analysis showed a significant positive association between circulating IGF1 levels and risk of advanced colorectal adenoma, suggesting that IGF1 is associated with the pivotal precursor to colorectal cancer.

Polymorphisms in the adenomatous polyposis coli ( APC) gene and advanced colorectal adenoma risk

While germline mutations in the adenomatous polyposis coli ( APC) gene cause the hereditary colon cancer syndrome (familial adenomatous polyposis (FAP)), the role of common germline APC variants in sporadic adenomatous polyposis remains unclear. We studied the association of eight APC single nucleotide polymorphisms (SNPs), possibly associated with functional consequences, and previously identified gene–environment (dietary fat intake and hormone replacement therapy (HRT) use) interactions, in relation to advanced colorectal adenoma in 758 cases and 767 sex- and race-matched controls, randomly selected from the screening arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Cases had at least one verified advanced adenoma of the distal colon; controls, a negative sigmoidoscopy. We did not observe an association between genotypes for any of the eight APC SNPs and advanced distal adenoma risk ( P global gene-based = 0.92). Frequencies of identified common haplotypes did not differ between cases and controls ( P global haplotype test = 0.97). However, the risk for advanced distal adenoma was threefold higher for one rare haplotype (cases: 2.7%; controls: 1.6%) (odds ratio (OR) = 3.27; 95% confidence interval (CI) = 1.08–9.88). The genetic association between D1822V and advanced distal adenoma was confined to persons consuming a high-fat diet ( P interaction = 0.03). Similar interactions were not observed with HRT use. In our large, nested case-control study of advanced distal adenoma and clinically verified adenoma-free controls, we observed no association between specific APC SNPs and advanced adenoma. Fat intake modified the APC D1822V-adenoma association, but further studies are warranted.

Abstract 1867: DNA repair gene polymorphisms and tobacco smoking and the risk of colorectal adenoma

Abstract Genetic variants of DNA repair genes may contribute to their altered capacity to repair endogenous and exogenous DNA damage. Although rare mutations in mismatch repair genes are known to lead to hereditary non-polyposis colorectal cancer, to date studies investigating common single nucleotide polymorphisms (SNPs) in DNA repair genes and colorectal cancer or adenoma risk have only examined a small number of variants in a limited number of genes. We conducted a comprehensive analysis of DNA repair gene polymorphisms and colorectal adenoma risk using a nested case-control study in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Effect modification by smoking, which is a known risk factor for adenoma, was also explored. A total of 1,338 advanced, left-sided colorectal adenoma cases and 1,503 frequency-matched controls without evidence of a left-sided polyp on sigmoidoscopy were included in the current study. Using DNA extracted from blood specimens, 3,401 tag SNPs in 153 DNA repair genes were genotyped. Logistic regression was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) for the associations between genetic variants and adenoma risk assuming a log-additive model for the genotype. Among Caucasians, 30 SNPs were associated with adenoma risk at p&amp;lt;0.01. The most significant finding was for a non-synonymous SNP in EXO1 (rs9350), which was predicted to be deleterious using the SIFT and PolyPhen databases. The C allele at EXO1 rs9350 was associated with a 1.30-fold increased risk (95% CI=1.11-1.51, P=0.001). The association appeared to be limited to smokers (OR=1.54, 95% CI=1.26-1.89) with the strongest risk for current smokers (OR=2.15, 95% CI=1.27-3.65), and an intermediate risk for former smokers (OR=1.45, 95% CI=1.14-1.82), compared to never smokers (OR=0.98, 95% CI=0.76-1.25) that exhibited no increased risk (Pinteraction=0.002). Among the top findings, a SNP (rs17503908) in ATM with an overall OR of 0.75 (95% CI=0.63-0.91) was also modified by smoking (Pinteraction=0.006); the T allele at ATM rs17503908 was protective among never smokers (OR=0.55, 95% CI=0.40-0.76) but not among smokers (OR=0.89, 95% CI=0.70-1.13). The study suggests that polymorphisms in EXO1 and ATM may be associated with risk of advanced colorectal adenoma with the effects modified by tobacco smoking status. Our findings warrant extended investigations of these associations for colorectal cancer risk. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1867.

Abstract B129: Xenobiotic metabolizing genes, meat intake and risk of advanced colorectal adenoma

Abstract B129 Red meat and processed meat are positively associated with risk of colorectal neoplasia. One of the potential mechanisms underlying the association of meat with cancer is via the mutagenic action of heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs) formed during high temperature cooking. Phase I xenobiotic metabolizing enzymes (XMEs) are involved in the initial steps of activation of xenobiotics to mutagenic and carcinogenic intermediates. Phase II XMEs convert original xenobiotic compounds and their phase I-activated metabolites to polar and detoxified metabolites. However, with certain compounds, such as HCAs, phase II XMEs may further activate metabolites to form other carcinogenic species. We evaluated 29 single nucleotide polymorphisms (SNPs) in several phase I (CYP1A1, CYP1B1, CYP2A6, CYP2C9, CYP2E1, and CYP3A4) and phase II (EPHX1, GSTM1, GSTM2, GSTT1, NAT1, NAT2, NQO1, SULT1A1, and SULT1A2) XME genes in relation to advanced colorectal adenoma and investigated potential effect modification by red meat, HCA, and PAH intake. All SNPS were selected based on known or suggested functional relevance and a minor allele frequency of 5% or greater in Caucasians. Participants were selected from individuals who were enrolled in the screening arm (n = 77,483) of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial between 1993 and 1999. We compared 720 cases with advanced colorectal adenoma (size of 1cm or greater, high grade dysplasia, or villous components, including tubulovillous) of the distal colon or rectum to 746 controls frequency matched on gender and ethnicity (negative for left-sided polyp by sigmoidoscopy). Using a 137-item food frequency questionnaire that included detailed questions on meat cooking methods and doneness levels in conjunction with a HCA and PAH database, we generated intake estimates of the HCAs, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine (PhIP), and the PAH, benzo[a]pyrene (B[a]P) in ng/day. Odd ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression adjusting for age, gender, and ethnicity. Tests for interaction were based on the likelihood ratio test by comparing models with and without interaction terms. Overall, we found weak or null associations between the individual XME genes or SNPs with risk of advanced colorectal adenoma. However, we observed interactions between intake of PhIP and variation in CYP1B1 (rs10012 Pinteraction = 0.019; rs1056836 Pinteraction = 0.019), and NQO1 (rs1800566 Pinteraction = 0.007) with advanced colorectal adenoma. We also found evidence of interaction with intake of B[a]P for variation in CYP1B1 (rs10012 Pinteraction = 0.005) and CYP3A4 (rs2242480 Pinteraction = 0.02). In addition, there was an interaction with intake of red meat and CYP1B1 (rs10012 Pinteraction = 0.013) and NAT1 variants (rs15561 Pinteraction = 0.037). However, when considering multiple comparisons, these interactions did not fall below a false discovery rate threshold of 0.20. Our results are intriguing and suggest that common variants in XME genes may modify the association of red meat, HCA, and PAH intake with advanced colorectal adenoma, but require confirmation in larger studies. Citation Information: Cancer Prev Res 2008;1(7 Suppl):B129.

Genetic Variation in Sodium-Dependent Vitamin C Transporters SLC23A1 and SLC23A2 and Risk of Advanced Colorectal Adenoma

Previous observational studies suggest that vitamin C may reduce risk of colorectal cancer. Vitamin C transport is facilitated by membrane bound sodium-dependent transporters, SVCT1 (encoded by SLC23A1) and SVCT2 (encoded by SLC23A2). To investigate if common genetic variants in these two genes are associated with risk of colorectal tumor development, we conducted a case-control study of 656 Caucasian advanced distal colorectal adenoma cases and 665 Caucasian sigmoidoscopy-negative controls nested within the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. The analysis of common single nucleotide polymorphisms in SLC23A1 revealed no association. For SLC23A2, overall, there was no association with haplotypes, but two SNPs located in intron 8 and exon 11 could be associated (odds ratio = 0.49, 95% confidence interval = 0.25–0.95 for haplotype G-C vs. haplotype C-C). The findings should be confirmed in follow-up studies, and further investigation is required to probe the functional basis of this finding.

Variation in the Selenoenzyme Genes and Risk of Advanced Distal Colorectal Adenoma

Epidemiologic and animal studies provide evidence for a chemopreventive effect of selenium on colorectal cancer, which may be mediated by the antioxidative and anti-inflammatory properties of selenoenzymes. We therefore investigated whether genetic variants in selenoenzymes abundantly expressed in the colon are associated with advanced colorectal adenoma, a cancer precursor. Cases with a left-sided advanced adenoma (n = 772) and matched controls (n = 777) screen negative for polyps based on sigmoidoscopy examination were randomly selected from participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. The underlying genetic variation was determined by resequencing. We genotyped 44 tagging single nucleotide polymorphisms (SNP) in six genes [glutathione peroxidase 1-4 (GPX1, GPX2, GPX3, and GPX4), selenoprotein P (SEPP1), and thioredoxin reductase 1 (TXNRD1)] to efficiently predict common variation across these genes. Four variants in SEPP1 were significantly associated with advanced adenoma risk. A rare variant in the 5' region of SEPP1 (-4166C>G) was present in nine cases but in none of the controls (exact P = 0.002). Three SNPs located in the 3' region of SEPP1, which is overlapping with the promoter region of an antisense transcript, were significantly associated with adenoma risk: homozygotes at two SEPP1 loci (31,174 bp 3' of STP A>G and 43,881 bp 3' of STP G>A) were associated with increased adenoma risk [odds ratio (OR), 1.48; 95% confidence interval (95% CI), 1.00-2.19 and OR, 1.53; 95% CI, 1.05-2.22, respectively] and the variant SEPP1 44,321 bp 3' of STP C>T was associated with a reduced adenoma risk (CT versus CC OR, 0.85; 95% CI, 0.63-1.15). Furthermore, we observed a significant 80% reduction for advanced colorectal adenoma risk for carriers of the variant allele at TXNRD1 IVS1-181C>G (OR, 0.20; 95% CI, 0.07-0.55; P trend = 0.004). Consistent with the individual SNP results, we observed a significant overall association with adenoma risk for SEPP1 and TXNRD1 (global P = 0.02 and 0.008, respectively) but not for the four GPX genes. Our study suggests that genetic variants at or near the SEPP1 and TXNRD1 loci may be associated with advanced colorectal adenoma. As this is the first study to comprehensively investigate this hypothesis, confirmation in independent study populations is needed.