Dietary Inflammatory Potential and the Risk of Serrated and Adenomatous Colorectal Polyps.

Studies of dietary inflammation potential and risks of colorectal cancer precursors are limited, particularly for sessile serrated lesions (SSLs). This study examines the association using the energy-adjusted dietary inflammatory index (E-DIITM), a measure of anti- and/or pro-inflammatory diet, in a large US colonoscopy-based case-control study of 3246 controls, 1530 adenoma cases, 472 hyperplastic polyp cases, and 180 SSL cases. Odds ratios (ORs) and 95% confidence intervals (CIs) were derived from logistic regression models. Analyses were stratified by participant characteristics, and urinary prostaglandin E2 metabolite (PGE-M) and high-sensitivity plasma C-reactive protein (hs-CRP) levels, inflammation biomarkers. Highest E-DII™ intake was associated with significantly increased risks of colorectal adenomas (OR 1.36, 95% CI 1.11, 1.67), and hyperplastic polyps (OR 1.43, 95% CI 1.06, 1.98), compared with participants consuming the lowest E-DII™ quartile. A similar, but non-significant, increased risk was also observed for SSLs (OR 1.41, 95% CI 0.82, 2.41). The positive association was stronger in females (pinteraction <0.001), normal weight individuals (ptrend 0.01), and in individuals with lower inflammatory biomarkers (ptrend 0.02 and 0.01 for PGE-M and hs-CRP, respectively). A high E-DII™ is associated with colorectal polyp risk, therefore promoting an anti-inflammatory diet may aid in preventing colorectal polyps.

Associations between traditional Chinese medicine body constitution and obesity risk among US adults.

Background: Traditional Chinese medicine (TCM) body constitution (BC), primarily determined by physiological and clinical characteristics, is an important process for clinical diagnosis and treatment and play a critical role in precision medicine in TCM. The purpose of the study was to explore whether the distributions of BC types differed by obesity status. Methods: We conducted a study to evaluate BC type in US population during 2012-2016. A total of 191 White participants from Personalized Prevention of Colorectal Cancer Trial (PPCCT) completed a self-administered Traditional Chinese Medicine Questionnaire (TCMQ, English version). In this study, we further compared the distribution of major types of TCM BC in the PPCCT to those Chinese populations stratified by obesity status. Results: We found the Blood-stasis frequency was higher in US White adults, 22.6% for individuals with BMI <30 and 11.2% for obese individuals, compared to 1.4% and 1.8%, respectively, in Chinese populations. We also found the percentages Inherited-special and Qi-stagnation were higher in US White adults than those in Chinese populations regardless of obesity status. However, the proportions of Yang-deficiency were higher in Chinese populations than those in our study conducted in US White adults regardless of obesity status. Conclusions: These new findings indicate the difference in distribution of BC types we observed between US and Chinese populations cannot be explained by the differences in prevalence of obesity. Further studies are needed to confirm our findings and understand the potential mechanism including genetic background and/or environmental factors.

NCCN Guidelines Insights: Colorectal Cancer Screening, Version 2.2020.

The NCCN Guidelines for Colorectal Cancer (CRC) Screening describe various colorectal screening modalities as well as recommended screening schedules for patients at average or increased risk of developing sporadic CRC. They are intended to aid physicians with clinical decision-making regarding CRC screening for patients without defined genetic syndromes. These NCCN Guidelines Insights focus on select recent updates to the NCCN Guidelines, including a section on primary and secondary CRC prevention, and provide context for the panel's recommendations regarding the age to initiate screening in average risk individuals and follow-up for low-risk adenomas.

Yogurt consumption and colorectal polyps.

Diet modifies the risk of colorectal cancer (CRC), and inconclusive evidence suggests that yogurt may protect against CRC. We analysed the data collected from two separate colonoscopy-based case-control studies. The Tennessee Colorectal Polyp Study (TCPS) and Johns Hopkins Biofilm Study included 5446 and 1061 participants, respectively, diagnosed with hyperplastic polyp (HP), sessile serrated polyp, adenomatous polyp (AP) or without any polyps. Multinomial logistic regression models were used to derive OR and 95 % CI to evaluate comparisons between cases and polyp-free controls and case-case comparisons between different polyp types. We evaluated the association between frequency of yogurt intake and probiotic use with the diagnosis of colorectal polyps. In the TCPS, daily yogurt intake v. no/rare intake was associated with decreased odds of HP (OR 0·54; 95 % CI 0·31, 0·95) and weekly yogurt intake was associated with decreased odds of AP among women (OR 0·73; 95 % CI 0·55, 0·98). In the Biofilm Study, both weekly yogurt intake and probiotic use were associated with a non-significant reduction in odds of overall AP (OR 0·75; 95 % CI 0·54, 1·04) and (OR 0·72; 95 % CI 0·49, 1·06) in comparison with no use, respectively. In summary, yogurt intake may be associated with decreased odds of HP and AP and probiotic use may be associated with decreased odds of AP. Further prospective studies are needed to verify these associations.

Meat intake, meat cooking methods, and meat-derived mutagen exposure and risk of sessile serrated lesions.

BACKGROUND: Red and processed meat, recognized carcinogens, are risk factors for colorectal neoplasia, including polyps, the precursor for colorectal cancer. The mechanism is unclear. One possible explanation is the mutagenic activity of these foods, perhaps due to generation during cooking [e.g., heterocyclic amine (HCA) intake]. Few studies have evaluated meat intake and sessile serrated lesion (SSL) risk, a recently recognized precursor, and no study has evaluated meat cooking methods and meat-derived mutagens with SSL risk. OBJECTIVE: We evaluated intakes of meat, meat cooking methods, and inferred meat mutagens with SSL risk and in comparison to risk of other polyps. METHODS: Meat, well-done meat, and inferred meat mutagen intakes were evaluated. Polytomous logistic regression models were used to estimate ORs and 95% CIs among cases (556 hyperplastic polyp, 1753 adenoma, and 208 SSL) and controls (3804) in the large colonoscopy-based, case-control study, the Tennessee Colorectal Polyp Study. RESULTS: The highest quartile intakes of red meat (OR: 2.38; 95% CI: 1.44, 3.93), processed meat (OR: 2.03; 95% CI: 1.30, 3.17), well-done red meat (OR: 2.19; 95% CI: 1.34, 3.60), and the HCA 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQX; OR: 2.48; 95% CI: 1.49, 4.16) were associated with increased risk of SSLs in comparison to the lowest quartile intake. CONCLUSIONS: High intakes of red and processed meats are strongly and especially associated with SSL risk and part of the association may be due to HCA intake. Future studies should evaluate other mechanism(s) and the potential for primary prevention.

NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 2.2019.

Identifying individuals with hereditary syndromes allows for improved cancer surveillance, risk reduction, and optimized management. Establishing criteria for assessment allows for the identification of individuals who are carriers of pathogenic genetic variants. The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal provide recommendations for the assessment and management of patients with high-risk colorectal cancer syndromes. These NCCN Guidelines Insights focus on criteria for the evaluation of Lynch syndrome and considerations for use of multigene testing in the assessment of hereditary colorectal cancer syndromes.

Arachidonic acid and colorectal adenoma risk: a Mendelian randomization study.

BACKGROUND: Previous studies have shown a link between increased dietary intake of arachidonic acid (ARA) and colorectal neoplasms. It has been shown that erythrocyte phospholipid membrane concentrations of ARA are strongly determined by genetic variation. Fatty acid desaturase (FADS) controls the rate limiting step in ARA production, and FADS variant rs174537 has been shown to be responsible for up to 18.6% of the variation seen. To determine if a causal association exists between erythrocyte membrane ARA concentrations and colorectal adenomas, we conducted a Mendelian randomization (MR) analysis using rs174537 as an instrumental variable (IV). MR analysis was chosen because it is less susceptible to bias and confounding. PATIENTS AND METHODS: A case-control study was performed using the Tennessee Colorectal Polyps Study. Patients were matched on age, gender, race, facility site, and year of colonoscopy. Cases were defined as any colorectal adenoma on colonoscopy (n=909) and controls were polyp free (n=855). A two-stage logistic regression was conducted using rs174537 as the IV with the dependent variable being the presence of a colorectal adenoma on colonoscopy. RESULTS: Cases were older (59 vs 57 years of age, P<0.0001), and more likely to use alcohol (47.4% vs 19.8%, P=0.001) and to smoke (77.0% vs 66.9%, P<0.0001). There was no statistically significant difference in: age, sex, alcohol use, body mass index (BMI), or NSAID use when stratified by the rs174537 alleles. Genotype was strongly associated with erythrocyte membrane ARA concentrations (P<0.0001). We found no evidence of an association between our IV (rs174537) and colorectal adenomas (P=0.41). CONCLUSION: In our MR study increased erythrocyte ARA concentrations were not associated with the risk of colorectal adenomas.

Magnesium status and supplementation influence vitamin D status and metabolism: results from a randomized trial.

Background: Previous in vitro and in vivo studies indicate that enzymes that synthesize and metabolize vitamin D are magnesium dependent. Recent observational studies found that magnesium intake significantly interacted with vitamin D in relation to vitamin D status and risk of mortality. According to NHANES, 79% of US adults do not meet their Recommended Dietary Allowance of magnesium. Objectives: The aim of this study was to test the hypothesis that magnesium supplementation differentially affects vitamin D metabolism dependent on baseline 25-hydroxyvitamin D [25(OH)D] concentration. Methods: The study included 180 participants aged 40-85 y and is a National Cancer Institute independently funded ancillary study, nested within the Personalized Prevention of Colorectal Cancer Trial (PPCCT), which enrolled 250 participants. The PPCCT is a double-blind 2 × 2 factorial randomized controlled trial conducted in the Vanderbilt University Medical Center. Doses for both magnesium and placebo were customized based on baseline dietary intakes. Subjects were randomly assigned to treatments using a permuted-block randomization algorithm. Changes in plasma 25-hydroxyvitamin D3 [25(OH)D3], 25-hydroxyvitamin D2 [25(OH)D2], 1,25-dihydroxyvitamin D3, 1,25-dihydroxyvitamin D2, and 24,25-dihydroxyvitamin D3 [24,25(OH)2D3] were measured by liquid chromatography-mass spectrometry. Results: The relations between magnesium treatment and plasma concentrations of 25(OH)D3, 25(OH)D2, and 24,25(OH)2D3 were significantly different dependent on the baseline concentrations of 25(OH)D, and significant interactions persisted after Bonferroni corrections. Magnesium supplementation increased the 25(OH)D3 concentration when baseline 25(OH)D concentrations were close to 30 ng/mL, but decreased it when baseline 25(OH)D was higher (from ∼30 to 50 ng/mL). Magnesium treatment significantly affected 24,25(OH)2D3 concentration when baseline 25(OH)D concentration was 50 ng/mL but not 30 ng/mL. On the other hand, magnesium treatment increased 25(OH)D2 as baseline 25(OH)D increased. Conclusion: Our findings suggest that optimal magnesium status may be important for optimizing 25(OH)D status. This trial was registered at clinicaltrials.gov as NCT03265483.

NCCN Guidelines Insights: Colorectal Cancer Screening, Version 1.2018.

The NCCN Guidelines for Colorectal Cancer (CRC) Screening outline various screening modalities as well as recommended screening strategies for individuals at average or increased-risk of developing sporadic CRC. The NCCN panel meets at least annually to review comments from reviewers within their institutions, examine relevant data, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize 2018 updates to the NCCN Guidelines, with a primary focus on modalities used to screen individuals at average-risk for CRC.

Modifiable lifestyle factors associated with risk of sessile serrated polyps, conventional adenomas and hyperplastic polyps.

OBJECTIVE: To identify modifiable factors associated with sessile serrated polyps (SSPs) and compare the association of these factors with conventional adenomas (ADs) and hyperplastic polyps (HPs). DESIGN: We used data from the Tennessee Colorectal Polyp Study, a colonoscopy-based case-control study. Included were 214 SSP cases, 1779 AD cases, 560 HP cases and 3851 polyp-free controls. RESULTS: Cigarette smoking was associated with increased risk for all polyps and was stronger for SSPs than for ADs (OR 1.74, 95% CI 1.16 to 2.62, for current vs never, ptrend=0.008). Current regular use of non-steroidal anti-inflammatory drugs was associated with a 40% reduction in SSP risk in comparison with never users (OR 0.68, 95% CI 0.48 to 0.96, ptrend=0.03), similar to the association with AD. Red meat intake was strongly associated with SSP risk (OR 2.59, 95% CI 1.41 to 4.74 for highest vs lowest intake, ptrend<0.001) and the association with SSP was stronger than with AD (ptrend=0.003). Obesity, folate intake, fibre intake and fat intake were not associated with SSP risk after adjustment for other factors. Exercise, alcohol use and calcium intake were not associated with risk for SSPs. CONCLUSIONS: SSPs share some modifiable risk factors for ADs, some of which are more strongly associated with SSPs than ADs. Thus, preventive efforts to reduce risk for ADs may also be applicable to SSPs. Additionally, SSPs have some distinctive risk factors. Future studies should evaluate the preventive strategies for these factors. The findings from this study also contribute to an understanding of the aetiology and biology of SSPs.

NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 3.2017.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal provide recommendations for the management of patients with high-risk syndromes associated with an increased risk of colorectal cancer (CRC). The NCCN Panel for Genetic/Familial High-Risk Assessment: Colorectal meets at least annually to assess comments from reviewers within their institutions, examine relevant data, and reevaluate and update their recommendations. These NCCN Guidelines Insights focus on genes newly associated with CRC risk on multigene panels, the associated evidence, and currently recommended management strategies.

PUFA levels in erythrocyte membrane phospholipids are differentially associated with colorectal adenoma risk.

Dietary intake of PUFA has been associated with colorectal neoplasm risk; however, results from observational studies have been inconsistent. Most prior studies have utilised self-reported dietary measures to assess fatty acid exposure which might be more susceptible to measurement error and biases compared with biomarkers. The purpose of this study was to determine whether erythrocyte phospholipid membrane PUFA percentages are associated with colorectal adenoma risk. We included data from 904 adenoma cases and 835 polyp-free controls who participated in the Tennessee Colorectal Polyp Study, a large colonoscopy-based case-control study. Erythrocyte membrane PUFA percentages were measured using GC. Conditional logistic regression was used to calculate adjusted OR for risk of colorectal adenomas with erythrocyte membrane PUFA. Higher erythrocyte membrane percentages of arachidonic acid was associated with an increased risk of colorectal adenomas (adjusted OR 1·66; 95 % CI 1·05, 2·62, P trend=0·02) comparing the highest tertile to the lowest tertile. The effect size for arachidonic acid was more pronounced when restricting the analysis to advanced adenomas only. Higher erythrocyte membrane EPA percentages were associated with a trend towards a reduced risk of advanced colorectal adenomas (P trend=0·05). Erythrocyte membrane arachidonic acid percentages are associated with an increased risk of colorectal adenomas.

Genetic variation in SLC7A2 interacts with calcium and magnesium intakes in modulating the risk of colorectal polyps.

Solute carrier family 7, member 2 (SLC7A2) gene encodes a protein called cationic amino acid transporter 2, which mediates the transport of arginine, lysine and ornithine. l-Arginine is necessary for cancer development and progression, including an important role in colorectal cancer pathogenesis. Furthermore, previous studies found that both calcium and magnesium inhibit the transport of arginine. Thus, calcium, magnesium or calcium:magnesium intake ratio may interact with polymorphisms in the SLC7A2 gene in association with colorectal cancer. We conducted a two-phase case-control study within the Tennessee Colorectal Polyps Study. In the first phase, 23 tagging single-nucleotide polymorphisms in the SLC7A2 gene were included for 725 colorectal adenoma cases and 755 controls. In the second phase conducted in an independent set of 607 cases and 2113 controls, we replicated the significant findings in the first phase. We observed that rs2720574 significantly interacted with calcium:magnesium intake ratio in association with odds of adenoma, particularly multiple/advanced adenoma. In the combined analysis, among those with a calcium:magnesium intake ratio below 2.78, individuals who carried GC/CC genotypes demonstrated higher odds of adenoma [OR (95% CI):1.36 (1.11-1.68)] and multiple/advanced adenoma [OR (95% CI): 1.68 (1.28, 2.20)] than those who carried the GG genotype. The P values for interactions between calcium:magnesium intake ratio and rs2720574 were .002 for all adenomas and <.001 for multiple/advanced adenoma. Among those with the GG genotype, a high calcium:magnesium ratio was associated with increased odds of colorectal adenoma [OR (95% CI): 1.73 (1.27-2.36)] and advanced/multiple adenomas [1.62 (1.05-2.50)], whereas among those with the GC/CC genotypes, high calcium:magnesium ratio was related to reduced odds of colorectal adenoma [0.64 (0.42-0.99)] and advanced/multiple adenomas [0.55 (0.31-1.00)].

Interactions between calcium intake and polymorphisms in genes essential for calcium reabsorption and risk of colorectal neoplasia in a two-phase study.

The SLC8A1 (solute carrier family 8, member 1) gene, encoding Na+ /Ca2+ exchanger, is essential in regulating calcium reabsorption and homeostasis. Calcium homeostasis plays a key role in cell proliferation and apoptosis. We hypothesized that polymorphisms in five calcium-regulating genes (SLC8A1, ATP2B1, CALB1, CALB2, and CABP1) interact with calcium intake in relation to the risk of colorectal neoplasia. A two-phase (discovery and replication) study was conducted within the Tennessee Colorectal Polyp Study, including a total of 1275 cases and 2811 controls. In Phase I, we identified six out of 135 SNPs that significantly interacted with calcium intake in relation to adenoma risk. In Phase II, the calcium intake by rs4952490 (SLC8A1) interaction was replicated (Pinteraction = 0.048). We found an inverse association between calcium intake (1000-2000 mg/day) and colorectal adenomas, particularly for multiple/advanced adenomas, among the G-allele carriers but not among homozygous carriers of the common variant (A) in rs4952490. In the joint analysis of SLC8A1, KCNJ1, and SLC12A1 SNPs, carriers of variant alleles in at least two genes and with calcium intake above the DRI (1000 mg/day) were approximately 30-57% less likely to have adenomas than those whose calcium intake was below the DRI. The association was stronger for multiple/advanced adenomas. No association was found among those who did not carry any variant alleles in these genes when calcium intake was below 2500 mg/day. These findings, if confirmed, may provide a new avenue for the personalized prevention of colorectal adenoma and cancer.

Comparison of biomarker expression between proximal and distal colorectal adenomas: The Tennessee-Indiana Adenoma Recurrence Study.

It is unclear if proximal and distal traditional adenomas present with differences in molecular events which contribute to cancer heterogeneity by tumor anatomical subsite. Participants from a colonoscopy-based study (n = 380) were divided into subgroups based on the location of their most advanced adenoma: proximal, distal, or "equivalent both sides." Eight biomarkers in the most advanced adenomas were evaluated by immunohistochemistry (Ki-67, COX-2, TGFßRII, EGFR, ß-catenin, cyclin D1, c-Myc) or TUNEL (apoptosis). After an adjustment for pathological features, there were no significant differences between proximal and distal adenomas for any biomarker. Conversely, expression levels did vary by other features, such as their size, villous component, and synchronousness. Large adenomas had higher expression levels of Ki-67(P < 0.001), TGFßRII (P < 0.0001), c-Myc (P < 0.001), and cyclin D1 (P < 0.001) in comparison to small adenomas, and tubulovillous/villous adenomas also were more likely to have similar higher expression levels in comparison to tubular adenomas. Adenoma location is not a major determinant of the expression of these biomarkers outside of other pathological features. This study suggests similarly important roles of Wnt/ß-catenin and TGF-ß pathways in carcinogenesis in both the proximal and distal colorectum. © 2016 Wiley Periodicals, Inc.

Genetic/Familial High-Risk Assessment: Colorectal Version 1.2016, NCCN Clinical Practice Guidelines in Oncology.

This is a focused update highlighting the most current NCCN Guidelines for diagnosis and management of Lynch syndrome. Lynch syndrome is the most common cause of hereditary colorectal cancer, usually resulting from a germline mutation in 1 of 4 DNA mismatch repair genes (MLH1, MSH2, MSH6, or PMS2), or deletions in the EPCAM promoter. Patients with Lynch syndrome are at an increased lifetime risk, compared with the general population, for colorectal cancer, endometrial cancer, and other cancers, including of the stomach and ovary. As of 2016, the panel recommends screening all patients with colorectal cancer for Lynch syndrome and provides recommendations for surveillance for early detection and prevention of Lynch syndrome-associated cancers.

Evaluation of pro-inflammatory markers plasma C-reactive protein and urinary prostaglandin-E2 metabolite in colorectal adenoma risk.

C-reactive protein (CRP) is a pro-inflammatory protein with potential as a biomarker in predicting colon cancer risk. However, little is known regarding its association with risk of colorectal adenomas, particularly by subtypes. We conducted a colonoscopy-based matched case-control study to assess whether elevated plasma CRP levels may be associated with colorectal adenoma risk and further whether this association may be modified by urinary prostaglandin E2 metabolite (PGE-M), a biomarker of systemic prostaglandin E2 production. Included in the study were 226 cases with a single small tubular adenoma, 198 cases with multiple small tubular adenomas, 283 cases with at least one advanced adenoma, and 395 polyp-free controls. No apparent association between CRP level and risk of single small tubular adenomas was found (ptrend = 0.59). A dose-response relationship with CRP level was observed for risk of either multiple small tubular adenomas (OR = 2.01, 95%CI = 1.10-3.68 for the highest versus lowest tertile comparison; ptrend = 0.03) or advanced adenomas (OR = 1.81, 95%CI = 1.10-2.96 for the highest versus lowest tertile comparison; ptrend = 0.02). In a joint analysis of CRP level and PGE-M, risk of multiple or advanced adenoma was greatest among those with highest levels of both CRP and PGE-M in comparison to those with low CRP and low PGE-M (OR = 3.72, 95%CI = 1.49-9.72). Our results suggest that elevated CRP, particularly in the context of concurrent elevated PGE-M, may be a biomarker of multiple or advanced adenoma risk in a screening age population. © 2015 Wiley Periodicals, Inc.

Calcium/magnesium intake ratio, but not magnesium intake, interacts with genetic polymorphism in relation to colorectal neoplasia in a two-phase study.

Some studies suggest that the calcium to magnesium ratio intakes modify the associations of calcium or magnesium with risk of colorectal adenoma, adenoma recurrence, and cancer. Parathyroid hormone (PTH) plays a key role in the regulation of homeostasis for both calcium and magnesium. We hypothesized that polymorphisms in PTH and 13 other genes may modify the association between the calcium/magnesium intake ratio and colorectal neoplasia risk. We conducted a two-phase study including 1336 cases and 2891 controls from the Tennessee Colorectal Polyp Study. In Phase I, we identified 19 SNPs that significantly interacted with the calcium/magnesium intake ratio in adenoma risk. In Phase II, rs11022858 in PTH was replicated. In combined analysis of phases I and II, we found high calcium/magnesium intake ratio tended to be associated with a reduced risk of colorectal adenoma (P for trend, 0.040) among those who carried the TT genotype in rs11022858. In stratified analyses, calcium intake (≥ 1000 mg/d) was significantly associated with 64% reduced adenoma risk (OR = 0.36 (95% CI : 0.18-0.74)) among those homozygous for the minor allele (TT genotype) (P for trend, 0.012), but not associated with risk in other genotypes (CC/TC). Conversely, we found that highest magnesium intake was significantly associated with 27% reduced risk (OR = 0.73 (95% CI : 0.54-0.97)) of colorectal adenoma (P for trend, 0.026) among those who possessed the CC/TC genotypes, particularly among those with the TC genotype, whereas magnesium intake was not linked to risk among those with the TT genotype. These findings, if confirmed, will help for the development of personalized prevention strategies for colorectal cancer. © 2015 Wiley Periodicals, Inc.