Metabolic factors and the risk of colorectal cancer by KRAS and BRAF mutation status

Factors related to energy metabolism and the metabolic syndrome, such as higher body mass index (BMI), blood glucose, or blood lipids, and blood pressure, are associated with an increased risk of colorectal cancer (CRC). However, CRC is a heterogeneous disease, developing through distinct pathways with differences in molecular characteristics and prognosis, and possibly also in risk factors. For subtypes defined by KRAS and BRAF mutation status, BMI is the only metabolic factor previously studied, with inconsistent findings. We investigated whether associations between BMI, blood glucose, blood lipids, and blood pressure and CRC risk differed by tumor KRAS and BRAF mutation status in 117,687 participants from two population-based cohorts within the Northern Sweden Health and Disease Study (NSHDS). Hazard ratios (HRs) for overall CRC and CRC subtypes by metabolic factors were estimated with Cox proportional hazards regression, using multiple imputation to handle missing exposure and tumor data. During a median follow-up of 15.6 years, we acquired 1,250 prospective CRC cases, of which 766 cases had complete baseline and molecular tumor data. Consistent with previous evidence, higher BMI, total cholesterol, triglyceride levels, and blood pressure were associated with an increased risk of overall CRC (HRs per 1 standard deviation increase: 1.07 to 1.12). These associations were similar regardless of CRC subtype by KRAS and BRAF mutation status (all p_{heterogeneity} > 0.05). The same was true for subtypes based on microsatellite instability status. Poor metabolic health may therefore be a universal mechanism for colorectal cancer, acting across multiple developmental pathways.     

Dietary intake of fiber,whole grains and risk of colorectal cancer: An updated analysis according to food sources,tumor location and molecular subtypes in two large US cohorts

Epidemiologic evidence relating fiber intake to colorectal cancer (CRC) remains inconclusive and data are limited on different food sources of fiber and heterogeneity by tumor subsite and molecular profile. We prospectively followed for CRC incidence 90,869 women from the Nurses’ Health Study (1980–2012) and 47,924 men from the Health Professionals Follow-up Study (1986–2012), who completed a validated food frequency questionnaire every 4 years. Cox proportional hazards regression was used to examine the associations with CRC risk for total, cereal, fruit and vegetable fiber and whole grains. We also assessed the associations according to tumor subsites (proximal colon, distal colon and rectum) and molecular markers (microsatellite instability, BRAF mutation, CpG island methylator phenotype and KRAS mutation). We documented 3,178 CRC cases during 3,685,903 person-years of follow-up in the NHS and HPFS. Intake of total dietary fiber was not associated with CRC risk after multivariable adjustment in either women (hazard ratio [HR] comparing extreme deciles, 1.17; 95% CI, 0.92–1.48, p_trend = 0.55) or men (HR, 0.90; 95% CI, 0.67–1.21, p_trend = 0.47). Higher intake of cereal fiber and whole grains was associated with lower CRC risk in men with an HR of 0.75 (95% CI, 0.57–1.00) and 0.72 (95% CI, 0.54–0.96), respectively. No heterogeneity was detected by tumor subsite or molecular markers (p_{heterogeneity} > 0.05). Higher intake of total dietary fiber within the range of a typical American diet is unlikely to substantially reduce CRC risk. The potential benefit of cereal fiber and whole grains in men warrants further confirmation.     

Association of apolipoprotein E polymorphisms and dietary factors in colorectal cancer

ApoE single nucleotide polymorphisms (SNPs) Cys112Arg (Epsilon-4), and Arg158Cys (Epsilon-2) have been implicated in cardiovascular and Alzheimer''s disease, but their role in colorectal cancer (CRC) has not been extensively studied. We investigated whether ApoE polymorphisms alone or in combination with dietary factors selectively contribute to mismatch-repair (MMR) proficient (microsatellite stable/low or MSS/L) vs deficient (microsatellite unstable or MSI-H) CRCs. We carried out a case–control study with 906 CRC cases and 911 unaffected controls to examine the associations between ApoE polymorphisms and dietary factors and assessed their contribution to MSS/L and MSI-H CRCs. We used unconditional logistic regression to evaluate the associations between ApoE SNPs, tumour MSI status, and dietary factors after adjusting for age and sex. All statistical tests were two-sided. No significant differences in ApoE genotype frequencies were observed between CRC cases and unaffected controls. We observed that increased dietary intake of total fat, saturated fat, cholesterol, and red meat was significantly associated with CRC. Among non-ApoE4 carriers, 2–4 and >4 red meat servings/week were associated with developing MSS/L CRC (OR=1.51, 95% CI 1.10–2.07 and OR=1.80, 95% CI 1.30–2.48, respectively), whereas among ApoE4 allele carriers, four or more red meat servings/week were associated with MSI-H CRC (OR=4.62, 95% CI 1.20–17.77) when compared with the controls. ApoE isoforms modulate the risk of MSI-H and MSS/L CRCs among high red meat consumers.     

Prospective study of NAT1 and NAT2 polymorphisms, tobacco smoking and meat consumption and risk of colorectal cancer

Heterocyclic amines in tobacco smoke and fried meat are activated or detoxified by N-acetyltransferases (NAT1 and NAT2). We identified 379 cases with colorectal cancer (CRC) and 769 sub-cohort members among a cohort of 57,000 members. There were no statistically significant associations between tobacco smoking, consumption of meat (red, processed and fried) and CRC risk. Preference for brown-dark pan-fried meat increased the CRC risk. NAT1 fast acetylators had a significantly higher risk of CRC than NAT1 slow acetylators, whereas NAT2 acetylator status did not affect the CRC risk. There were no statistically significant interactions between tobacco smoking and either NAT1 or NAT2 acetylator status in relation to CRC risk. However, smoking intensity increased CRC risk among carriers of both NAT1 and NAT2 fast. This indicates that N-acetylator status affects the relationship between smoking and CRC risk.     

Red blood cell folate and plasma folate are not associated with risk of incident colorectal cancer in the Women's Health Initiative observational study

The relationship between folate and colorectal cancer (CRC) risk is unclear. We investigated the association of two biomarkers of folate status, plasma folate and red blood cell (RBC) folate, with CRC risk using a nested case–control design in the Women's Health Initiative Observational Study. Postmenopausal women (n = 93,676) aged 50–79 years were enrolled in the Women's Health Initiative Observational Study (1993–1998). A fasting blood draw and extensive health, dietary and lifestyle data were collected upon enrollment. Through 2008, 988 incident CRC cases were reported and confirmed with medical records adjudication. Cases and controls were matched on age (±3 years), enrollment date (±1 year), race/ethnicity, blood draw date (±6 months) and hysterectomy status. Plasma and RBC folate were determined by radio assay. Folate biomarker values were divided into quartiles, and conditional logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CI) for the associations of folate with total CRC, by tumor site and by stage at diagnosis. Additional analyses examined whether risks varied across time periods corresponding to the United States folic acid fortification policy: prefortification (1994–1995), perifortification (1996–1997) and postfortification (1998). ORs for overall CRC risk comparing Q4 vs. Q1 were 0.91 (95% CI 0.67–1.24) and 0.91 (95% CI 0.67–1.23) for RBC and plasma folate, respectively. There were no changes in risk attributable to food supply fortification. These results do not support an overall association of folate with CRC risk and suggest that folic acid fortification of the US food supply did not alter the associations in these postmenopausal women.     

Dairy product consumption and risk of colorectal cancer in an older mediterranean population at high cardiovascular risk

Prospective studies have reported an inverse association between the consumption of total dairy products and milk and the risk of colorectal cancer (CRC). Nonetheless, there is little and inconsistent evidence regarding subtypes of dairy product and CRC risk. We assessed the associations between the consumption of total dairy products, their different subtypes and CRC risk in older Mediterranean individuals at high cardiovascular risk. We analyzed data from 7,216 men and women (55–80 years) without CRC at baseline from the PREvención con DIeta MEDiterránea study. Individuals were recruited between 2003 and 2009 and followed up until December 2012. At baseline and yearly thereafter, consumption of total and specific dairy products was assessed using a validated 137‐item food‐frequency questionnaire. Cox proportional hazards ratios (HRs) of CRC incidence were estimated for tertiles of mean consumption of dairy products during the follow‐up. During a median [interquartile range] follow‐up of 6.0 [4.4–7.3] years, we documented 101 incident CRC cases. In the multivariable‐adjusted models, HRs and 95% confidence intervals (CIs) of CRC for the comparison of extreme tertiles of total dairy product and low‐fat milk consumption were 0.55 (95% CI: 0.31–0.99; p‐trend = 0.037) and 0.54 (95% CI: 0.32–0.92; p‐trend = 0.022), respectively. No significant associations with other dairy products (whole‐fat and low‐fat dairy products; total, low‐fat and whole‐fat yogurt; cheese; total, low‐fat and whole‐fat milk; concentrated full‐fat dairy products, sugar‐enriched dairy products and fermented dairy products) were found. A high consumption of total dairy products and low‐fat milk was significantly associated with a reduced CRC risk.     

Folate,methionine, alcohol,and colorectal cancer in a prospective study of women in the United States

Objective: We investigated the associations of folate, methionine, and alcohol intake, as well as combinations of these factors, with risk of colorectal cancer (CRC). Methods: We assessed diet using a 62-item food-frequency questionnaire among 45,264 women in the Breast Cancer Detection Demonstration Project (BCDDP) Follow-up Study. After an average of 8.5 years of follow-up, 490 cases of CRC were identified. Results: Dietary folate showed only a slight inverse association with the risk of CRC (RR = 0.86, 95% CI 0.65–1.13 for high vs. low quintile, p for trend = 0.14), and the association for total folate was null. Consuming more than two servings of alcohol per day was only slightly associated with CRC in this cohort (RR = 1.16, 95% CI 0.63–2.14). Combinations of high alcohol and low total folate did not result in a higher risk of CRC. There was no association between methionine and colorectal cancer. Conclusions: This study shows limited association between alcohol intake and CRC. The non-association of total folate and methionine with CRC, and the null results from the combined folate and alcohol analyses, suggest that what effect alcohol may have on CRC is unrelated to the methyl-group metabolism pathway.     

Dietary and biomarker estimates of fatty acids and risk of colorectal cancer

The associations between intake of or circulating fatty acids and risk of colorectal cancer (CRC) are unclear. We examined prospectively the associations between dietary or biomarker fatty acids and CRC. For 41,514 men and women, aged 40–69 years, baseline (1990–94) dietary intakes of fatty acids were estimated using a food frequency questionnaire and plasma phospholipid (PPL) fatty acids were measured for 4,205 participants including 395 CRC cases, according to a case‐cohort design. Hazard ratios were computed using Cox regression adjusting for education, alcohol intake, smoking status, physical activity and total energy intake; and stratified for gender, ethnicity and family history of cancer, with age as the time scale. We assessed the heterogeneity of associations with colon and rectal cancers. PPL saturated fatty acids (SFAs) were positively associated with CRC risk, while total n‐3 polyunsaturated fatty acids (PUFA) and long chain marine n‐3 PUFAs showed inverse associations, significant only for 22:5 n‐3. No significant associations were observed for dietary fatty acid intakes but positive associations with CRC of borderline significance were seen for both dietary and PPL linoleic acid. Positive associations with dietary palmitic acid (16:0), MUFAs and n‐6 PUFAs were seen for rectal but not colon cancers. PPL 22:6 n‐3 was inversely associated with rectal cancer. Limiting intakes of SFAs and MUFAs could be assisted by following existing guidelines to limit red and processed meats which are important sources in the Australian diet. Our observations regarding linoleic acid should be examined further.     

Biomarkers of inflammation are associated with colorectal cancer risk in women but are not suitable as early detection markers

Initial studies have investigated the association between inflammation and colorectal cancer (CRC) using C‐reactive protein (CRP) as a proinflammatory biomarker and have noted inconsistent results among women. We here report the findings from a large prospective study with repeat measurements of CRP, as well as serum amyloid A (SAA), an additional biomarker of inflammation, and risk of CRC. In the Women's Health Initiative Observational Study, we examined associations of CRP and SAA with CRC using repeat assessments (baseline and 3‐year follow‐up) among 953 matched case–control pairs for CRP and 966 pairs for SAA. Multivariate‐adjusted conditional‐logistic regression models were used with two‐sided tests of significance. Receiver operating characteristic (ROC) curve analysis assessed their utility as early detection markers. Colon cancer risk (odds ratio [OR] and 95% confidence intervals) among women in the highest quintiles of CRP or SAA compared to those in the lowest quintiles was OR_colon/CRP = 1.37 (0.95–1.97, p‐trend = 0.04) and OR_colon/SAA = 1.26 (0.88–1.80, p‐trend = 0.10), respectively. Women with elevated concentrations of both CRP and SAA had an increased risk of OR_colon = 1.50 (1.12–2.00, p‐value = 0.006) compared to those with low concentrations. No positive associations were observed with rectal cancer and weaker associations for CRC overall. Temporal changes in biomarkers more than 3 years did not predict risk. The area under the 6‐month ROC curve for CRP+SAA was 0.62 (95% confidence interval = 0.55–0.68). Elevated inflammatory biomarkers are associated with an increased risk of CRC, mainly colon cancer. Nevertheless, changes in the biomarkers over time do not suggest that they merit consideration as early detection markers for CRC.     

Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer

While elevated blood cholesterol has been associated with an increased risk of colorectal cancer (CRC) in observational studies, causality is uncertain. Here we apply a Mendelian randomisation (MR) analysis to examine the potential causal relationship between lipid traits and CRC risk. We used single nucleotide polymorphisms (SNPs) associated with blood levels of total cholesterol (TC), triglyceride (TG), low‐density lipoprotein (LDL), and high‐density lipoprotein (HDL) as instrumental variables (IV). We calculated MR estimates for each risk factor with CRC using SNP‐CRC associations from 9,254 cases and 18,386 controls. Genetically predicted higher TC was associated with an elevated risk of CRC (odds ratios (OR) per unit SD increase = 1.46, 95% confidence interval [CI]: 1.20–1.79, p = 1.68 × 10⁻⁴). The pooled ORs for LDL, HDL, and TG were 1.05 (95% CI: 0.92–1.18, p = 0.49), 0.94 (95% CI: 0.84–1.05, p = 0.27), and 0.98 (95% CI: 0.85–1.12, p = 0.75) respectively. A genetic risk score for 3‐hydoxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR ) to mimic the effects of statin therapy was associated with a reduced CRC risk (OR = 0.69, 95% CI: 0.49–0.99, p = 0.046). This study supports a causal relationship between higher levels of TC with CRC risk, and a further rationale for implementing public health strategies to reduce the prevalence of hyperlipidaemia.     

Dietary fatty acids and colorectal cancer risk in men: A report from the Shanghai Men's Health Study and a meta‐analysis

Evidence from animal models suggests that dietary fatty acids have both anticancer and tumor‐promoting effects. Whether dietary fatty acids are associated with colorectal cancer (CRC) in humans remains inconclusive. We investigated associations between dietary fatty acids and risk of CRC among 59 986 men who participated in the Shanghai Men's Health Study (SMHS), an ongoing population‐based prospective cohort study. We identified 876 incident CRC cases in the SMHS during a mean follow‐up of 9.8 years. Associations between dietary fatty acid intake and CRC risk were evaluated by Cox proportional hazard regression analyses. Consumption of saturated fatty acids (SFA), monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) was not significantly associated with CRC risk. Multivariate hazard ratios (HRs) and respective 95% confidence intervals (CIs) for Quartile 4 vs Quartile 1 were 0.92 (0.74‐1.14; P_trend = 0.47) for SFA, 0.95 (0.79‐1.16; P_trend = 0.74) for MUFA and 1.18 (0.95‐1.46; P_trend = 0.21) for PUFA. No significant associations were found for total n‐6 PUFA or total n‐3 PUFA. Additionally, we performed a meta‐analysis to summarize results from the present study and 28 reports from 26 additional cohorts, which supported the overall null association between dietary fatty acid intake and CRC risk among men. Docosahexanoic acid and eicosapentaenoic acid were associated with 11% to 12% reduced risk, and linoleic acid a 19% increased risk, of CRC in the meta‐analysis of combined sexes. In conclusion, this population‐based prospective study and meta‐analysis of cohort studies found little evidence that dietary fatty acid intake was associated with risk of CRC in men.     

Associations of alcohol intake,smoking, physical activity and obesity with survival following colorectal cancer diagnosis by stage,anatomic site and tumor molecular subtype

The influence of lifestyle factors on survival following a diagnosis of colorectal cancer (CRC) is not well established. We examined associations between lifestyle factors measured before diagnosis and CRC survival. The Melbourne Collaborative Cohort Study collected data on alcohol intake, cigarette smoking and physical activity, and body measurements at baseline (1990–1994) and wave 2 (2003–2007). We included participants diagnosed to 31 August 2015 with incident stages I–III CRC within 10‐years post exposure assessment. Information on tumor characteristics and vital status was obtained. Tumor DNA was tested for microsatellite instability (MSI) and somatic mutations in oncogenes BRAF (V600E) and KRAS. We estimated hazard ratios (HRs) for associations between lifestyle factors and overall and CRC‐specific mortality using Cox regression. Of 724 eligible CRC cases, 339 died (170 from CRC) during follow‐up (average 9.0 years). Exercise (non‐occupational/leisure‐time) was associated with higher CRC‐specific survival for stage II (HR = 0.25, 95% CI: 0.10–0.60) but not stages I/III disease (p for interaction = 0.01), and possibly for colon and KRAS wild‐type tumors. Waist circumference was inversely associated with CRC‐specific survival (HR = 1.25 per 10 cm increment, 95% CI: 1.08–1.44), independent of stage, anatomic site and tumor molecular status. Cigarette smoking was associated with lower overall survival, with suggestive evidence of worse survival for BRAF mutated CRC, but not with CRC‐specific survival. Alcohol intake was not associated with survival. Survival did not differ by MSI status. We have identified pre‐diagnostic predictors of survival following CRC that may have clinical and public health relevance.     

Vitamin B2 intake and colorectal cancer risk; results from the Nurses' Health Study and the Health Professionals Follow‐Up Study cohort

Vitamin B2 serves as a cofactor to enhance one‐carbon metabolism, maintain mucous membranes, and has been implicated in lowering colorectal cancer (CRC) risk. However, few prospective studies have examined the association between vitamin B2 intake and CRC. In this study, we estimated the associations between vitamin B2 intake and CRC risk using the Nurses' Health Study (NHS) and the Health Professionals Follow‐Up Study (HPFS) cohorts. Vitamin B2 intake was measured by a validated food frequency questionnaire every 4 years. Among 100,033 women in the NHS and 44,007 men in the HPFS we documented a total of 3,037 incident CRC cases (2,093 women and 944 men) during 24–26 years of follow‐up until 2010. Intakes of total (from food and supplements), dietary (from food only), and supplemental vitamin B2 were inversely related to CRC risk in age‐adjusted analysis in NHS. However, the association was attenuated and no longer statistically significant in multivariate analysis (p‐trend ≥0.08). The pooled multivariate relative risks (95% confidence interval) comparing individuals in the extreme quintiles of intakes were 0.93 (0.81–1.06) for total vitamin B2, 0.89 (0.61–1.28) for dietary vitamin B2 and 0.94 (0.81–1.08) for supplemental vitamin B2. These associations of total vitamin B2 intake were similar for risk of CRC with varying lag‐time periods (0–4, 4–8, 8–12 or 12–16 years), for risk of CRC subtypes by tumor location, and across strata of intake of folate or alcohol. Our prospective data do not support a beneficial role of vitamin B2 intake in lowering incidence of CRC.     

Contribution of common monoallelic MUTYH gene variants in German patients with familial colorectal cancer

Mutations of the base excision repair gene MUTYH have been reported as underlying genetic defects in autosomal-recessive familial adenomatous polyposis (FAP). Our aim was to determine the frequency of the most common mutations (p.Tyr165Cys and p.Gly382Asp) in patients with strong evidence for familial colorectal cancer (fCRC). METHODS: We recruited 93 patients with fCRC but no indication for monogenic CRC syndromes (FAP, hereditary non-polyposis colorectal cancer). Tumors showed regular expression of MLH1 and MSH2, and microsatellite instability was excluded. Sporadic CRC patients (n=93) and 'hyper-normal' controls without any adenomas in screening colonoscopies (n=93) were studied for comparison. RESULTS: In the fCRC group, two patients carried biallelic mutations (p.Tyr165Cys/p.Tyr165Cys, p.Tyr165Cys/p.Gly382Asp), while four patients displayed a heterozygous genotype (3 x p.Tyr165Cys/wt, 1 x p.Gly382Asp/wt). In contrast, only two p.Gly382Asp/wt patients were detected in the sporadic CRC group and one p.Gly382Asp carrier was observed in 'hyper-normal' controls, and the p.Tyr165Cys risk allele was absent in both control groups. Association tests demonstrated an increased odds ratio (OR) for CRC in carriers of the p.Tyr165Cys risk allele among fCRC patients, as compared to sporadic CRC patients and controls (OR 2.38; p=0.03). CONCLUSIONS: In our cohort the prevalence of pathogenic MUTYH mutations was increased among fCRC patients compared to sporadic CRC and controls. The association of the p.Tyr165Cys mutation with fCRC indicates that this variant represents a susceptibility factor in a defined subgroup of CRC patients with a positive family history.     

Saturated fatty acid intake,genetic risk and colorectal cancer incidence: A large-scale prospective cohort study

Previous investigations mainly focused on the associations of dietary fatty acids with colorectal cancer (CRC) risk, which ignored gene-environment interaction and mechanisms interpretation. We conducted a case-control study (751 cases and 3058 controls) and a prospective cohort study (125 021 participants) to explore the associations between dietary fatty acids, genetic risks, and CRC. Results showed that high intake of saturated fatty acid (SFA) was associated with a higher risk of CRC than low SFA intake (HR =1.22, 95% CI:1.02-1.46). Participants at high genetic risk had a greater risk of CRC with the HR of 2.48 (2.11-2.91) than those at low genetic risk. A multiplicative interaction of genetic risk and SFA intake with incident CRC risk was found (P_Interaction = 7.59 × 10⁻²⁰), demonstrating that participants with high genetic risk and high SFA intake had a 3.75-fold greater risk of CRC than those with low genetic risk and low SFA intake. Furthermore, incorporating PRS and SFA into traditional clinical risk factors improved the discriminatory accuracy for CRC risk stratification (AUC from 0.706 to 0.731). Multi-omics data showed that exposure to SFA-rich high-fat dietary (HFD) can responsively induce epigenome reprogramming of some oncogenes and pathological activation of fatty acid metabolism pathway, which may contribute to CRC development through changes in gut microbiomes, metabolites, and tumor-infiltrating immune cells. These findings suggest that individuals with high genetic risk of CRC may benefit from reducing SFA intake. The incorporation of SFA intake and PRS into traditional clinical risk factors will help improve high-risk sub-populations in individualized CRC prevention.     

Meta-analysis of 16 studies of the association of alcohol with colorectal cancer

Alcohol consumption is an established risk factor for colorectal cancer (CRC). However, while studies have consistently reported elevated risk of CRC among heavy drinkers, associations at moderate levels of alcohol consumption are less clear. We conducted a combined analysis of 16 studies of CRC to examine the shape of the alcohol–CRC association, investigate potential effect modifiers of the association, and examine differential effects of alcohol consumption by cancer anatomic site and stage. We collected information on alcohol consumption for 14,276 CRC cases and 15,802 controls from 5 case-control and 11 nested case-control studies of CRC. We compared adjusted logistic regression models with linear and restricted cubic splines to select a model that best fit the association between alcohol consumption and CRC. Study-specific results were pooled using fixed-effects meta-analysis. Compared to non-/occasional drinking (≤1 g/day), light/moderate drinking (up to 2 drinks/day) was associated with a decreased risk of CRC (odds ratio [OR]: 0.92, 95% confidence interval [CI]: 0.88–0.98, p = 0.005), heavy drinking (2–3 drinks/day) was not significantly associated with CRC risk (OR: 1.11, 95% CI: 0.99–1.24, p = 0.08) and very heavy drinking (more than 3 drinks/day) was associated with a significant increased risk (OR: 1.25, 95% CI: 1.11–1.40, p < 0.001). We observed no evidence of interactions with lifestyle risk factors or of differences by cancer site or stage. These results provide further evidence that there is a J-shaped association between alcohol consumption and CRC risk. This overall pattern was not significantly modified by other CRC risk factors and there was no effect heterogeneity by tumor site or stage.     

Lifestyle factors and risk of sporadic colorectal cancer by microsatellite instability status: a systematic review and meta-analyses

IntroductionThe association of lifestyle factors with molecular pathological subtypes of colorectal cancer (CRC), such as microsatellite instability (MSI), could provide further knowledge about the colorectal carcinogenic process. The aim of this review was to evaluate possible associations between lifestyle factors and risk of sporadic CRC by MSI status.MethodsPubMed and Web of Science were searched for studies investigating the association between alcohol, body mass index, dietary fiber, hormone replacement therapy (HRT), non-steroidal anti-inflammatory drugs, physical activity, red meat, smoking, or statin use, with MSI-high (MSI-H) and microsatellite stable (MSS) CRC. Meta-analyses were carried out to calculate summary relative risks (sRR).ResultsOverall, 31 studies reporting on the association between lifestyle factors and CRC according to MSI status were included in this review. Ever smoking was associated with MSI-H (sRR = 1.62; 95% CI: 1.40–1.88) and MSS/MSI-low CRC (sRR = 1.10; 95% CI: 1.01–1.20), but the association was significantly stronger for MSI-H CRC. The use of HRT was associated with a 20% decrease (sRR = 0.80; 95% CI: 0.73–0.89) in the risk of MSS CRC, but was not associated with MSI-H CRC. An increase in body mass index per 5 kg/m² was equally associated with MSS and MSI-H CRC (sRR = 1.22, in both cases), but was statistically significant for MSS CRC only (95% CI: 1.11–1.34 and 0.94–1.58, respectively). Limited evidence for associations between other lifestyle factors and CRC by MSI status exists.ConclusionsLifestyle factors, such as HRT and smoking are differentially associated with the risk of MSI-H and MSS CRC. Further research on associations of lifestyle factors and CRC subtypes is necessary to provide a better understanding of the CRC disease pathway.     

Serology of Streptococcus gallolyticus subspecies gallolyticus and its association with colorectal cancer and precursors

Streptococcus gallolyticus subspecies gallolyticus (SGG) is potentially associated with colorectal cancer (CRC) and its precursors. A previous case‐control study measured antibody responses to SGG pilus proteins Gallo2178 and Gallo2179 and identified significant associations with a small fraction of CRC cases. We aimed at replicating and expanding these findings in an independent study including additional SGG antigens and explored the association with precancerous lesions. We applied multiplex serology to measure antibodies to eleven SGG proteins in serum samples of a screening colonoscopy trial (BliTz study) including participants diagnosed with either non‐advanced adenoma (NAA, n = 30), advanced adenoma (AA, n = 100), CRC (n = 50) or controls (n = 228). In addition, we analyzed CRC samples (n = 318) from patients recruited in a clinical setting (DACHSplus study). The association of antibody responses to SGG pilus proteins Gallo2178 and Gallo2179 with CRC was replicated with 4% positive DACHSplus cases compared to 0% positive BliTz controls. Positivity to two or more proteins of a newly defined panel of six SGG markers was significantly associated with CRC in the DACHSplus study (OR: 1.81, 95% CI: 1.07–3.06). Odds for CRC, AA and NAA in the BliTz study were also increased with antibody responses to SGG, and the association was significant for NAA (OR: 2.98, 95% CI: 1.18–7.57). Antibody responses to SGG are associated with CRC and its precursors. The newly identified SGG six‐marker panel and associations found with precancerous lesions should be further explored.     

Lack of association between the hOGG1 Ser326Cys polymorphism and breast cancer risk: evidence from 11 case–control studies

The functional Ser326Cys polymorphism in the human 8-oxogunaine DNA glycosylase (hOGG1) gene has been implicated in breast cancer risk. However, the published findings are inconsistent. We therefore performed a meta-analysis to investigate this relationship. Eleven published case–control studies, including 6,804 breast cancer cases and 6,725 controls were identified. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association. Overall, no significant associations between the hOGG1 Ser326Cys polymorphism and breast cancer risk were found for Cys/Cys versus Ser/Ser (OR = 1.07, 95% CI: 0.94–1.20), Ser/Cys versus Ser/Ser (OR = 0.99, 95% CI: 0.91–1.07), Cys/Cys + Ser/Cys versus Ser/Ser (OR = 1.00, 95% CI = 0.93–1.08), and Cys/Cys versus Ser/Cys + Ser/Ser (OR = 1.07, 95% CI: 0.97–1.18). In the stratified analysis by ethnicity, source of controls, and menopausal status, significant associations were still not observed in all genetic models. Taken together, the results suggest that the hOGG1 Ser326Cys polymorphism is not associated with breast cancer risk.     

Prediagnosis body mass index and waist–hip circumference ratio in association with colorectal cancer survival

The association of obesity on survival among patients with colorectal cancer (CRC) has not been well characterized. We investigated the association of prediagnostic body mass index (BMI)/waist–hip ratio (WHR) and total/cause‐specific mortality in CRC patients. Our study included 1,452 patients who participated in two large cohort studies and were diagnosed with CRC during follow‐up period. Participants were measured for anthropometrics and interviewed to collect relevant information at baseline, prior to any cancer diagnosis. Data on site‐specific cancer incidence and cause‐specific mortality were obtained via in‐person surveys and annual record linkage with cancer and vital statistics registries. Cox proportional hazard models were used to evaluate the associations of BMI and WHR with survival. A total of 547 participants died during the follow‐up period, including 499 who died of CRC. Relative to normal BMI (18.5 to <25.0 kg/m²), obesity (BMI ≥ 30 kg/m²) was associated with increased mortality resulting from all causes [hazard ratio (HR) = 1.5, 95% confidence interval (CI): 1.1–2.1] and CRC (HR = 1.5, 95% CI: 1.1–2.1). Elevated risk of death was also found among underweight patients (BMI < 18.5 kg/m²), although not all risk estimates were statistically significant. Overweight BMI (25.0 to <30.0 kg/m²) was not associated with risk of death among CRC patients, nor was WHR. In conclusion, prediagnostic BMI was associated with survival among CRC patients following a U‐shape pattern; obesity was associated with high mortality after CRC diagnosis. These findings provide support for maintaining healthy weight to improve the survival of CRC patients.