Periodontal pathogens are a risk factor of oral cavity squamous cell carcinoma,independent of tobacco and alcohol and human papillomavirus

Over the past decade, there has been a change in the epidemiology of oral cavity squamous cell cancer (OC-SCC). Many new cases of OC-SCC lack the recognized risk factors of smoking, alcohol and human papilloma virus. The aim of this study was to determine if the oral microbiome may be associated with OC-SCC in nonsmoking HPV negative patients. We compared the oral microbiome of HPV-negative nonsmoker OC-SCC(n = 18), premalignant lesions(PML) (n = 8) and normal control patients (n = 12). Their oral microbiome was sampled by oral wash and defined by 16S rRNA gene sequencing. We report that the periodontal pathogens Fusobacterium, Prevotella, Alloprevotella were enriched while commensal Streptococcus depleted in OC-SCC. Based on the four genera plus a marker genus Veillonella for PML, we classified the oral microbiome into two types. Gene/pathway analysis revealed a progressive increase of genes encoding HSP90 and ligands for TLRs 1, 2 and 4 along the controls→PML → OC-SCC progression sequence. Our findings suggest an association between periodontal pathogens and OC-SCC in non smoking HPV negative patients.     

Prospective evaluation of antibody response to Streptococcus gallolyticus and risk of colorectal cancer

The gut microbiome is increasingly implicated in colorectal cancer (CRC) development. A subgroup of patients diagnosed with CRC show high antibody responses to Streptococcus gallolyticus subspecies gallolyticus (SGG). However, it is unclear whether the association is also present pre‐diagnostically. We assessed the association of antibody responses to SGG proteins in pre‐diagnostic serum samples with CRC risk in a case–control study nested within a prospective cohort. Pre‐diagnostic serum samples from 485 first incident CRC cases (mean time between blood draw and diagnosis 3.4 years) and 485 matched controls in the European Prospective Investigation into Nutrition and Cancer (EPIC) study were analyzed for antibody responses to 11 SGG proteins using multiplex serology. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using multivariable conditional logistic regression models. Antibody positivity for any of the 11 SGG proteins was significantly associated with CRC risk with 56% positive controls compared to 63% positive cases (OR: 1.36, 95% CI: 1.04–1.77). Positivity for two or more proteins of a previously identified SGG 6‐marker panel with greater CRC‐specificity was also observed among 9% of controls compared to 17% of CRC cases, corresponding to a significantly increased CRC risk (OR: 2.17, 95% CI: 1.44–3.27). In this prospective nested case–control study, we observed a positive association between antibody responses to SGG and CRC development in serum samples taken before evident disease onset. Further work is required to establish the possibly etiological significance of these observations and whether SGG serology may be applicable for CRC risk stratification.     

Oral health and risk of colorectal cancer: results from three cohort studies and a meta-analysis

BackgroundWhile studies have shown that poor oral health status may increase the risk of cancer, evidence of a specific association with the risk of colorectal cancer (CRC) is inconclusive. We evaluated the association between oral health and CRC risk using data from three large cohorts: the Shanghai Men's Health Study (SMHS), the Shanghai Women's Health Study (SWHS), and the Southern Community Cohort Study (SCCS), and carried out a meta-analysis of results from other relevant published studies.Patients and methodsThis study applied a nested case–control study design and included 825 cases/3298 controls from the SMHS/SWHS and 238 cases/2258 controls from the SCCS. The association between oral health status (i.e. tooth loss/tooth decay) and CRC risk was assessed using conditional logistic regression models. A meta-analysis was carried out based on results from the present study and three published studies.ResultsWe found that tooth loss was not associated with increased risk of CRC. ORs and respective 95% CIs associated with loss of 1–5, 6–10, and >10 teeth compared with those with full teeth are 0.87 (0.69–1.10), 0.93 (0.70–1.24), and 0.85 (0.66–1.11) among SMHS/SWHS participants; and 1.13 (0.72–1.79), 0.87 (0.52–1.43), and 1.00 (0.63–1.58) for those with loss of 1–4, 5–10, and >10 teeth among SCCS participants. Data regarding tooth decay were available in the SCCS, but were not associated with CRC risk. Meta-analysis confirmed the null association between tooth loss/periodontal disease and CRC risk (OR 1.05, 95% CI 0.86–1.29).ConclusionIn this analysis of three cohorts and a meta-analysis, we found no evidence supporting an association between oral health and CRC risk.     

Circulating sex hormone levels and colorectal cancer risk in Japanese postmenopausal women: The JPHC nested case–control study

Previous epidemiological studies evaluated endogenous sex hormone levels and colorectal cancer (CRC) risk have yielded inconsistent results. Also, it is unknown if consumption of dietary isoflavones may influence the endogenous sex hormones and CRC relationships. We conducted a nested case–control study within the JPHC Study Cohort II wherein 11,644 women provided blood samples at the 5-year follow-up survey. We selected two matched controls for each case from the cohort (185 CRC cases and 361 controls). Multivariable conditional logistic regression was used to estimate odds ratios (ORs), 95% confidence intervals (CIs) for the association between circulating sex hormone levels and CRC risk. Comparing extreme tertiles, circulating testosterone levels were positively associated with CRC risk (OR = 2.10, 95% CI = 1.11–3.99, p for trend = 0.03). Levels of estradiol, SHBG, and progesterone were not associated with CRC risk. In a subgroup analysis by dietary isoflavone intake, SHBG levels were positively associated with CRC risk among those with low total isoflavone intake (p for trend = 0.03), with a statistically nonsignificant inverse association among those with high total isoflavone intake (p for trend = 0.22; p for interaction = 0.002). Endogenous levels of testosterone were positively associated with CRC among postmenopausal women. The association of endogenous SHBG with CRC development may be altered by the level of dietary isoflavone intake.     

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.     

Endogenous sex hormones and colorectal cancer survival among men and women

Although previous studies have suggested a potential role of sex hormones in the etiology of colorectal cancer (CRC), no study has yet examined the associations between circulating sex hormones and survival among CRC patients. We prospectively assessed the associations of prediagnostic plasma concentrations of estrone, estradiol, free estradiol, testosterone, free testosterone and sex hormone-binding globulin (SHBG) with CRC-specific and overall mortality among 609 CRC patients (370 men and 239 postmenopausal women not taking hormone therapy at blood collection) from four U.S. cohorts. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard regression. We identified 174 deaths (83 CRC-specific deaths) in men and 106 deaths (70 CRC-specific deaths) in women. In men, higher circulating level of free testosterone was associated with lower risk of overall (the highest vs. lowest tertiles, HR = 0.66, 95% CI, 0.45–0.99, p_trend = 0.04) and possibly CRC-specific mortality (HR = 0.73, 95% CI, 0.41–1.29, p_trend = 0.27). We generally observed nonsignificant inverse associations for other sex steroids, and a positive association for SHBG with CRC-specific mortality among male patients. In women, however, we found a suggestive positive association of estrone with overall (HR = 1.54, 95% CI, 0.92–2.60, p_trend = 0.11) and CRC-specific mortality (HR = 1.96, 95% CI, 1.01–3.84, p_trend = 0.06). Total estradiol, free estradiol and free testosterone were generally suggestively associated with higher risk of mortality among female patients, although not statistically significant. These findings implicated a potential role of endogenous sex hormones in CRC prognosis, which warrant further investigation.     

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.     

Inflammatory potential of the diet and risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition study

Proinflammatory diets are associated with risk of developing colorectal cancer (CRC), however, inconsistencies exist in subsite- and sex-specific associations. The relationship between CRC and combined lifestyle-related factors that contribute toward a low-grade inflammatory profile has not yet been explored. We examined the association between the dietary inflammatory potential and an inflammatory profile and CRC risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. This cohort included 476,160 participants followed-up of 14 years and 5,991 incident CRC cases (3,897 colon and 2,094 rectal tumors). Dietary inflammatory potential was estimated using an Inflammatory Score of the Diet (ISD). An Inflammatory Profile Score (IPS) was constructed, incorporating the ISD, physical activity level and abdominal obesity. The associations between the ISD and CRC and IPS and CRC were assessed using multivariable regression models. More proinflammatory diets were related to a higher CRC risk, particularly for colon cancer; hazard ratio (HR) for highest versus lowest ISD quartile was 1.15 (95% confidence interval [CI] 1.04–1.27) for CRC, 1.24 (95% CI 1.09–1.41) for colon cancer and 0.99 (95% CI 0.83–1.17) for rectal cancer. Associations were more pronounced in men and not significant in women. The IPS was associated with CRC risk, particularly colon cancer among men; HRs for the highest versus lowest IPS was 1.62 (95% CI 1.31–2.01) for colon cancer overall and 2.11 (95% CI 1.50–2.97) for colon cancer in men. Our study shows that more proinflammatory diets and a more inflammatory profile are associated with higher risk of CRC, principally colon cancer and in men.     

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.     

Current evidence on the relationship between SNP309 polymorphism in the MDM2 gene and colorectal cancer risk

It has been demonstrated that MDM2 is a well-established negative regulator of the p53 protein and might be associated with a significantly earlier age of onset of several tumors, including colorectal cancer (CRC). In recent years, a T to G substitution (SNP309) in the promoter of MDM2 has been extensively studied as a potential CRC risk factor; however, the results are inconsistent. To derive a more precise estimation of association between MDM2 SNP309 polymorphism and CRC risk, we conducted a meta-analysis of 11 studies with 4,050 CRC cases and 3,688 controls. For MDM2 SNP309 polymorphism, no obvious associations were found for all genetic models when all studies were pooled into the meta-analysis. In the subgroup analyses by ethnicity, source of controls, and Hardy–Weinberg equilibrium (HWE) in controls, a significantly increased risk was observed among Asians (heterozygous model: odds ratio (OR)?=?1.21, 95 % confidence interval (CI)?=?1.06–1.39, P?=?0.005), population-based studies (heterozygous model: OR?=?1.17, 95 % CI?=?1.02–1.34, P?=?0.027), and among studies without the HWE (recessive model: OR?=?1.42, 95 % CI?=?1.03–1.94, P?=?0.030). When excluding three studies deviated from HWE, the significant results were also observed for heterozygous model in overall population (OR?=?1.16, 95 % CI?=?1.02–1.31, P?=?0.020). No publication bias was found in the present study. In conclusion, this meta-analysis suggests that MDM2 SNP309 polymorphism was associated with CRC susceptibility, especially among Asians. Further research is needed to assess possible gene–gene or gene–environment–lifestyle interactions on 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.     

One-carbon metabolite ratios as functional B-vitamin markers and in relation to colorectal cancer risk

One-carbon metabolism biomarkers are easily measured in plasma, but analyzing them one at a time in relation to disease does not take into account the interdependence of the many factors involved. The relative dynamics of major one-carbon metabolism branches can be assessed by relating the functional B-vitamin marker total homocysteine (tHcy) to transsulfuration (total cysteine) and methylation (creatinine) outputs. We validated the ratios of tHcy to total cysteine (Hcy:Cys), tHcy to creatinine (Hcy:Cre) and tHcy to cysteine to creatinine (Hcy:Cys:Cre) as functional markers of B-vitamin status. We also calculated the associations of these ratios to colorectal cancer (CRC) risk. Furthermore, the relative contribution of potential confounders to the variance of the ratio-based B-vitamin markers was calculated by linear regression in a nested case–control study of 613 CRC cases and 1,190 matched controls. Total B-vitamin status was represented by a summary score comprising Z-standardized plasma concentrations of folate, cobalamin, betaine, pyridoxal 5′-phosphate and riboflavin. Associations with CRC risk were estimated using conditional logistic regression. We found that the ratio-based B-vitamin markers all outperformed tHcy as markers of total B-vitamin status, in both CRC cases and controls. In addition, associations with CRC risk were similar for the ratio-based B-vitamin markers and total B-vitamin status (approximately 25% lower risk for high vs. low B-vitamin status). In conclusion, ratio-based B-vitamin markers were good predictors of total B-vitamin status and displayed similar associations as total B-vitamin status with CRC risk. Since tHcy and creatinine are routinely clinically analyzed, Hcy:Cre could be easily implemented in clinical practice.     

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.     

Evaluation of genetic variants in association with colorectal cancer risk and survival in Asians

Genome‐wide association studies (GWAS) have identified over 40 genetic loci associated with colorectal cancer (CRC) risk. The association of single nucleotide polymorphisms (SNPs) at these loci with CRC risk and survival has not been adequately evaluated in East Asians. GWAS‐identified CRC risk variants were used to construct weighted genetic risk scores (GRSs). We evaluated these GRSs in association with CRC risk in 3,303 CRC cases and 3,553 controls using logistic regression models. Associations with overall and CRC‐specific survival were assessed in 731 CRC patients using Cox regression models. The association between the GRSs (overall and Asian‐specific) and CRC risk was approximately twofold (highest vs . lowest quintile), and the shape of the dose–response was linear (p _trend = 1.24 × 10^?13 and 3.02 × 10^?14 for overall GRS and Asian‐specific GRS, respectively). The association of the GRS with CRC risk was stronger among those with a family history of CRC (p _interaction = 0.007). Asian‐specific GRS using previously reported survival SNPs increased risk for mortality and the shape of the dose–response was linear for CRC‐specific and all‐cause mortality (p _trend = 0.01 and 0.006, respectively). Furthermore, the minor alleles of rs6983267 and rs1957636 were associated with worse CRC‐specific and overall survival. We show that GRSs constructed using GWAS‐identified common variants are strongly associated with CRC risk in Asians. We confirm previous findings for the possible association between some SNPs with survival, and provide evidence for two additional CRC risk variants that may be related to CRC survival.     

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.     

Consumption of meat,traditional and modern processed meat and colorectal cancer risk among the Moroccan population: A large-scale case–control study

The current study aimed to investigate the relationship between red and white meat subtypes, processed meat (divided into traditional “Khlii, Kaddid” and industrially processed meat) and colorectal cancer (CRC) risk, considering CRC subsites, in Moroccan adults. A case–control study was conducted including 2,906 matched case–control pairs recruited from the five largest university hospitals in Morocco. Dietary data were collected through a validated Food Frequency Questionnaire (FFQ). Multivariable odds ratios (OR) and 95% confidence intervals (CI), for the association of CRC risk with meat consumption (high vs. low intake), were estimated using conditional logistic regression models, adjusted for relevant confounding variables. Overall, consumption of red meat was positively associated with colon cancer and CRC risk (OR = 1.23, 95% CI = 1.05–1.44; OR = 1.14, 95% CI = 1.02–1.27), respectively. In contrast, no significant association was observed between the consumption of red meat and rectal cancer risk (OR = 1.05, 95% = 0.90–1.23). Interestingly, while processed meat from industrial processes was positively associated with colon cancer, rectal cancer and CRC (OR = 1.61, 95% CI = 1.27–2.04; OR = 1.73, 95% CI = 1.34–2.23; OR = 1.67, 95% CI = 1.41–1.98), processed meat prepared using traditional methods was inversely associated with colon cancer and CRC risk (OR = 0.74, 95% CI = 0.57–0.98; OR = 0.77, 95% CI = 0.64–0.93), respectively. Furthermore, positive associations were observed between poultry intake and colon cancer risk among men (OR = 1.27, 95% CI = 1.01–1.59). Our study showed similar associations between the consumption of red meat and CRC risk in Morocco as in developed countries, while inverse associations were found for traditionally processed meat products. This is the first study to investigate the differential effects of traditional vs. westernized processed meat products in a developing country. Other studies are needed to confirm these findings and to understand the physiological pathways underlying these associations.     

GSTP1 Ala114Val polymorphism and colorectal cancer risk: a meta-analysis

Studies investigating the association between cytochrome glutathione S-transferase P1 (GSTP1) Ala114Val polymorphism and colorectal cancer (CRC) risk report conflicting results. The aim of this study was to quantitatively summarize the evidence for such a relationship. Two investigators independently searched the Medline, Embase, China National Knowledge Infrastructure, and Chinese Biomedicine databases. Summary odds ratios (ORs) and 95 % confidence intervals (95 % CIs) for GSTP1 polymorphism and CRC were calculated in a fixed effects model (the Mantel–Haenszel method) and a random effects model (the DerSimonian and Laird method) when appropriate. The pooled ORs were performed for co-dominant model (ValVal vs. AlaAla, AlaVal vs. AlaAla), dominant model (ValVal + AlaVal vs. AlaAla), and recessive model (ValVal vs. AlaVal + AlaAla). This meta-analysis included seven case–control studies, which included 3,173 CRC cases and 3,323 controls. Overall, the variant genotypes (ValVal and AlaVal) of the Ala114Val were not associated with CRC risk when compared with the wild-type AlaAla homozygote. Similarly, no associations were found in the dominant and recessive models. When stratifying for ethnicity, Hardy–Weinberg equilibrium in controls, study sample size, and source of controls, a significantly increased risk was observed among Asians (AlaVal vs. AlaAla, OR?=?1.67, 95 % CI?=?1.08–2.59; dominant model, OR?=?1.74, 95 % CI?=?1.14–2.67). No heterogeneity or publication bias was found in the present study. This meta-analysis suggests that the GSTP1 Ala114Val polymorphism may not be associated with CRC risk, while the observed increase in risk of CRC may be due to small-study bias.     

Pre-diagnostic circulating resistin concentrations and mortality among individuals with colorectal cancer: Results from the European Prospective Investigation into Cancer and Nutrition study

Resistin is a protein involved in inflammation and angiogenesis processes and may play a role in the progression of colorectal cancer (CRC). However, it remains unclear whether resistin is associated with increased mortality after CRC diagnosis. We examined pre-diagnostic serum resistin concentrations in relation to CRC-specific and all-cause mortality among 1343 incident CRC cases from the European Prospective Investigation into Cancer and Nutrition cohort. For CRC-specific mortality as the primary outcome, hazard ratios (HRs) and 95% confidence intervals (95% CI) were estimated from competing risk analyses based on cause-specific Cox proportional hazards models and further in sensitivity analyses using Fine–Gray proportional subdistribution hazards models. For all-cause mortality as the secondary outcome, Cox proportional hazards models were used. Subgroup analyses were performed by sex, tumor subsite, tumor stage, body mass index and time to CRC diagnosis. Resistin was measured on a median of 4.8 years before CRC diagnosis. During a median follow-up of 8.2 years, 474 deaths from CRC and 147 deaths from other causes were observed. Resistin concentrations were not associated with CRC-specific mortality (HR_Q4vsQ1 = 0.95, 95% CI: 0.73–1.23; P_trend = .97; and HR_{per doubling of resistin concentration} = 1.00; 95% CI: 0.84–1.19; P = .98) or all-cause mortality. Results from competing risk (sensitivity) analysis were similar. No associations were found in any subgroup analyses. These findings suggest no association between pre-diagnostic circulating resistin concentrations and CRC-specific or all-cause mortality among persons with CRC, and the potential insignificance of resistin in CRC progression.     

Associations between genetically predicted levels of blood metabolites and pancreatic cancer risk

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid malignancies, which is featured by systematic metabolism. Thus, a better understanding of metabolic dysregulation in PDAC is important to better characterize its etiology. Here, we performed a large metabolome-wide association study (MWAS) to systematically explore associations between genetically predicted metabolite levels in blood and PDAC risk. Using data from 881 subjects of European descent in the TwinsUK Project, comprehensive genetic models were built to predict serum metabolite levels. These prediction models were applied to the genetic data of 8275 cases and 6723 controls included in the PanScan (I, II and III) and PanC4 consortia. After assessing the metabolite-PDAC risk associations by a slightly modified TWAS/FUSION framework, we identified five metabolites (including two dipeptides) showing significant associations with PDAC risk at false discovery rate (FDR) <0.05. Integrated with gut microbial information, two-sample Mendelian randomization (MR) analyses were further performed to investigate the relationship among serum metabolites, gut microbiome features and PDAC. The flavonoid-degrading bacteria Flavonifractor sp90199495 was found to be associated with metabolite X-21849 and it was also shown to be associated with PDAC risk. Collectively, our study identified novel candidate metabolites for PDAC risk, which could lead to new insights into the etiology of PDAC and improved treatment options.     

The association between −1304T>G polymorphism in the promoter of MKK4 gene and the risk of sporadic colorectal cancer in southern Chinese population

MKK4 (mitogen‐activated protein kinase kinase 4, NM_003010.2), which belongs to the mitogen‐activated protein kinase pathways, possesses functions in tumorigenesis. We hypothesized the genetic variants in MKK4 gene may alter its functions and thus cancer risk. In current hospital‐based case‐control study of 706 patients with sporadic colorectal cancer (CRC) and 723 sex‐age–frequency‐matched control subjects in a southern Chinese population, we genotyped two polymorphisms of MKK4 promoter (i.e., ?1304T>G, rs3826392 and ?1044A>T, rs3809728) and assessed their associations with the risk of sporadic CRC. Compared with ?1304TT genotypes, ?1304TG had a significantly decreased risk of CRC (adjusted odds ratios [OR] = 0.56; 95% CI = 0.44–0.72; p = 3.53 × 10^?6), the ?1304GG carriers had a further decreased risk of CRC (OR = 0.40; 95% CI = 0.23–0.70; p = 1.32 × 10^?3), and there was a significant trend for an allele dose effect on risk of CRC (p_trend = 2.64 × 10^?7). The decreased risk associated with ?1304G variant genotypes (i.e., TG+GG) was more pronounced in the subjects older than 60 years (adjusted OR = 0.41; 95% CI = 0.29–0.57; p = 2.25 × 10^?7), in ever drinkers (adjusted OR = 0.41; 95% CI = 0.28–0.59; p = 2.42 × 10^?6). The age and alcohol drinking status interacted with ?1304G variant genotypes on reducing cancer risk (p values for interaction were 0.015 and 0.043, respectively). Western blotting analysis showed that the levels of Mkk4 protein in sporadic CRC neoplastic tissues were significantly higher in the carriers of ?1304G variant genotypes than that in those with ?1304TT genotypes. However, no significant association was observed between ?1044A>T polymorphism and risk of CRC. To the best of our knowledge, this is the first study of genetic variants in MKK4 and cancer susceptibility. Larger studies are needed to validate our findings. © 2009 UICC