The Bidirectional Association of Chronic Kidney Disease, Type 2 Diabetes, Atherosclerotic Cardiovascular Disease, and Heart Failure: The Cardio-Renal-Metabolic Syndrome.

Background: The cardiometabolic syndrome focuses on the association between type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD), whereas the cardiorenal syndrome focuses on the association between chronic kidney disease (CKD) and heart failure (HF). Consideration of these two syndromes as a single entity has not been well described. Methods: We used the electronic medical records of Kaiser Permanente Northwest to identify 387,985 members aged 18+ years with a serum creatinine measured from 2005 to 2017. If the estimated glomerular filtration rate was <60 mL/min per 1.73 m2, we required a second confirmatory measurement 3-12 months later. Patients were followed through 2019. We calculated the age- and gender-adjusted incidence and progression of CKD per 1000 person-years using generalized estimating equations. We used Cox proportional hazard models to assess the time-dependent effect of each condition on incidence of the other conditions. Results: CKD incidence rates were highest in patients with T2DM, ASCVD, and HF (27.0 per 1000 person-years [95% confidence interval (CI) 24.8-29.4] vs. 5.9 [5.8-6.0] in patients with none of these conditions). Similar results were obtained for CKD progression (309.0, 283.9-336.4 for all three conditions vs. 147.9, 143.3-152.4 for no condition). In time-dependent models, all three conditions were independently associated with CKD incidence, being highest for HF (hazard ratio 2.14, 95% CI 2.07-2.21). All relationships between CKD, T2DM, ASCVD, and HF were significant and bidirectional. Conclusions: The presence of CKD, T2DM, HF, and ASCVD each conveys risk on the others. A cardiometabolic renal syndrome comprising these conditions may be an important disease entity that requires a comprehensive treatment approach.

Prognostic role of detailed colorectal location and tumor molecular features: analyses of 13,101 colorectal cancer patients including 2994 early-onset cases.

BACKGROUND: The pathogenic effect of colorectal tumor molecular features may be influenced by several factors, including those related to microbiota, inflammation, metabolism, and epigenetics, which may change along colorectal segments. We hypothesized that the prognostic association of colon cancer location might differ by tumor molecular characteristics. METHODS: Utilizing a consortium dataset of 13,101 colorectal cancer cases, including 2994 early-onset cases, we conducted survival analyses of detailed tumor location stratified by statuses of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF oncogenic mutation. RESULTS: There was a statistically significant trend for better colon cancer-specific survival in relation to tumor location from the cecum to sigmoid colon (Ptrend = 0.002), excluding the rectum. The prognostic association of colon location differed by MSI status (Pinteraction = 0.001). Non-MSI-high tumors exhibited the cecum-to-sigmoid trend for better colon cancer-specific survival [Ptrend < 0.001; multivariable hazard ratio (HR) for the sigmoid colon (vs. cecum), 0.80; 95% confidence interval (CI) 0.70-0.92], whereas MSI-high tumors demonstrated a suggestive cecum-to-sigmoid trend for worse survival (Ptrend = 0.020; the corresponding HR, 2.13; 95% CI 1.15-3.92). The prognostic association of colon tumor location also differed by CIMP status (Pinteraction = 0.003) but not significantly by age, stage, or other features. Furthermore, MSI-high status was a favorable prognostic indicator in all stages. CONCLUSIONS: Both detailed colonic location and tumor molecular features need to be accounted for colon cancer prognostication to advance precision medicine. Our study indicates the important role of large-scale studies to robustly examine detailed colonic subsites in molecular oncology research.

Molecular Characteristics of Early-Onset Colorectal Cancer According to Detailed Anatomical Locations: Comparison With Later-Onset Cases.

INTRODUCTION: Early-onset colorectal cancer diagnosed before the age of 50 years has been increasing. Likely reflecting the pathogenic role of the intestinal microbiome, which gradually changes across the entire colorectal length, the prevalence of certain tumor molecular characteristics gradually changes along colorectal subsites. Understanding how colorectal tumor molecular features differ by age and tumor location is important in personalized patient management. METHODS: Using 14,004 cases with colorectal cancer including 3,089 early-onset cases, we examined microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF mutations in carcinomas of the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum and compared early-onset cases with later-onset cases. RESULTS: The proportions of MSI-high, CIMP-high, and BRAF -mutated early-onset tumors were lowest in the rectum (8.8%, 3.4%, and 3.5%, respectively) and highest in the ascending colon (46% MSI-high; 15% CIMP-high) or transverse colon (8.6% BRAF -mutated) (all Ptrend <0.001 across the rectum to ascending colon). Compared with later-onset tumors, early-onset tumors showed a higher prevalence of MSI-high status and a lower prevalence of CIMP-high status and BRAF mutations in most subsites. KRAS mutation prevalence was higher in the cecum compared with that in the other subsites in both early-onset and later-onset tumors ( P < 0.001). Notably, later-onset MSI-high tumors showed a continuous decrease in KRAS mutation prevalence from the rectum (36%) to ascending colon (9%; Ptrend <0.001), followed by an increase in the cecum (14%), while early-onset MSI-high cancers showed no such trend. DISCUSSION: Our findings support biogeographical and pathogenic heterogeneity of colorectal carcinomas in different colorectal subsites and age groups.

Validation of the prognostic value of CD3 and CD8 cell densities analogous to the Immunoscore® by stage and location of colorectal cancer: an independent patient cohort study.

In addition to the traditional staging system in colorectal cancer (CRC), the Immunoscore® has been proposed to characterize the level of immune infiltration in tumor tissue and as a potential prognostic marker. The aim of this study was to examine and validate associations of an immune cell score analogous to the Immunoscore® with established molecular tumor markers and with CRC patient survival in a routine setting. Patients from a population-based cohort study with available CRC tumor tissue blocks were included in this analysis. CD3+ and CD8+ tumor infiltrating lymphocytes in the tumor center and invasive margin were determined in stained tumor tissue slides. Based on the T-cell density in each region, an  immune cell score closely analogous to the concept of the Immunoscore® was calculated and tumors categorized into IS-low, IS-intermediate, or IS-high. Logistic regression models were used to assess associations between clinicopathological characteristics with the immune cell score, and Cox proportional hazards models to analyze associations with cancer-specific, relapse-free, and overall survival. From 1,535 patients with CRC, 411 (27%) had IS-high tumors. Microsatellite instability (MSI-high) was strongly associated with higher immune cell score levels (p < 0.001). Stage I-III patients with IS-high had better CRC-specific and relapse-free survival compared to patients with IS-low (hazard ratio [HR] = 0.42 [0.27-0.66] and HR = 0.45 [0.31-0.67], respectively). Patients with microsatellite stable (MSS) tumors and IS-high had better survival (HRCSS  = 0.60 [0.42-0.88]) compared to MSS/IS-low patients. In this population-based cohort of CRC patients, the immune cell score was significantly associated with better patient survival. It was a similarly strong prognostic marker in patients with MSI-high tumors and in the larger group of patients with MSS tumors. Additionally, this study showed that it is possible to implement an analogous immune cell score approach and validate the Immunoscore® using open source software in an academic setting. Thus, the Immunoscore® could be useful to improve the traditional staging system in colon and rectal cancer used in clinical practice.

Reproductive Factors and Colorectal Cancer Risk: A Population-Based Case-Control Study.

BACKGROUND: Hormone-replacement therapy (HRT) is associated with lower colorectal cancer (CRC) risk among postmenopausal women. However, little is known about the effects of lifetime exposure of women to varying levels of estrogen and progesterone through reproductive factors such as parity, use of oral contraceptives (OC), breastfeeding, and menstruation on CRC risk. METHODS: We assessed associations between reproductive factors and CRC risk among 2650 female CRC patients aged 30+ years and 2175 matched controls in a population-based study in Germany, adjusting for potential confounders by multiple logistic regression. RESULTS: Inverse associations with CRC risk were found for numbers of pregnancies (odds ratio [OR] per pregnancy = 0.91, 95% confidence interval [CI] = 0.86 to 0.97), breastfeeding for 12 months and longer (OR = 0.74, 95% CI = 0.61 to 0.90), and use of either OC or HRT (OR = 0.75, 95% CI = 0.64 to 0.87) or both (OR = 0.58, 95% CI = 0.48 to 0.70). Similar results were found for postmenopausal women only and when adjusting for number of pregnancies and for all reproductive factors analyzed together. Breastfeeding duration of 12 months and longer was associated with lower risk of cancer only in the proximal colon (OR = 0.58, 95% CI = 0.45 to 0.74). CONCLUSIONS: Several reproductive factors were associated with lower CRC risk in women, including number of pregnancies, breastfeeding duration, and use of OC and HRT. This suggests that women's exposure to female reproductive hormones plays a key role in the difference in CRC risk between women and men and in site-specific CRC risk.

Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures.

Carriers of germline biallelic pathogenic variants in the MUTYH gene have a high risk of colorectal cancer. We test 5649 colorectal cancers to evaluate the discriminatory potential of a tumor mutational signature specific to MUTYH for identifying biallelic carriers and classifying variants of uncertain clinical significance (VUS). Using a tumor and matched germline targeted multi-gene panel approach, our classifier identifies all biallelic MUTYH carriers and all known non-carriers in an independent test set of 3019 colorectal cancers (accuracy = 100% (95% confidence interval 99.87-100%)). All monoallelic MUTYH carriers are classified with the non-MUTYH carriers. The classifier provides evidence for a pathogenic classification for two VUS and a benign classification for five VUS. Somatic hotspot mutations KRAS p.G12C and PIK3CA p.Q546K are associated with colorectal cancers from biallelic MUTYH carriers compared with non-carriers (p = 2 × 10-23 and p = 6 × 10-11, respectively). Here, we demonstrate the potential application of mutational signatures to tumor sequencing workflows to improve the identification of biallelic MUTYH carriers.

Diabetes mellitus in relation to colorectal tumor molecular subtypes: A pooled analysis of more than 9000 cases.

Diabetes is an established risk factor for colorectal cancer. However, colorectal cancer is a heterogeneous disease and it is not well understood whether diabetes is more strongly associated with some tumor molecular subtypes than others. A better understanding of the association between diabetes and colorectal cancer according to molecular subtypes could provide important insights into the biology of this association. We used data on lifestyle and clinical characteristics from the Colorectal Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), including 9756 colorectal cancer cases (with tumor marker data) and 9985 controls, to evaluate associations between reported diabetes and risk of colorectal cancer according to molecular subtypes. Tumor markers included BRAF and KRAS mutations, microsatellite instability and CpG island methylator phenotype. In the multinomial logistic regression model, comparing colorectal cancer cases to cancer-free controls, diabetes was positively associated with colorectal cancer regardless of subtype. The highest OR estimate was found for BRAF-mutated colorectal cancer, n = 1086 (ORfully adj : 1.67, 95% confidence intervals [CI]: 1.36-2.05), with an attenuated association observed between diabetes and colorectal cancer without BRAF-mutations, n = 7959 (ORfully adj : 1.33, 95% CI: 1.19-1.48). In the case only analysis, BRAF-mutation was differentially associated with diabetes (Pdifference  = .03). For the other markers, associations with diabetes were similar across tumor subtypes. In conclusion, our study confirms the established association between diabetes and colorectal cancer risk, and suggests that it particularly increases the risk of BRAF-mutated tumors.

Risk Factors of Inadequate Bowel Preparation for Screening Colonoscopy.

The success of a colonoscopy in detecting and removing pre-cancerous and cancerous lesions depends heavily on the quality of bowel preparation. Despite efforts, 20-44% of colonoscopy participants have an inadequate bowel preparation. We aimed to assess and compare risk factors for inadequate bowel preparation and for the presence of advanced colorectal neoplasms in routine screening practice. In this cross-sectional study, among 8125 participants of screening colonoscopy in Germany with a comprehensive assessment of sociodemographic factors, lifestyle and medical history, we examined factors associated with inadequate bowel preparation and with findings of advanced neoplasms using adjusted log-binomial regression models. Among the identified risk factors assessed, three factors were identified that were significantly associated with inadequate bowel preparation: age ≥ 70 years (adjusted prevalence ratios, aPR, 1.50 95%CI 1.31-1.71), smoking (aPR 1.29 95%CI 1.11-1.50) and abdominal symptoms (aPR 1.14 95%CI 1.02-1.27). The same risk factors were also associated with the prevalence of advanced neoplasms in our study (aPR 1.72, 1.62 and 1.44, respectively). The risk factors associated with inadequate bowel preparation in this study were also associated with a higher risk for advanced neoplasms. Inadequate bowel preparation for colonoscopy might lead to missed colorectal cancer (CRC) precursors and the late diagnosis of CRC. People at high risk of advanced neoplasms are in particular need of enhanced bowel preparation.

To what extent is male excess risk of advanced colorectal neoplasms explained by known risk factors? Results from a large German screening population.

Colorectal cancer (CRC) incidence and prevalence of its precursors are substantially higher among males than among females in most countries but the reasons for the male excess risk are incompletely understood. We aimed to assess to what extent it is explained by known risk factors. Prevalence of advanced neoplasia (AN, ie, CRC or advanced adenoma) and CRC risk and preventive factors were ascertained among 15 985 participants of screening colonoscopy aged 55-79 years in Germany. Logistic regression was used to calculate odds ratios (ORs) for the association between male sex and AN with and without adjustment for known risk and preventive factors. In age-adjusted comparisons, men had 2-fold increased risk for AN compared to women (OR = 1.98, 95% confidence interval [CI] 1.79-2.19). After comprehensive adjustment for medical, lifestyle and dietary factors, the OR was reduced to 1.52 (95% CI 1.30-1.77), suggesting that these factors accounted for 47% of male excess risk. Male excess risk increased from proximal colon to distal colon and rectum, with age-adjusted ORs (95% CI) of 1.63 (1.38-1.91), 2.13 (1.85-2.45) and 2.36 (1.95-2.85), respectively, and with the proportion of excess risk explained by covariates being lower for AN in the rectum (26%) than for AN in the proximal (52%) or distal colon (46%). Male excess risk was somewhat lower (age-adjusted OR 1.87) and explained excess risk was smaller (36%) when men were compared to women who never used hormone replacement therapy. In conclusion, most of the male excess risk and the potential to overcome it remain to be explored by further research.

Potential sex differences in human milk leptin and their association with asthma and wheeze phenotypes: Results of the Ulm Birth Cohorts.

BACKGROUND: The hormone leptin has been suggested to play a role in the respiratory and immune systems. Evidence on sex-specific concentrations of leptin in human milk and sex-specific associations with the development of asthma and wheeze has been put forward but is still scarce. OBJECTIVE: To investigate whether male and female infants receive different levels of leptin through human milk and whether leptin is implicated in the development of asthma and wheeze in a sex-dependent manner using data from the two Ulm Birth Cohort studies. METHODS: Leptin data were available from human milk samples collected at 6 weeks (Ulm Birth Cohort Study [UBCS, n = 678; Ulm SPATZ Health Study, n = 587]), and, in SPATZ only, at 6 months (n = 377) and 12 months (n = 66) of lactation. Sex-specific associations with doctor-diagnosed asthma and wheeze phenotypes were assessed in crude and adjusted models using logistic regression. Adjustments were made for maternal allergy, exclusive breastfeeding, infant age at the time of milk sampling, and child BMI z-score. RESULTS: At 6 weeks, leptin levels (median [min, max], in ng/L) were higher in the milk for girls (197 [0.100, 4120]) than in milk for boys (159 [1.02, 3280], p = .045) in UBCS. No significant sex differences were observed in SPATZ (p = .152). There were no significant associations of leptin with asthma or wheeze in both studies, even in a sex-dependent manner (p > .05). CONCLUSION: It remains unclear whether male and female infants receive different levels of leptin through human milk. However, leptin in human milk may not be associated with history and development of asthma and wheeze in a sex-specific manner.

The Effects of Different Invitation Schemes on the Use of Fecal Occult Blood Tests for Colorectal Cancer Screening: Systematic Review of Randomized Controlled Trials.

Personal invitations for fecal occult blood tests (nowadays mostly fecal immunochemical tests) are increasingly used to raise their usage for colorectal cancer screening. However, there is a large heterogeneity in applied invitation schemes. We aimed to review evidence for the effectiveness of various invitation schemes. The main outcome was the fecal occult blood test usage rate. A systematic search was performed in Medline and Web of Science (up to 9 July 2020). Randomized controlled trials or cluster-randomized controlled trials were eligible, which reported on general invitations for fecal occult blood test-based colorectal cancer screening sent to the general population at average colorectal cancer risk. (PROSPERO 2020 CRD42020169409). Overall, 34 studies were included. Invitations with an attached, i.e., mailed fecal occult blood test consistently increased test usage by 4-19.7% points, compared to other methods of test provision. Likewise, the introduction of advance notification consistently led to a higher usage rate, with an increase of 3.3-10.8% points. Reminders showed positive but varying effects by method. With an increase of 8.5-15.8% points, letter or email reminders were more effective than reminders by phone call or text message (0.6-6.5% points). Inconsistent results were found for financial incentives ((-8.4)-20% points) and for added or changed invitation material ((-3.5)-11.8% points). With 3.5-24.7% points, the strongest increases in use were achieved by multifaceted invitation, implementing multiple components. Any invitation scheme was superior over no invitation. Advance notification, mailing of fecal occult blood test, and reminders were consistently shown to have major, complementary potential to increase participation in fecal occult blood test-based colorectal cancer screening settings.

Intake of Dietary Fruit, Vegetables, and Fiber and Risk of Colorectal Cancer According to Molecular Subtypes: A Pooled Analysis of 9 Studies.

Protective associations of fruits, vegetables, and fiber intake with colorectal cancer risk have been shown in many, but not all epidemiologic studies. One possible reason for study heterogeneity is that dietary factors may have distinct effects by colorectal cancer molecular subtypes. Here, we investigate the association of fruit, vegetables, and fiber intake with four well-established colorectal cancer molecular subtypes separately and in combination. Nine observational studies including 9,592 cases with molecular subtypes for microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and somatic mutations in BRAF and KRAS genes, and 7,869 controls were analyzed. Both case-only logistic regression analyses and polytomous logistic regression analyses (with one control set and multiple case groups) were used. Higher fruit intake was associated with a trend toward decreased risk of BRAF-mutated tumors [OR 4th vs. 1st quartile = 0.82 (95% confidence interval, 0.65-1.04)] but not BRAF-wildtype tumors [1.09 (0.97-1.22); P difference as shown in case-only analysis = 0.02]. This difference was observed in case-control studies and not in cohort studies. Compared with controls, higher fiber intake showed negative association with colorectal cancer risk for cases with microsatellite stable/MSI-low, CIMP-negative, BRAF-wildtype, and KRAS-wildtype tumors (P trend range from 0.03 to 3.4e-03), which is consistent with the traditional adenoma-colorectal cancer pathway. These negative associations were stronger compared with MSI-high, CIMP-positive, BRAF-mutated, or KRAS-mutated tumors, but the differences were not statistically significant. These inverse associations for fruit and fiber intake may explain, in part, inconsistent findings between fruit or fiber intake and colorectal cancer risk that have previously been reported. SIGNIFICANCE: These analyses by colorectal cancer molecular subtypes potentially explain the inconsistent findings between dietary fruit or fiber intake and overall colorectal cancer risk that have previously been reported.

Colonoscopy and Reduction of Colorectal Cancer Risk by Molecular Tumor Subtypes: A Population-Based Case-Control Study.

INTRODUCTION: In previous studies, the protective effect of colonoscopy was generally stronger for distal colorectal cancer than for proximal colorectal cancer (CRC). This study aimed to investigate whether reduction of CRC risk through colonoscopy varies according to major tumor markers and pathways of CRC. METHODS: This is a population-based case-control study from Germany, including 2,132 patients with a first diagnosis of CRC and information on major molecular tumor markers and 2,486 control participants without CRC. Detailed participant characteristics were collected by standardized questionnaires. Information on previous colonoscopy was derived from medical records. Polytomous logistic regression was used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the association between previous colonoscopy and subtypes of CRC. RESULTS: Overall, we observed strong risk reduction of CRC after colonoscopy that was weaker for microsatellite instable (MSI) than for non-MSI CRC (OR 0.70, 95% CI 0.50-0.97 vs OR 0.28, 95% CI 0.24-0.33), for CpG island methylator phenotype high CRC than for CpG island methylator phenotype low/negative CRC (OR 0.45, 95% CI 0.34-0.59 vs OR 0.29, 95% CI 0.25-0.34), for BRAF-mutated than for BRAF nonmutated CRC (OR 0.62, 95% CI 0.42-0.91 vs OR 0.30, 95% CI 0.25-0.35), for KRAS nonmutated than for KRAS-mutated CRC (OR 0.34, 95% CI 0.29-0.40 vs OR 0.26, 95% CI 0.20-0.32), and for CRC classified into the sessile serrated pathway than for CRC of the traditional pathway (OR 0.57, 95% CI 0.36-0.91 vs OR 0.30, 95% CI 0.25-0.37). After colonoscopy with the detection of adenomas or hyperplastic polyps, no risk reduction was found for sessile serrated pathway CRC, MSI, and BRAF-mutated subtypes. DISCUSSION: Our study extends the molecular understanding of existing differences in risk reduction of proximal and distal CRCs reported by previous studies and may imply important information for improving strategies for timely detection of relevant precursors.

Landscape of somatic single nucleotide variants and indels in colorectal cancer and impact on survival.

Colorectal cancer (CRC) is a biologically heterogeneous disease. To characterize its mutational profile, we conduct targeted sequencing of 205 genes for 2,105 CRC cases with survival data. Our data shows several findings in addition to enhancing the existing knowledge of CRC. We identify PRKCI, SPZ1, MUTYH, MAP2K4, FETUB, and TGFBR2 as additional genes significantly mutated in CRC. We find that among hypermutated tumors, an increased mutation burden is associated with improved CRC-specific survival (HR = 0.42, 95% CI: 0.21-0.82). Mutations in TP53 are associated with poorer CRC-specific survival, which is most pronounced in cases carrying TP53 mutations with predicted 0% transcriptional activity (HR = 1.53, 95% CI: 1.21-1.94). Furthermore, we observe differences in mutational frequency of several genes and pathways by tumor location, stage, and sex. Overall, this large study provides deep insights into somatic mutations in CRC, and their potential relationships with survival and tumor features.

Impact of Inadequate Bowel Cleansing on Colonoscopic Findings in Routine Screening Practice.

INTRODUCTION: Colonoscopy is an imperfect gold standard for detecting colorectal neoplasms because some proportion of adenomas may be missed, mainly small lesions. This proportion is expected to be higher in case of inadequate bowel cleansing, which is frequently seen in routine practice. We estimated the proportions of neoplasms that are in principle detectable by colonoscopy but might be missed in case of incomplete bowel preparation. METHODS: For 8,193 participants of screening colonoscopy in South-Western Germany, recruited between 2005 and 2016, the prevalence and numbers of different findings were extracted from colonoscopy reports and compared according to the reported bowel preparation quality. RESULTS: Bowel preparation quality was reported as good, poor, or was unspecified in 30.3%, 11.1%, and 58.6% of colonoscopy records. Reported prevalences of nonadvanced adenomas (NAAs) were similar among participants with poor and unspecified bowel preparation quality but substantially lower than among participants with good bowel preparation (adjusted prevalence rate ratio [RR] 0.86, 95% confidence interval [CI]: 0.77-0.96). The differences were observed for proximal but not for distal NAAs (RRs 0.82, 95% CI: 0.71-0.95 and 0.95, 95% CI: 0.82-1.10). DISCUSSION: Our study suggests that a significant proportion of NAAs located in the proximal colon might be missed during colonoscopy if bowel cleansing is not adequate. Major efforts should be made to further facilitate and enhance high-quality bowel preparation in routine screening practice.

Smoking, alcohol consumption and colorectal cancer risk by molecular pathological subtypes and pathways.

BACKGROUND: Smoking and alcohol increase risk for colorectal malignancies. However, colorectal cancer (CRC) is a heterogenic disease and associations with the molecular pathological pathways are unclear. METHODS: This population-based case-control study includes 2444 cases with first-diagnosis CRC and 2475 controls. Tumour tissue was analysed for MSI (microsatellite instability), CIMP (CpG island methylator phenotype), BRAF (B-Raf proto-oncogene serine/threonine kinase gene) and KRAS (Kirsten rat sarcoma viral oncogene homologue gene) mutations. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated for associations between alcohol and smoking and CRC molecular subtypes and pathways. RESULTS: Current smoking showed higher ORs for MSI-high (OR = 2.79, 95% CI: 1.86-4.18) compared to MSS (OR = 1.41, 1.14-1.75, p-heterogeneity (p-het) = 0.001), BRAF-mutated (mut) (OR = 2.40, 1.41-4.07) compared to BRAF-wild type (wt) (OR = 1.52, 1.24-1.88, p-het = 0.074), KRAS-wt (OR = 1.70, 1.36-2.13) compared to KRAS-mut (OR = 1.26, 0.95-1.68, p-het = 0.039) and CIMP-high (OR = 2.01, 1.40-2.88) compared to CIMP-low/negative CRC (OR = 1.50, 1.22-1.85, p-het=0.101). Current smoking seemed more strongly associated with sessile serrated pathway (CIMP-high + BRAF-mut; OR = 2.39, 1.27-4.52) than with traditional pathway CRC (MSS + CIMP-low/negative + BRAF-wt; OR = 1.50, 1.16-1.94) and no association was observed with alternate pathway CRC (MSS + CIMP-low/negative + KRAS-wt; OR = 1.08, 0.77-1.43). No heterogeneity was observed in alcohol consumption association by molecular subtypes. CONCLUSIONS: In this large case-control study, smoking was more strongly associated with MSI-high and KRAS-wt CRC and with cases showing features of the sessile serrated pathway. Association patterns were less clear for alcohol consumption.

Postmenopausal hormone replacement therapy and colorectal cancer risk by molecular subtypes and pathways.

Postmenopausal hormone replacement therapy (HRT) was found to be associated with lower risk of colorectal cancer (CRC). However, little is known regarding associations with molecular subtypes of CRC. The current study includes female participants of a large German population-based case-control study (922 CRC cases and 1,183 controls). Tumor tissue samples were analyzed for microsatellite instability (MSI), CpG island methylator phenotype (CIMP), BRAF and KRAS mutation status. Multivariable logistic regression models were used to assess the association of HRT use with molecular subtypes and pathways. Postmenopausal HRT use was overall associated with reduced risk of CRC (adjusted odds ratio (aOR) 0.62, 95% confidence interval (CI) 0.50-0.76) and no major differences were observed for molecular subtypes or for tumor marker combinations representing molecular pathways. When stratified by median age (≤/>71 years) potentially stronger risk reductions were observed in the older group for subtypes showing MSI (OR = 0.36, 95% CI 0.17-0.76), BRAF mutation (OR = 0.40, 95% CI 0.30-0.83) and CIMP-high (OR = 0.40, 95% CI 0.21-0.73) and for CRC suggestive of the sessile serrated pathway (OR = 0.45, 95% CI 0.20-1.01). In conclusion, postmenopausal use of HRT was similarly associated with risk reduction of major molecular tumor subtypes and pathways of CRC. Potentially stronger risk reductions with CRC subtypes diagnosed at higher ages require confirmation and clarification from other studies. The current study extends the limited understanding of the mechanisms of HRT in CRC prevention.

Association of BMI and major molecular pathological markers of colorectal cancer in men and women.

BACKGROUND: Observational studies have consistently shown that a high BMI is associated with increased risk of colorectal cancer (CRC). However, the underlying mechanisms linking obesity to CRC remain unclear. OBJECTIVES: To investigate the associations of BMI and CRC by major molecular pathological subtypes of CRC. METHODS: This analysis included 2407 cases and 2454 controls from a large German population-based case-control study. Information on recent weight and height as well as other demographic and lifestyle data were obtained by standardized interviews. Multinomial logistic regression was used to estimate ORs and 95% CIs for the associations between BMI and risk of CRC by major molecular pathological features: microsatellite instability (MSI), CpG island methylator phenotype (CIMP), B-Raf proto-oncogene serine/threonine kinase (BRAF) mutation, and Kirsten rat sarcoma viral oncogene homolog gene (KRAS) mutation. RESULTS: Among women, a higher BMI was differentially and more strongly associated with risk of MSI CRC (OR per 5 kg/m2: 1.69; 95% CI: 1.34, 2.12; Pheterogeneity ≤ 0.001), CIMP-high CRC (OR per 5 kg/m2: 1.57; 95% CI: 1.30, 1.89; Pheterogeneity ≤ 0.001), BRAF-mutated CRC (OR per 5 kg/m2: 1.56; 95% CI: 1.22, 1.99; Pheterogeneity = 0.04), and KRAS-wildtype CRC (OR per 5 kg/m2: 1.35; 95% CI: 1.17, 1.54; Pheterogeneity = 0.01), compared with the risk of CRC in subjects with the molecular feature counterpart. In men, no meaningful differences in CRC risk were observed for the investigated molecular feature pairs. For the association of BMI with MSI CRC, we observed effect modification by sex (Pinteraction = 0.04). Also, in women, the risk of CRC with the serrated pathway features was more strongly increased with higher BMI than risk of CRC with the traditional pathway features (OR per 5 kg/m2: 1.73; 95% CI: 1.28, 2.34; Pheterogeneity = 0.01). CONCLUSIONS: In women, the relation between BMI and MSI-high CRC seems to be stronger than that between BMI and microsatellite-stable CRC. However, a validation in an independent cohort is needed. This observational study was registered at the German Clinical Trials Register (http://www.drks.de; study ID: DRKS00011793), an approved primary register in the WHO network.