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Alterations within the tryptophan-kynurenine metabolic pathway have been linked to the etiology of colorectal cancer (CRC), but the relevance of this pathway for prognostic outcomes in CRC patients needs further elucidation. Therefore, we investigated associations between circulating concentrations of tryptophan-kynurenine pathway metabolites and all-cause mortality among CRC patients. This study utilizes data from 2102 stage I-III CRC patients participating in six prospective cohorts involved in the international FOCUS Consortium. Preoperative circulating concentrations of tryptophan, kynurenine, kynurenic acid (KA), 3-hydroxykynurenine (HK), xanthurenic acid (XA), 3-hydroxyanthranilic acid (HAA), anthranilic acid (AA), picolinic acid (PA), and quinolinic acid (QA) were measured by liquid chromatography-tandem mass spectrometry. Using Cox proportional hazards regression, we examined associations of above-mentioned metabolites with all-cause mortality, adjusted for potential confounders. During a median follow-up of 3.2 years (interquartile range: 2.2-4.9), 290 patients (13.8%) deceased. Higher blood concentrations of tryptophan, XA, and PA were associated with a lower risk of all-cause mortality (per doubling in concentrations: tryptophan: HR = 0.56; 95%CI:0.41,0.76, XA: HR = 0.74; 95%CI:0.64,0.85, PA: HR = 0.76; 95%CI:0.64,0.92), while higher concentrations of HK and QA were associated with an increased risk of death (per doubling in concentrations: HK: HR = 1.80; 95%CI:1.47,2.21, QA: HR = 1.31; 95%CI:1.05,1.63). A higher kynurenine-to-tryptophan ratio, a marker of cell-mediated immune activation, was associated with an increased risk of death (per doubling: HR = 2.07; 95%CI:1.52,2.83). In conclusion, tryptophan-kynurenine pathway metabolites may be prognostic markers of survival in CRC patients., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Aim: The aim of this study was to longitudinally investigate dietary and lifestyle inflammation scores and their interaction in relation to risk of colorectal cancer (CRC) recurrence and all-cause mortality., Methods: Data of two prospective cohort studies among CRC survivors was used. Information about diet and/or lifestyle was available for 2739 individuals for at least one of the following time points: at diagnosis, six months after diagnosis and two years after diagnosis. The dietary and lifestyle inflammation scores (DIS and LIS) were used to evaluate the inflammatory potential of diet and lifestyle. Joint modelling, combining mixed models and Cox proportional hazards regression, were used to assess associations between DIS and LIS over time and CRC recurrence and all-cause mortality. Interactions between DIS and LIS were assessed using time-dependent Cox proportional hazard regression., Results: The median follow-up time was 4.8 (IQR 2.9-6.9) years for recurrence and 5.7 (IQR 3.5-8.5) years for all-cause mortality, with 363 and 453 events, respectively. A higher DIS as well as LIS was associated with a higher risk of all-cause mortality (HR DIScontinuous 1.09 95%CI 1.02; 1.15; HR LIScontinuous 1.24 95%CI 1.05; 1.46). Individuals who were in the upper tertile of both DIS and LIS had the highest all-cause mortality risk (HR 1.62 95%CI 1.16; 2.28), compared to the individuals in the lowest tertile of both DIS and LIS. No consistent associations with recurrence were observed., Conclusion: A more pro-inflammatory diet and lifestyle was associated with a higher risk of all-cause mortality, but not recurrence, in CRC survivors., Competing Interests: Conflict of interest The authors declare no conflicts of interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

We previously demonstrated that intake of low-fat dairy, but not high-fat dairy, was associated with a decreased colorectal cancer (CRC) recurrence risk. These risks, however, may differ by sex, primary tumour location, and disease stage. Combining data from two similar prospective cohort studies of people with stage I-III CRC enabled these subgroup analyses. Participants completed a food frequency questionnaire at diagnosis (n = 2283). We examined associations between low- and high-fat dairy intake and recurrence risk using multivariable Cox proportional hazard models, stratified by sex, and primary tumour location (colon and rectum), and disease stage (I/II and III). Upper quartiles were compared to lower quartiles of intake, and recurrence was defined as a locoregional recurrence and/or metastasis. During a median follow-up of 5.0 years, 331 recurrences were detected. A higher intake of low-fat dairy was associated with a reduced risk of recurrence (hazard ratio [HR]: 0.60, 95% confidence interval [CI]: 0.43-0.83), which seemed more pronounced in men (HR: 0.51, 95% CI: 0.34-0.77) than in women (HR: 0.84, 95% CI: 0.47-1.49). A higher intake of high-fat dairy was associated with an increased risk of recurrence in participants with colon cancer (HR: 1.60, 95% CI: 1.03-2.50), but not rectal cancer (HR: 0.88, 95% CI: 0.54-1.45). No differences in associations were observed between strata of disease stage. Concluding, our findings imply that dietary advice regarding low-fat dairy intake may be especially important for men with CRC, and that dietary advice regarding high-fat dairy intake may be specifically important in people with colon cancer., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Purpose: A healthy diet reduces the risk of non-alcoholic fatty liver disease (NAFLD) in the general population, especially in individuals who are genetically predisposed to NAFLD. Little is known in patients who suffered from a myocardial infarction (MI). We examined the interaction between diet quality and genetic predisposition in relation to NAFLD in post-MI patients., Methods: We included 3437 post-MI patients from the Alpha Omega Cohort. Diet quality was assessed with adherence to the Dutch Healthy Diet index 2015 (DHD15-index). A weighted genetic risk score (GRS) for NAFLD was computed using 39 genetic variants. NAFLD prevalence was predicted using the Fatty Liver Index. Prevalence ratios (PR) with 95% confidence intervals of DHD15-index and GRS in relation to NAFLD were obtained with multivariable Cox proportional hazards models. The interaction between DHD15-index and GRS in relation to NAFLD was assessed on an additive and multiplicative scale., Results: Patients had a mean age of 69 (± 5.5) years, 77% was male and 20% had diabetes. The DHD15-index ranged from 28 to 120 with a mean of 73. Patients with higher diet quality were less likely to suffer from NAFLD, with a PR of 0.76 (0.62, 0.92) for the upper vs lower quintile of DHD15-index. No association between the GRS and NAFLD prevalence was found (PR of 0.92 [0.76, 1.11]). No statistically significant interaction between the DHD15-index and GRS was observed., Conclusion: In Dutch post-MI patients, adherence to the Dutch dietary guidelines was associated with a lower prevalence of NAFLD, as assessed by the FLI. This association was present regardless of genetic predisposition in this older aged cohort., (© 2024. The Author(s).)

Coffee consumption has been associated with a reduced risk of developing colorectal cancer (CRC). However, it is not clear whether coffee consumption is related to CRC progression. Hence, we assessed the association of coffee consumption with CRC recurrence and all-cause mortality using data from a prospective cohort study of 1719 stage I-III CRC patients in the Netherlands. Coffee consumption and other lifestyle characteristics were self-reported using questionnaires at the time of diagnosis. We retrieved recurrence and all-cause mortality data from the Netherlands Cancer Registry and the Personal Records Database, respectively. Cox proportional hazard regression models with and without restricted cubic splines were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) adjusted for age, sex, education, smoking status, cancer stage and tumor location. We observed 257 recurrences during a 6.2-year median follow-up and 309 deaths during a 6.6-year median follow-up. Consuming more than 4 cups/d of coffee compared to an intake of <2 cups/d was associated with a 32% lower risk of CRC recurrence (95% CI: 0.49, 0.94,). The association between coffee consumption and all-cause mortality was U-shaped; coffee intake seemed optimal at 3-5 cups/d with the lowest risk at 4 cups/d (HR: 0.68, 95% CI: 0.53, 0.88). Our results suggest that coffee consumption may be associated with a lower risk of CRC recurrence and all-cause mortality. The association between coffee consumption and all-cause mortality appeared nonlinear. More studies are needed to understand the mechanism by which coffee consumption might improve CRC prognosis., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk., Methods: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated., Results: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10 -8 ). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%-4.0%) vs 6.1% (5.7%-6.5%) (difference 2.4%, P-value = 1.83 × 10 -14 ); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%-1.8%) vs 2.2% (1.9%-2.4%) (difference 0.6%, P-value = 1.01 × 10 -3 ), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk., Conclusions: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use., (© 2024. The Author(s).)

Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769 ), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047 ), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.

Background: Traditional body-shape indices such as Waist Circumference (WC), Hip Circumference (HC), and Waist-to-Hip Ratio (WHR) are associated with colorectal cancer (CRC) risk, but are correlated with Body Mass Index (BMI), and adjustment for BMI introduces a strong correlation with height. Thus, new allometric indices have been developed, namely A Body Shape Index (ABSI), Hip Index (HI), and Waist-to-Hip Index (WHI), which are uncorrelated with weight and height; these have also been associated with CRC risk in observational studies, but information from Mendelian randomization (MR) studies is missing., Methods: We used two-sample MR to examine potential causal cancer site- and sex-specific associations of the genetically-predicted allometric body-shape indices with CRC risk, and compared them with BMI-adjusted traditional body-shape indices, and BMI. Data were obtained from UK Biobank and the GIANT consortium, and from GECCO, CORECT and CCFR consortia., Results: WHI was positively associated with CRC in men (OR per SD: 1.20, 95% CI: 1.03-1.39) and in women (1.15, 1.06-1.24), and similarly for colon and rectal cancer. ABSI was positively associated with colon and rectal cancer in men (1.27, 1.03-1.57; and 1.40, 1.10-1.77, respectively), and with colon cancer in women (1.20, 1.07-1.35). There was little evidence for association between HI and colon or rectal cancer. The BMI-adjusted WHR and HC showed similar associations to WHI and HI, whereas WC showed similar associations to ABSI only in women., Conclusions: This large MR study provides strong evidence for a potential causal positive association of the allometric indices ABSI and WHI with CRC in both sexes, thus establishing the association between abdominal fat and CRC without the limitations of the traditional waist size indices and independently of BMI. Among the BMI-adjusted traditional indices, WHR and HC provided equivalent associations with WHI and HI, while differences were observed between WC and ABSI., (© 2024. The Author(s).)

Introduction: Physical activity (PA) is associated with higher quality of life and probably better prognosis among colorectal cancer (CRC) patients. This study focuses on determinants of PA among CRC patients from diagnosis until 5 yr postdiagnosis., Methods: Sociodemographic and disease-related factors of participants of two large CRC cohort studies were combined. Moderate-to-vigorous PA during sport and leisure time (MVPA-SL) was measured at diagnosis (T0) and 6, 12, 24, and 60 months (T6 to T60) postdiagnosis, using the SQUASH questionnaire. Mixed-effects models were performed to identify sociodemographic and disease-related determinants of MVPA-SL, separately for stage I-III colon (CC), stage I-III rectal cancer (RC), and stage IV CRC (T0 and T6 only). Associations were defined as consistently present when significant at ≥4 timepoints for the stage I-III subsets. MVPA-SL levels were compared with an age- and sex-matched sample of the general Dutch population., Results: In total, 2905 CC, 1459 RC and 436 stage IV CRC patients were included. Patients with higher fatigue scores, and women compared with men had consistently lower MVPA-SL levels over time, regardless of tumor type and stage. At T6, having a stoma was significantly associated with lower MVPA-SL among stage I-III RC patients. Systemic therapy and radiotherapy were not significantly associated with MVPA-SL changes at T6. Compared with the general population, MVPA-SL levels of CRC patients were lower at all timepoints, most notably at T6., Conclusions: Female sex and higher fatigue scores were consistent determinants of lower MVPA-SL levels among all CRC patients, and MVPA-SL levels were lowest at 6 months postdiagnosis. Our results can inform the design of intervention studies aimed at improving PA, and guide healthcare professionals in optimizing individualized support., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Sports Medicine.)

Background: Cancer-related fatigue (CRF) is a frequent symptom in colorectal cancer survivors. It is unknown to what extent anemia may contribute to CRF in colorectal cancer survivors. This study aimed to investigate the association between hematocrit, as marker for anemia, and CRF among colorectal cancer survivors from diagnosis until two years thereafter., Methods: The study population included 1,506 newly diagnosed colorectal cancer survivors at any stage of disease from a prospective cohort study. Hematocrit and CRF (EORTC QLQ-C30) were assessed at diagnosis, six months, and two years after diagnosis. Multivariable logistic regression or multivariable linear mixed models were used to assess the associations of hematocrit with CRF prevalence, or CRF severity over time, respectively., Results: A low hematocrit (levels <40% men/<36% women) was present in a third of the survivors at diagnosis and six months thereafter, and among 16% two years after diagnosis. The prevalence of CRF was 15% at diagnosis, peaked at 27% at six months, and was 14% two years after diagnosis. Hematocrit was associated with the prevalence of CRF at diagnosis [OR, 0.92; confidence interval (CI), 0.88-0.95], 6 months (OR, 0.89; 95% CI, 0.86-0.92), and 2 years (OR, 0.91; CI, 0.87-0.96) after diagnosis. Lower hematocrit was associated with higher severity of CRF over time (beta-coefficient = 1.3; CI, 1.5-1.1)., Conclusions: Lower hematocrit levels were longitudinally associated with a higher prevalence and severity of CRF in colorectal cancer., Impact: Our findings emphasize the importance of long-term anemia monitoring and a potential role of anemia in CRF among colorectal cancer survivors., (©2024 American Association for Cancer Research.)

Background: High red meat and/or processed meat consumption are established colorectal cancer risk factors. We conducted a genome-wide gene-environment (GxE) interaction analysis to identify genetic variants that may modify these associations., Methods: A pooled sample of 29,842 colorectal cancer cases and 39,635 controls of European ancestry from 27 studies were included. Quantiles for red meat and processed meat intake were constructed from harmonized questionnaire data. Genotyping arrays were imputed to the Haplotype Reference Consortium. Two-step EDGE and joint tests of GxE interaction were utilized in our genome-wide scan., Results: Meta-analyses confirmed positive associations between increased consumption of red meat and processed meat with colorectal cancer risk [per quartile red meat OR = 1.30; 95% confidence interval (CI) = 1.21-1.41; processed meat OR = 1.40; 95% CI = 1.20-1.63]. Two significant genome-wide GxE interactions for red meat consumption were found. Joint GxE tests revealed the rs4871179 SNP in chromosome 8 (downstream of HAS2); greater than median of consumption ORs = 1.38 (95% CI = 1.29-1.46), 1.20 (95% CI = 1.12-1.27), and 1.07 (95% CI = 0.95-1.19) for CC, CG, and GG, respectively. The two-step EDGE method identified the rs35352860 SNP in chromosome 18 (SMAD7 intron); greater than median of consumption ORs = 1.18 (95% CI = 1.11-1.24), 1.35 (95% CI = 1.26-1.44), and 1.46 (95% CI = 1.26-1.69) for CC, CT, and TT, respectively., Conclusions: We propose two novel biomarkers that support the role of meat consumption with an increased risk of colorectal cancer., Impact: The reported GxE interactions may explain the increased risk of colorectal cancer in certain population subgroups., (©2023 American Association for Cancer Research.)

Background: Research on calcium intake as well as variants in the calcium sensor receptor ( CaSR) gene and their interaction in relation to CRC survival is still limited., Methods: Data from 18,952 CRC patients, were included. Associations between primarily pre-diagnostic dietary ( n  = 13.085), supplemental ( n  = 11,837), total calcium intake ( n  = 5970) as well as 325 single nucleotide polymorphisms (SNPs) of the CaSR gene ( n  = 15,734) in relation to CRC-specific and all-cause mortality were assessed using Cox proportional hazard models. Also interactions between calcium intake and variants in the CaSR gene were assessed., Results: During a median follow-up of 4.8 years (IQR 2.4-8.4), 6801 deaths occurred, of which 4194 related to CRC. For all-cause mortality, no associations were observed for the highest compared to the lowest sex- and study-specific quartile of dietary (HR 1.00, 95%CI 0.92-1.09), supplemental (HR 0.97, 95%CI 0.89-1.06) and total calcium intake (HR 0.99, 95%CI 0.88-1.11). No associations with CRC-specific mortality were observed either. Interactions were observed between supplemental calcium intake and several SNPs of the CaSR gene., Conclusion: Calcium intake was not associated with all-cause or CRC-specific mortality in CRC patients. The association between supplemental calcium intake and all-cause and CRC-specific mortality may be modified by genetic variants in the CaSR gene., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2024.)

Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values < 0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice., (© 2023. Springer Nature Limited.)

Purpose: Higher dairy consumption is associated with a lower risk of colorectal cancer (CRC), but no studies thus far have investigated its relation with recurrence in CRC. Few studies have investigated total dairy in relation to mortality in CRC, and yielded inconsistent results., Methods: In this prospective cohort study, people newly diagnosed with stage I-III CRC filled out a food frequency questionnaire at diagnosis (n = 1812) and six months after diagnosis (n = 1672). We examined associations between pre- and post-diagnostic intake of total dairy, low-fat dairy, high-fat dairy, milk, yoghurt, and cheese with recurrence and all-cause mortality using multivariable Cox proportional hazard models and restricted cubic splines (RCS)., Results: A total of 176 recurrences and 301 deaths occurred during a median follow-up of 3.0 and 5.9 years, respectively. Before diagnosis, a higher low-fat dairy intake was associated with a lower risk of recurrence (HR Q4vsQ1 : 0.42, 95% CI 0.26-0.67; P RCS : 0.008) and all-cause mortality (HR Q4vsQ1 : 0.58, 95% CI 0.41-0.81; P RCS  < 0.001), whereas a higher high-fat dairy consumption tended to be associated with an increased all-cause mortality risk (HR Q4vsQ1 : 1.41, 95% CI 0.98-2.01; P RCS : 0.030). After diagnosis, only the associations between low- and high-fat dairy in relation to all-cause mortality remained., Conclusions: This study demonstrated that higher pre- and post-diagnostic intakes of low-fat dairy were associated with a reduced all-cause mortality risk in people with stage I-III CRC, whereas higher intakes of high-fat dairy were associated with an increased all-cause mortality risk. Also, a higher pre-diagnostic low-fat dairy intake was associated with a reduced risk of recurrence., Trial Registration: Clinical Trials.gov identifier: NCT03191110., (© 2023. The Author(s).)

Background: Diabetes is an established risk factor for colorectal cancer. However, the mechanisms underlying this relationship still require investigation and it is not known if the association is modified by genetic variants. To address these questions, we undertook a genome-wide gene-environment interaction analysis., Methods: We used data from 3 genetic consortia (CCFR, CORECT, GECCO; 31,318 colorectal cancer cases/41,499 controls) and undertook genome-wide gene-environment interaction analyses with colorectal cancer risk, including interaction tests of genetics(G)xdiabetes (1-degree of freedom; d.f.) and joint testing of Gxdiabetes, G-colorectal cancer association (2-d.f. joint test) and G-diabetes correlation (3-d.f. joint test)., Results: Based on the joint tests, we found that the association of diabetes with colorectal cancer risk is modified by loci on chromosomes 8q24.11 (rs3802177, SLC30A8 - OR AA : 1.62, 95% CI: 1.34-1.96; OR AG : 1.41, 95% CI: 1.30-1.54; OR GG : 1.22, 95% CI: 1.13-1.31; p-value 3-d.f. : 5.46 × 10 -11 ) and 13q14.13 (rs9526201, LRCH1 - OR GG : 2.11, 95% CI: 1.56-2.83; OR GA : 1.52, 95% CI: 1.38-1.68; OR AA : 1.13, 95% CI: 1.06-1.21; p-value 2-d.f. : 7.84 × 10 -09 )., Discussion: These results suggest that variation in genes related to insulin signaling (SLC30A8) and immune function (LRCH1) may modify the association of diabetes with colorectal cancer risk and provide novel insights into the biology underlying the diabetes and colorectal cancer relationship., (© 2023. The Author(s).)

Aim: Colorectal anastomotic leakage (AL) is a serious complication. Studies on the impact of AL on health-related quality of life (HRQoL) are scarce. We aimed to investigate the association between AL and HRQoL in colorectal cancer patients up to 2 years after diagnosis, and to evaluate whether AL is associated with a clinically relevant decrease in HRQoL over time., Methods: Patients diagnosed with Stage I-III colorectal cancer undergoing elective surgical resection with primary anastomosis between 2010 and 2017 were included. HRQoL was evaluated using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30, represented by the summary score, and analysed at diagnosis and at 6 months and 2 years post-diagnosis. Multivariable linear regression was performed to assess the association between AL and HRQoL, while multivariable logistic regression was used to investigate the association between AL and a clinically relevant HRQoL decrease (≥10 points) during follow-up compared to the time of diagnosis., Results: In total, 1197 patients were included of whom 63 (5%) developed AL. AL was not associated with HRQoL at 6 months post-diagnosis nor at 2 years post-diagnosis. However, having AL was associated with an increased risk of a clinically relevant decrease in HRQoL at 6 months post-diagnosis (OR 3.65, 95% CI 1.62-8.21) but not at 2 years after diagnosis (OR 1.91, 95% CI 0.62-5.93)., Conclusion: Although AL was not associated with HRQoL at 6 months or 2 years post-diagnosis, AL was a determinant of a clinically relevant decrease in HRQoL at 6 months after diagnosis. Future work should identify feasible and effective strategies to prevent declines in QoL in this patient population., (© 2023 The Authors. Colorectal Disease published by John Wiley & Sons Ltd on behalf of Association of Coloproctology of Great Britain and Ireland.)

Colorectal cancer (CRC) is increasingly recognized as a heterogeneous disease. No studies have prospectively examined associations of blood metabolite concentrations with all-cause mortality in patients with colon and rectal cancer separately. Targeted metabolomics (Biocrates Absolute IDQ p180) and pathway analyses (MetaboAnalyst 4.0) were performed on pre-surgery collected plasma from 674 patients with non-metastasized (stage I-III) colon ( n = 394) or rectal cancer ( n = 283). Metabolomics data and covariate information were received from the international cohort consortium MetaboCCC. Cox proportional hazards models were computed to investigate associations of 148 metabolite levels with all-cause mortality adjusted for age, sex, tumor stage, tumor site (whenever applicable), and cohort; the false discovery rate (FDR) was used to account for multiple testing. A total of 93 patients (14%) were deceased after an average follow-up time of 4.4 years (60 patients with colon cancer and 33 patients with rectal cancer). After FDR adjustment, higher plasma creatinine was associated with a 39% increase in all-cause mortality in patients with rectal cancer. HR: 1.39, 95% CI 1.23-1.72, p FDR = 0.03; but not colon cancer: p FDR = 0.96. Creatinine is a breakdown product of creatine phosphate in muscle and may reflect changes in skeletal muscle mass. The starch and sucrose metabolisms were associated with increased all-cause mortality in colon cancer but not in rectal cancer. Genes in the starch and sucrose metabolism pathways were previously linked to worse clinical outcomes in CRC. In summary, our findings support the hypothesis that colon and rectal cancer have different etiological and clinical outcomes that need to be considered for targeted treatments.

Background: Tobacco smoking is an established risk factor for colorectal cancer. However, genetically defined population subgroups may have increased susceptibility to smoking-related effects on colorectal cancer., Methods: A genome-wide interaction scan was performed including 33,756 colorectal cancer cases and 44,346 controls from three genetic consortia., Results: Evidence of an interaction was observed between smoking status (ever vs. never smokers) and a locus on 3p12.1 (rs9880919, P = 4.58 × 10-8), with higher associated risk in subjects carrying the GG genotype [OR, 1.25; 95% confidence interval (CI), 1.20-1.30] compared with the other genotypes (OR <1.17 for GA and AA). Among ever smokers, we observed interactions between smoking intensity (increase in 10 cigarettes smoked per day) and two loci on 6p21.33 (rs4151657, P = 1.72 × 10-8) and 8q24.23 (rs7005722, P = 2.88 × 10-8). Subjects carrying the rs4151657 TT genotype showed higher risk (OR, 1.12; 95% CI, 1.09-1.16) compared with the other genotypes (OR <1.06 for TC and CC). Similarly, higher risk was observed among subjects carrying the rs7005722 AA genotype (OR, 1.17; 95% CI, 1.07-1.28) compared with the other genotypes (OR <1.13 for AC and CC). Functional annotation revealed that SNPs in 3p12.1 and 6p21.33 loci were located in regulatory regions, and were associated with expression levels of nearby genes. Genetic models predicting gene expression revealed that smoking parameters were associated with lower colorectal cancer risk with higher expression levels of CADM2 (3p12.1) and ATF6B (6p21.33)., Conclusions: Our study identified novel genetic loci that may modulate the risk for colorectal cancer of smoking status and intensity, linked to tumor suppression and immune response., Impact: These findings can guide potential prevention treatments., (©2022 American Association for Cancer Research.)

Background: Polygenic risk scores (PRS) which summarize individuals' genetic risk profile may enhance targeted colorectal cancer screening. A critical step towards clinical implementation is rigorous external validations in large community-based cohorts. This study externally validated a PRS-enhanced colorectal cancer risk model comprising 140 known colorectal cancer loci to provide a comprehensive assessment on prediction performance., Methods: The model was developed using 20,338 individuals and externally validated in a community-based cohort (n = 85,221). We validated predicted 5-year absolute colorectal cancer risk, including calibration using expected-to-observed case ratios (E/O) and calibration plots, and discriminatory accuracy using time-dependent AUC. The PRS-related improvement in AUC, sensitivity and specificity were assessed in individuals of age 45 to 74 years (screening-eligible age group) and 40 to 49 years with no endoscopy history (younger-age group)., Results: In European-ancestral individuals, the predicted 5-year risk calibrated well [E/O = 1.01; 95% confidence interval (CI), 0.91-1.13] and had high discriminatory accuracy (AUC = 0.73; 95% CI, 0.71-0.76). Adding the PRS to a model with age, sex, family and endoscopy history improved the 5-year AUC by 0.06 (P < 0.001) and 0.14 (P = 0.05) in the screening-eligible age and younger-age groups, respectively. Using a risk-threshold of 5-year SEER colorectal cancer incidence rate at age 50 years, adding the PRS had a similar sensitivity but improved the specificity by 11% (P < 0.001) in the screening-eligible age group. In the younger-age group it improved the sensitivity by 27% (P = 0.04) with similar specificity., Conclusions: The proposed PRS-enhanced model provides a well-calibrated 5-year colorectal cancer risk prediction and improves discriminatory accuracy in the external cohort., Impact: The proposed model has potential utility in risk-stratified colorectal cancer prevention., (©2023 American Association for Cancer Research.)

Objectives: Timely identification of colorectal cancer (CRC) survivors at risk of experiencing low health-related quality of life (HRQoL) in the near future is important for enabling appropriately tailored preventive actions. We previously developed and internally validated risk prediction models to estimate the 1-year risk of low HRQoL in long-term CRC survivors. In this article, we aim to externally validate and update these models in a population of short-term CRC survivors., Study Design and Setting: In a pooled cohort of 1,596 CRC survivors, seven HRQoL domains (global QoL, cognitive/emotional/physical/role/social functioning, and fatigue) were measured prospectively at approximately 5 months postdiagnosis (baseline for prediction) and approximately 1 year later by a validated patient-reported outcome measure (European Organization for Research and Treatment of Cancer Quality of life Questionnaire-Core 30). For each HRQoL domain, 1-year scores were dichotomized into low vs. normal/high HRQoL. Performance of the previously developed multivariable logistic prediction models was evaluated (calibration and discrimination). Models were updated to create a more parsimonious predictor set for all HRQoL domains., Results: Updated models showed good calibration and discrimination (AUC ≥0.75), containing a single set of 15 predictors, including nonmodifiable (age, sex, education, time since diagnosis, chemotherapy, radiotherapy, stoma, and comorbidities) and modifiable predictors (body mass index, physical activity, smoking, anxiety/depression, and baseline fatigue and HRQoL domain scores)., Conclusion: Externally validated and updated prediction models performed well for estimating the 1-year risk of low HRQoL in CRC survivors within 6 months postdiagnosis. The impact of implementing the models in oncology practice to improve HRQoL outcomes in CRC survivors needs to be evaluated., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk., Methods: We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2- or 3-degree-of-freedom joint test. A set-based score test was applied for rare genetic variants., Results: The use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2-degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P < 1.2 × 10-4)., Conclusion: Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)