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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 (HRDIScontinuous 1.09 95%CI 1.02; 1.15; HRLIScontinuous 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.
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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.
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Predisposición Genética a la Enfermedad , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Enfermedad del Hígado Graso no Alcohólico/genética , Masculino , Femenino , Anciano , Persona de Mediana Edad , Países Bajos/epidemiología , Estudios de Cohortes , Enfermedad Coronaria/epidemiología , Enfermedad Coronaria/genética , Factores de Riesgo , Dieta/métodos , Dieta/estadística & datos numéricos , Prevalencia , Dieta Saludable/estadística & datos numéricos , Dieta Saludable/métodos , Infarto del Miocardio/epidemiología , Infarto del Miocardio/genéticaRESUMEN
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.
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Neoplasias Colorrectales , Productos Lácteos , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Humanos , Masculino , Femenino , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/epidemiología , Persona de Mediana Edad , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/epidemiología , Anciano , Estudios Prospectivos , Grasas de la Dieta/administración & dosificación , Grasas de la Dieta/efectos adversos , Factores Sexuales , Factores de Riesgo , Modelos de Riesgos Proporcionales , Dieta Alta en Grasa/efectos adversosRESUMEN
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.
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Café , Neoplasias Colorrectales , Humanos , Factores de Riesgo , Estudios Prospectivos , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/prevención & control , Causas de Muerte , Encuestas y CuestionariosRESUMEN
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.
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Índice de Masa Corporal , Neoplasias Colorrectales , Análisis de la Aleatorización Mendeliana , Relación Cintura-Cadera , Humanos , Análisis de la Aleatorización Mendeliana/métodos , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/genética , Masculino , Femenino , Factores de Riesgo , Circunferencia de la CinturaRESUMEN
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.
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Anemia , Neoplasias Colorrectales , Masculino , Humanos , Femenino , Hematócrito , Estudios Prospectivos , Sobrevivientes , Fatiga/epidemiología , Fatiga/etiología , Anemia/epidemiología , Anemia/etiología , Neoplasias Colorrectales/complicaciones , Neoplasias Colorrectales/epidemiologíaRESUMEN
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.
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Neoplasias Colorrectales , Calidad de Vida , Masculino , Humanos , Femenino , Ejercicio Físico , Estudios de Cohortes , Neoplasias Colorrectales/diagnóstico , FatigaRESUMEN
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.
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Neoplasias Colorrectales , Carne Roja , Humanos , Interacción Gen-Ambiente , Carne Roja/efectos adversos , Carne/efectos adversos , Factores de Riesgo , Neoplasias Colorrectales/genéticaRESUMEN
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.
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Neoplasias Colorrectales , Etnicidad , Humanos , Etnicidad/genética , Estudio de Asociación del Genoma Completo , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Herencia Multifactorial , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genéticaRESUMEN
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 (HRQ4vsQ1: 0.42, 95% CI 0.26-0.67; PRCS: 0.008) and all-cause mortality (HRQ4vsQ1: 0.58, 95% CI 0.41-0.81; PRCS < 0.001), whereas a higher high-fat dairy consumption tended to be associated with an increased all-cause mortality risk (HRQ4vsQ1: 1.41, 95% CI 0.98-2.01; PRCS: 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.
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Queso , Neoplasias Colorrectales , Humanos , Animales , Productos Lácteos , Estudios Prospectivos , Leche , Neoplasias Colorrectales/diagnóstico , Dieta con Restricción de Grasas , Factores de Riesgo , DietaRESUMEN
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 AbsoluteIDQ 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, pFDR = 0.03; but not colon cancer: pFDR = 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.
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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.
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Fuga Anastomótica , Neoplasias Colorrectales , Humanos , Fuga Anastomótica/epidemiología , Calidad de Vida , Neoplasias Colorrectales/etiología , Anastomosis Quirúrgica/efectos adversos , Colectomía/efectos adversosRESUMEN
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.
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Supervivientes de Cáncer , Neoplasias Colorrectales , Humanos , Calidad de Vida , Neoplasias Colorrectales/epidemiología , Sobrevivientes , Fatiga , Encuestas y CuestionariosRESUMEN
BACKGROUND: Fatigue is often reported by colorectal cancer survivors and largely impacts their quality of life. Inflammation has been linked to fatigue mainly in patients with breast cancer. Therefore, we investigated how inflammation is longitudinally associated with fatigue in colorectal cancer survivors, up to 2 years posttreatment. METHODS: A total of 257 patients from the ongoing Energy for life after ColoRectal cancer cohort study were included in the analysis. Plasma levels of IL6, IL8, IL10, TNFα, high-sensitivity C-reactive protein (hsCRP), and fatigue were measured at 6 weeks, 6, 12, and 24 months posttreatment. Fatigue was measured through the validated Checklist Individual Strength (CIS; total, 20-140), consisting of four subscales - subjective fatigue (8-56), motivation (4-28), physical activity (3-21), and concentration (5-35), and the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 fatigue subscale (0-100). Linear mixed-models were used to assess the confounder-adjusted longitudinal associations between inflammatory markers and overall fatigue along with the subscales. RESULTS: Mean levels of CIS fatigue decreased from 62.9 at 6 weeks to 53.0 at 24 months. In general, levels of inflammatory markers also decreased over time. No statistically significant longitudinal associations were found between IL6, IL8, IL10, TNFα, and fatigue. Higher levels of hsCRP were associated with more CIS fatigue (ß per SD 3.21, 95% confidence interval (CI), 1.42-5.01) and EORTC fatigue (ß 2.41, 95% CI, 0.72-4.10). CONCLUSIONS: Increased levels of hsCRP are longitudinally associated with more posttreatment fatigue in colorectal cancer survivors. IMPACT: These findings suggest that low-grade inflammation may play a role in fatigue reported by colorectal cancer survivors up to 2 years posttreatment.
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Neoplasias Colorrectales , Calidad de Vida , Biomarcadores , Proteína C-Reactiva/metabolismo , Estudios de Cohortes , Fatiga/etiología , Humanos , Inflamación , Interleucina-10 , Interleucina-6 , Interleucina-8 , Factor de Necrosis Tumoral alfaRESUMEN
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 28â486 postmenopausal women (11â519 CRC patients and 16â967 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.
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Neoplasias Colorrectales , Progestinas , Estudios de Casos y Controles , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/genética , Estrógenos , Femenino , Humanos , Menopausia , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
BACKGROUND: Folate-mediated 1-carbon metabolism requires several nutrients, including vitamin B6. Circulating biomarker concentrations indicating high vitamin B6 status are associated with a reduced risk of colorectal cancer (CRC). However, little is known about the effect of B6 status in relation to clinical outcomes in CRC patients. OBJECTIVES: We investigated survival outcomes in relation to vitamin B6 status in prospectively followed CRC patients. METHODS: A total of 2031 patients with stage I-III CRC participated in 6 prospective patient cohorts in the international FOCUS (folate-dependent 1-carbon metabolism in colorectal cancer recurrence and survival) Consortium. Preoperative blood samples were used to measure vitamin B6 status by the direct marker pyridoxal 5'-phosphate (PLP), as well as the functional marker HK-ratio (HKr)[3'-hydroxykynurenine: (kynurenic acid + xanthurenic acid + 3'-hydroxy anthranilic acid + anthranilic acid)]. Using Cox proportional hazards regression, we examined associations of vitamin B6 status with overall survival (OS), disease-free survival (DFS), and risk of recurrence, adjusted for patient age, sex, circulating creatinine concentrations, tumor site, stage, and cohort. RESULTS: After a median follow-up of 3.2 y for OS, higher preoperative vitamin B6 status as assessed by PLP and the functional marker HKr was associated with 16-32% higher all-cause and disease-free survival, although there was no significant association with disease recurrence (doubling in PLP concentration: HROS, 0.68; 95% CI: 0.59, 0.79; HRDFS, 0.84; 95% CI: 0.75, 0.94; HRRecurrence, 0.96; 95% CI: 0.84, 1.09; HKr: HROS, 2.04; 95% CI: 1.67, 2.49; HRDFS, 1.56; 95% CI: 1.31, 1.85; HRRecurrence, 1.21; 95% CI: 0.96,1. 52). The association of PLP with improved OS was consistent across colorectal tumor site (right-sided colon: HROS, 0.75; 95% CI: 0.59, 0.96; left-sided colon: HROS, 0.71; 95% CI: 0.55, 0.92; rectosigmoid junction and rectum: HROS, 0.61; 95% CI: 0.47, 0.78). CONCLUSION: Higher preoperative vitamin B6 status is associated with improved OS among stage I-III CRC patients.
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Neoplasias Colorrectales , Vitamina B 6 , Biomarcadores , Carbono , Neoplasias Colorrectales/cirugía , Ácido Fólico , Humanos , Recurrencia Local de Neoplasia , Estudios Prospectivos , Fosfato de PiridoxalRESUMEN
BACKGROUND: The etiology of colorectal cancer is not fully understood. METHODS: Using genetic variants and metabolomics data including 217 metabolites from the Framingham Heart Study (n = 1,357), we built genetic prediction models for circulating metabolites. Models with prediction R2 > 0.01 (Nmetabolite = 58) were applied to predict levels of metabolites in two large consortia with a combined sample size of approximately 46,300 cases and 59,200 controls of European and approximately 21,700 cases and 47,400 controls of East Asian (EA) descent. Genetically predicted levels of metabolites were evaluated for their associations with colorectal cancer risk in logistic regressions within each racial group, after which the results were combined by meta-analysis. RESULTS: Of the 58 metabolites tested, 24 metabolites were significantly associated with colorectal cancer risk [Benjamini-Hochberg FDR (BH-FDR) < 0.05] in the European population (ORs ranged from 0.91 to 1.06; P values ranged from 0.02 to 6.4 × 10-8). Twenty one of the 24 associations were replicated in the EA population (ORs ranged from 0.26 to 1.69, BH-FDR < 0.05). In addition, the genetically predicted levels of C16:0 cholesteryl ester was significantly associated with colorectal cancer risk in the EA population only (OREA: 1.94, 95% CI, 1.60-2.36, P = 2.6 × 10-11; OREUR: 1.01, 95% CI, 0.99-1.04, P = 0.3). Nineteen of the 25 metabolites were glycerophospholipids and triacylglycerols (TAG). Eighteen associations exhibited significant heterogeneity between the two racial groups (PEUR-EA-Het < 0.005), which were more strongly associated in the EA population. This integrative study suggested a potential role of lipids, especially certain glycerophospholipids and TAGs, in the etiology of colorectal cancer. CONCLUSIONS: This study identified potential novel risk biomarkers for colorectal cancer by integrating genetics and circulating metabolomics data. IMPACT: The identified metabolites could be developed into new tools for risk assessment of colorectal cancer in both European and EA populations.
Asunto(s)
Neoplasias Colorrectales , Pueblo Asiatico , Estudios de Casos y Controles , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Glicerofosfolípidos , Humanos , Lípidos , Metabolómica/métodosRESUMEN
Post-treatment adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) lifestyle recommendations were associated with health-related quality of life (HRQoL), fatigue, and chemotherapy-induced peripheral neuropathy (CIPN) in colorectal cancer (CRC) survivors. In a prospective cohort among CRC survivors (n = 459), repeated home-visits were performed at 6 weeks, 6, 12, and 24 months post-treatment. Dietary intake, body composition, sedentary behaviour, and physical activity were assessed to construct a lifestyle score based on adherence to seven 2018 WCRF/AICR recommendations. Longitudinal associations of the lifestyle score with HRQoL, fatigue, and CIPN were analysed by confounder-adjusted linear mixed models. A higher lifestyle score was associated with better physical functioning and less activity-related fatigue, but not with CIPN. Adjustment for physical activity substantially attenuated observed associations, indicating its importance in the lifestyle score with regards to HRQoL. In contrast, adjustment for body composition and alcohol inflated observed associations, indicating that both recommendations had a counteractive influence within the lifestyle score. Our findings suggest that CRC survivors benefit from an overall adherence to the WCRF/AICR lifestyle recommendations in terms of HRQoL and fatigue, but not CIPN. Specific recommendations have a varying influence on these associations, complicating the interpretation and requiring further study.
RESUMEN
BACKGROUND: Glycemic traits-such as hyperinsulinemia, hyperglycemia, and type 2 diabetes-have been associated with higher colorectal cancer risk in observational studies; however, causality of these associations is uncertain. We used Mendelian randomization (MR) to estimate the causal effects of fasting insulin, 2-hour glucose, fasting glucose, glycated hemoglobin (HbA1c), and type 2 diabetes with colorectal cancer. METHODS: Genome-wide association study summary data were used to identify genetic variants associated with circulating levels of fasting insulin (n = 34), 2-hour glucose (n = 13), fasting glucose (n = 70), HbA1c (n = 221), and type 2 diabetes (n = 268). Using 2-sample MR, we examined these variants in relation to colorectal cancer risk (48 214 case patient and 64 159 control patients). RESULTS: In inverse-variance models, higher fasting insulin levels increased colorectal cancer risk (odds ratio [OR] per 1-SD = 1.65, 95% confidence interval [CI] = 1.15 to 2.36). We found no evidence of any effect of 2-hour glucose (OR per 1-SD = 1.02, 95% CI = 0.86 to 1.21) or fasting glucose (OR per 1-SD = 1.04, 95% CI = 0.88 to 1.23) concentrations on colorectal cancer risk. Genetic liability to type 2 diabetes (OR per 1-unit increase in log odds = 1.04, 95% CI = 1.01 to 1.07) and higher HbA1c levels (OR per 1-SD = 1.09, 95% CI = 1.00 to 1.19) increased colorectal cancer risk, although these findings may have been biased by pleiotropy. Higher HbA1c concentrations increased rectal cancer risk in men (OR per 1-SD = 1.21, 95% CI = 1.05 to 1.40), but not in women. CONCLUSIONS: Our results support a causal effect of higher fasting insulin, but not glucose traits or type 2 diabetes, on increased colorectal cancer risk. This suggests that pharmacological or lifestyle interventions that lower circulating insulin levels may be beneficial in preventing colorectal tumorigenesis.