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Background: To study how caretaker gene silencing relates to gatekeeper mutations in colorectal cancer (CRC), we investigated whether O6-methylguanine DNA methyltransferase (MGMT) and Human Mut-L Homologue 1 (MLH1) promoter hypermethylation are associated with APC, KRAS and BRAF mutations among 734 CRC patients. [ABSTRACT FROM PUBLISHER]

Case-cohort analyses were performed on meat and fish consumption in relation to K-ras mutations in 448 colon and 160 rectal cancers that occurred during 7.3 years of follow-up, excluding the first 2.3 years, and 2948 subcohort members of The Netherlands Cohort Study on diet and cancer. Adjusted incidence rate ratios and 95% confidence intervals were computed for colon and rectal cancer and for K-ras mutation status subgroups. Total fresh meat, most types of fresh meat and fish were not associated with colon or rectal cancer, neither overall nor with K-ras mutation status. However, several weak associations were observed for tumours with a wild-type K-ras, including beef and colon tumours, and an inverse association for pork with colon and rectal tumours; for meat products, an increased association was observed with wild-type K-ras tumours in the colon and possibly with G>A transitions in rectal tumours. [ABSTRACT FROM AUTHOR]

Cigarette smoking has inconsistently been associated with an increased risk of colorectal cancer. One of the enzymes responsible for the detoxification of the carcinogenic compounds present in tobacco smoke is glutathione S -transferase-μ (GST-μ). The gene that codes for this enzyme is GSTM1 . In this study, we evaluated the associations and interaction between GSTM1 deletion, smoking behaviour and the development of colorectal cancer. We performed a pooled analysis within the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens (GSEC). We selected six studies on colorectal cancer, including 1130 cases and 2519 controls, and restricted our analyses to Caucasians because the number of patients from other races was too limited. In addition we performed a meta-analysis including the studies from the GSEC database and other studies identified on MEDLINE on the same subject. The prevalence of the GSTM1 null genotype was within the range reported in other studies: 51.8% of the cases had the GSTM1 null genotype versus 56.6% of the controls. No significant association between the GSTM1 null genotype and colorectal cancer was found (odds ratio 0.92, 95% confidence interval 0.73-1.14). Our results suggest a possible positive association between lack of the GST-μ enzyme and colorectal cancer for non-smoking women (odds ratio 1.47, 95% confidence interval 0.80-2.70). There was no interaction between the effects of smoking and GSTM1 genotype on colorectal cancer risk in men and women (χ 2 =0.007, p =0.97). Our findings do not support an association between the GSTM1 null genotype and colorectal cancer. In addition, we did not find any modification of the smoking-induced colorectal cancer risk by GSTM1 genotype [ABSTRACT FROM AUTHOR]

Purpose: Evidence from cross-sectional studies suggests that higher levels of light-intensity physical activity (LPA) are associated with better health-related quality of life (HRQoL) in colorectal cancer (CRC) survivors. However, these associations have not been investigated in longitudinal studies that provide the opportunity to analyse how within-individual changes in LPA affect HRQoL. We investigated longitudinal associations of LPA with HRQoL outcomes in CRC survivors, from 6 weeks to 2 years post-treatment. Methods: Data were used of a prospective cohort study among 325 stage I–III CRC survivors (67% men, mean age: 67 years), recruited between 2012 and 2016. Validated questionnaires were used to assess hours/week of LPA (SQUASH) and HRQoL outcomes (EORTC QLQ-C30, Checklist Individual Strength) at 6 weeks, and 6, 12 and 24 months post-treatment. We applied linear mixed regression to analyse longitudinal confounder-adjusted associations of LPA with HRQoL. Results: We observed statistically significant longitudinal associations between more LPA and better global quality of life and physical, role and social functioning, and less fatigue over time. Intra-individual analysis showed that within-person increases in LPA (per 8 h/week) were related to improved HRQoL, including better global quality of life (β = 1.67, 95% CI 0.71; 2.63; total range scale: 0–100) and less fatigue (β = − 1.22, 95% CI − 2.37; − 0.07; scale: 20–140). Stratified analyses indicated stronger associations among participants below the median of moderate-to-vigorous physical activity (MVPA) at diagnosis. Conclusion: Higher levels of LPA were longitudinally associated with better HRQoL and less fatigue in CRC survivors up to two years post-treatment. Further prospective studies using accelerometer data are necessary to inform development of interventions targeting LPA. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) treatment is associated with a high morbidity which may result in a reduced health-related quality of life (HRQoL). The pre-operative measurement of handgrip strength (HGS) might be a tool to predict the patient's outcome after CRC surgery. The aim of this study was to evaluate the association of pre-operative HGS with the occurrence of postoperative complications and postoperative HRQoL. Stage I to III CRC patients ≥ 18 years were included at diagnosis. Demographic and clinical data as well as HGS were collected before start of treatment. HGS was classified as weak if it was below the gender-specific 25th percentile of our study population; otherwise HGS was classified as normal. The occurrence of postoperative complications within 30 days after surgery was collected from medical records. Cancer-specific HRQoL was measured 6 weeks after treatment using the EORTC QLQ-C30 and the EORTC QLQ-CR29 questionnaire. Of 295 patients who underwent surgical treatment for CRC, 67 (23%) patients had a weak HGS while 228 (77%) patients had normal HGS. 118 patients (40%) developed a postoperative complication. Complications occurred in 37% of patients with a weak HGS and in 41% of patients with a normal HGS (p = 0.47). After adjustment for age, sex, ASA, BMI and TNM, no significant associations between pre-operative HGS and the occurrence of postoperative complications and between HGS and HRQoL were found. We conclude that a single pre-operative HGS measurement was not associated with the occurrence of postoperative complications or post-treatment HRQoL in stage I–III CRC patients. [ABSTRACT FROM AUTHOR]

Background: In cancer patients with a poor prognosis, low skeletal muscle radiographic density is associated with higher mortality. Whether this association also holds for early-stage cancer is not very clear. We aimed to study the association between skeletal muscle density and overall mortality among early-stage (stage I-III) colorectal cancer (CRC) patients. Furthermore, we investigated the association between skeletal muscle density and both CRC-specific mortality and disease-free survival in a subset of the study population.Methods: Skeletal muscle density was assessed in 1681 early-stage CRC patients, diagnosed between 2006 and 2015, using pre-operative computed tomography images. Adjusted Cox proportional hazard models were used to evaluate the association between muscle density and overall mortality, CRC-specific mortality and disease-free survival.Results: The median follow-up time was 48 months (range 0-119 months). Low muscle density was detected in 39% of CRC patients. Low muscle density was significantly associated with higher mortality (low vs. normal: adjusted HR 1.91, 95% CI 1.53-2.38). After stratification for comorbidities, the association was highest in patients with ≥ 2 comorbidities (HR 2.11, 95% CI 1.55-2.87). Furthermore, low skeletal muscle density was significantly associated with poorer disease-free survival (HR 1.68, 95% CI 1.14-2.47), but not with CRC-specific mortality (HR 1.68, 95% CI 0.89-3.17) in a subset of the study population.Conclusion: In early-stage CRC patients, low muscle density was significantly associated with higher overall mortality, and worse disease-free survival. [ABSTRACT FROM AUTHOR]

Insulin-like growth factors (IGFs) have been associated with growth, body size, physical activity and colorectal cancer (CRC). We hypothesized that variants in IGF-related genes increase the CRC susceptibility associated with a larger body size and a lack of physical activity. We assessed this in The Netherlands Cohort Study. Participants (n = 120 852) completed a baseline questionnaire on diet and cancer. ~75% returned toenail clippings. Using a case-cohort approach and 16.3 years of follow-up, toenail DNA from 3768 subcohort members and 2580 CRC cases was genotyped. We aggregated unfavorable alleles (potentially increasing CRC risk) for 18 single nucleotide polymorphisms in 8 genes into a sum score. The sum score (in tertiles) and an IGF1 19-CA repeat polymorphism (19/19, 19/non-19 and non-19/non-19 repeats) in combination with body size (mostly in tertiles) and (non-)occupational physical activity (>12, 8-12 and <8 kJ/min in the job and >90, >60-90, >30-60 and =30 min/day) were analyzed by Cox regression. Increasingly higher hazard ratios (HRs) for CRC were observed for a larger adult body mass index, larger trouser size and tallness in the presence of more unfavorable alleles in men. HRs (95% confidence intervals) for joint effects were 1.55 (1.06-2.25), 1.78 (1.29-2.46) and 1.48 (1.01-2.17), respectively. In women, variant repeat alleles halved CRC risk irrespective of body size and physical activity. Almost no interactions tested significant. To conclude, a larger body size was a CRC risk factor in men in the presence of an accumulation of unfavorable alleles in IGF-related genes, but interactions were generally nonsignificant. [ABSTRACT FROM AUTHOR]

Background We studied the overlap between the major (epi)genomic events microsatellite instability (MSI), the CpG island methylator phenotype (CIMP) and chromosomal instability (CIN) in colorectal cancer (CRC), and whether specific (epi)genotypes were associated with CRC-related deaths. Patients and methods Molecular analyses using tumor DNA were successful in 509 CRC cases identified within the Netherlands Cohort Study in the period 1989–1993. Follow-up for the vital status until May 2005 was 100%. Results MSI (12.6%), CIMP-only (5.3%), CIMP + CIN (13.4%), CIN-only (58.2%) and triple-negative tumors (10.6%) differed significantly regarding tumor localization, differentiation grade, initial adjuvant therapy (AT) use and genetic characteristics (P ≤ 0.03). CIMP-only, CIMP + CIN and triple-negative tumors, compared with CIN-only tumors, were significantly associated with a 3.67, 2.44 and 3.78-fold risk of CRC-related deaths after 2-year follow-up (95% confidence intervals, CIs, 1.70–7.91, 1.35–4.41 and 1.97–7.25, respectively), but not after late follow-up. MSI tumors were borderline significantly associated with a 0.40-fold risk of CRC-related deaths after late follow-up (95% CI 0.15–1.03). Conclusion(s) This is the first study to show that specific (epi)genotypes may hold a differential prognostic value that may vary over time. Although no specific treatment data were available, an explanation for the differential findings over time might be that (epi)genotypes modify therapy response. [ABSTRACT FROM PUBLISHER]

Energy-adjusted magnesium intake was nonsignificantly inversely related to risk of colorectal cancer (n=2328) in the Netherlands Cohort Study on Diet and Cancer that started in 1986 (n=58 279 men and 62 573 women). Statistically significant inverse trends in risk were observed in overweight subjects for colon and proximal colon cancer across increasing quintiles of magnesium uptake (P-trend, 0.05 and 0.02, respectively). Although an overall protective effect was not afforded, our results suggest an effect of magnesium in overweight subjects, possibly through decreasing insulin resistance.British Journal of Cancer (2007) 96, 510–513. doi:10.1038/sj.bjc.6603577 www.bjcancer.com [ABSTRACT FROM AUTHOR]