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Background: Previous research suggests that Warburg‐subtypes are related to potentially important survival differences in colorectal cancer (CRC) patients. In the present study, we investigated whether mutational subgroups based on somatic mutations in RAS, BRAF, PIK3CA, and MET, which are known to promote the Warburg‐effect, as well as mismatch repair (MMR) status, hold prognostic value in CRC. In addition, we investigated whether Warburg‐subtypes provide additional prognostic information, independent of known prognostic factors like TNM stage. Methods: CRC patients (n = 2344) from the prospective Netherlands Cohort Study (NLCS) were classified into eight mutually exclusive mutational subgroups, based on observed mutations in RAS, BRAF, PIK3CA, and MET, and MMR status: All‐wild‐type + MMRproficient, KRASmut + MMRproficient, KRASmut + PIK3CAmut + MMRproficient, PIK3CAmut + MMRproficient, BRAFmut + MMRproficient, BRAFmut + MMRdeficient, other + MMRproficient, and other + MMRdeficient. Kaplan–Meier curves and Cox regression models were used to investigate associations between mutational subgroups and survival, as well as associations between our previously established Warburg‐subtypes and survival within these mutational subgroups. Results: Compared to patients with all‐wild‐type + MMRproficient CRC, patients with KRASmut + MMRproficient, KRASmut + PIK3CAmut + MMRproficient, BRAFmut + MMRproficient, or other + MMRproficient CRC had a statistically significant worse survival (HRCRC‐specific ranged from 1.29 to 1.88). In contrast, patients with other + MMRdeficient CRC had the most favorable survival (HRCRC‐specific 0.48). No statistically significant survival differences were observed for the Warburg‐subtypes within mutational subgroups. Conclusion: Our results highlight the prognostic potential of mutational subgroups in CRC. Warburg‐subtypes did not provide additional prognostic information within these mutational subgroups. Future larger‐scale prospective studies are necessary to validate our findings and to examine the potential clinical utility of CRC subtyping based on mutational subgroups. [ABSTRACT FROM AUTHOR]

Background: Energy balance-related factors [body mass index (BMI), waist circumference, physical activity] have been associated with colorectal cancer risk. Warburg effect activation via PI3K/Akt signaling is one of the proposed mechanisms. We investigated whether energy balance-related factors were associated with risk of Warburg subtypes in colorectal cancer. Methods: We investigated this using immunohistochemistry for six proteins involved in the Warburg effect (LDHA, GLUT1, MCT4, PKM2, P53, PTEN) on tissue microarrays of 2,399 incident colorectal cancer cases from the prospective Netherlands Cohort Study (ntotal = 120,852; nsubcohort = 5,000; aged 55-69 in 1986; 20.3 years follow-up). Data analyses included 3,911 subcohort members and 1,972 colorectal cancer cases with complete covariate data. Expression levels of all proteins were combined into a pathway-based sum score and categorized into three "Warburg subtypes" (Warburg-low/moderate/high). Multivariable Cox regression analyses were used to estimate associations of BMI, clothing size (waist circumference proxy), and physical activity with Warburg subtypes in colorectal cancer. Results: BMI and clothing size were positively associated with Warburg-moderate and Warburg-high colon cancer risk in men (Pheterogeneity = 0.192). In women, clothing size was positively associated with Warburg-low and Warburg-high colon cancer (Pheterogeneity = 0.005). Nonoccupational physical activity was inversely associated with Warburg-low and Warburg-moderate colon cancer in women (Pheterogeneity = 0.045), but positively associated with Warburg-high rectal cancer in men (Pheterogeneity = 0.089). Conclusions: The Warburg effect might be involved in associations between adiposity and colon cancer risk, though additional mechanisms could be at play in women as well. The inverse association between physical activity and colon cancer might be explained by mechanisms other than the Warburg effect. [ABSTRACT FROM AUTHOR]

Background: Scoring of immunohistochemistry (IHC) staining is often done by non-pathologists, especially in large-scale tissue microarray (TMA)-based studies. Studies on the validity and reproducibility of scoring results from non-pathologists are limited. Therefore, our main aim was to assess interobserver agreement between trained non-pathologists and an experienced histopathologist for three IHC markers with different subcellular localization (nucleus/membrane/cytoplasm). Methods: Three non-pathologists were trained in recognizing adenocarcinoma and IHC scoring by a senior histopathologist. Kappa statistics were used to analyze interobserver and intraobserver agreement for 6,249 TMA cores from a colorectal cancer series. Results: Interobserver agreement between non-pathologists (independently scored) and the histopathologist was "substantial" for nuclear and membranous IHC markers (Krange= 0.67-0.75 and Krange= 0.61-0.69, respectively), and "moderate" for the cytoplasmic IHC marker (Krange= 0.43-0.57). Scores of the three non-pathologists were also combined into a "combination score" (if at least two non-pathologists independently assigned the same score to a core, this was the combination score). This increased agreement with the pathologist (Knuclear = 0.74; Kmembranous = 0.73; Kcytopasmic = 0.57). Interobserver agreement between non-pathologists was "substantial" (Knuclear = 0.78; Kmembranous = 0.72; Kcytopasmic = 0.61). Intraobserver agreement of non-pathologists was "substantial" to "almost perfect" (Knuclear,range = 0.83-0.87; Kmembranous,range = 0.75-0.82; Kcytopasmic = 0.69). Overall, agreement was lowest for the cytoplasmic IHC marker. Conclusions: This study shows that adequately trained non-pathologists are able to generate reproducible IHC scoring results, that are similar to those of an experienced histopathologist. A combination score of at least two non-pathologists yielded optimal results. [ABSTRACT FROM AUTHOR]

Adult‐attained height is a marker for underlying mechanisms, such as cell growth, that may also influence postmenopausal breast cancer (BC) risk, perhaps specifically hormone‐sensitive BC subtypes. Early life energy restriction may inhibit these mechanisms, resulting in shorter height and a reduced postmenopausal BC risk. Women (62,573) from the Netherlands Cohort Study completed a self‐administered questionnaire in 1986 when 55–69 years old, and were followed‐up for 20.3 years (case–cohort: Nsubcohort = 2,438; Ncases = 3,354). Cox multivariable‐adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated for BC risk overall and by estrogen and progesterone receptor subtypes in relation to height and early life energy restriction during the Hunger Winter, War Years, and Economic Depression. Although energy restriction can only influence longitudinal growth in women exposed before and/or during the growth spurt, it may also influence BC risk when occurring after the growth spurt, possibly through different growth processes. Therefore, Cox analyses were additionally conducted according to timing of energy restriction in relation to the growth spurt. Height was associated with an increased BC risk (HRper 5cm = 1.07, 95%CI:1.01–1.13), particularly hormone receptor‐positive BC. Energy restriction before and/or during the growth spurt was associated with a decreased hormone receptor‐positive BC risk. Energy restriction during the Hunger Winter increased the estrogen receptor‐negative BC risk regardless of the timing of energy restriction. In conclusion, height and energy restriction before and/or during the growth spurt were both associated with hormone receptor‐positive BC risk, in the direction as expected, indicating critical exposure windows for hormonal growth‐related mechanisms. What's new? Evidence suggests that postmenopausal breast cancer risk increases with height, while risk is reduced among individuals who experience reduced caloric intake in early life, which can result in shorter adult stature. In this investigation of women in the Netherlands Cohort Study, significant early‐life energy restriction, either before or during the pubertal growth spurt, was associated specifically with a decreased risk of estrogen receptor‐positive and progesterone receptor‐positive postmenopausal breast cancer. Greater adult‐attained height was significantly associated with increased hormone receptor‐positive postmenopausal breast cancer risk. The findings highlight the influence of hormonal growth‐related mechanisms on later postmenopausal breast cancer risk. [ABSTRACT FROM AUTHOR]

Alcohol consumption has consistently been shown to increase breast cancer (BC) risk. This association may be modified by single nucleotide polymorphisms (SNPs) in alcohol dehydrogenase (ADH) isoenzymes ADH1B and ADH1C. The Netherlands Cohort Study comprises 62 573 women, aged 55–69 years at baseline (1986). Follow-up for postmenopausal BC for 20.3 years was available. Genotyping of six tag SNPs in ADH1B and ADH1C was performed on DNA from toenails. A case−cohort approach was used for analysis (complete data available for n subcohort = 1301; n cases = 1630). Cox regression models for postmenopausal BC were applied to determine marginal effects of alcohol intake and SNPs using a dominant genetic model, as well as multiplicative interaction of the two. Results were also obtained for subtypes by estrogen receptor (ER) and progesterone receptor (PR) status. Multiple testing was adjusted for by applying the false discovery rate (FDR). Alcohol intake (categorical) increased the risk of postmenopausal BC (P trend = 0.031). Trends for ER and PR subgroups followed a similar pattern. Continuous modeling of alcohol resulted in a hazard rate ratio (HR) for overall postmenopausal BC of 1.09 (95% confidence interval: 1.01–1.19) per 10 g/day of alcohol. SNPs were not associated with BC risk. No effect modification of the alcohol−BC association by SNP genotype was seen after FDR correction in overall BC and ER/PR subgroups. In conclusion, alcohol consumption was shown to increase the risk of postmenopausal BC. This association was not significantly modified by common SNPs in ADH1B and ADH1C, neither in overall BC nor in hormone receptor-defined subtypes. [ABSTRACT FROM AUTHOR]

Low mitochondrial DNA (mtDNA) copy number in tumors has been associated with worse prognosis in colorectal cancer (CRC). This study further deciphers the role of mtDNA copy number in CRC by comparing mtDNA copy number between healthy, adenoma and carcinoma tissue, by investigating its association according to several clinicopathological characteristics in CRC, and by relating it to CRC-specific survival in CRC patients. A hospital-based series of samples including cancer, adenoma and adjacent histologically normal tissue from primary CRC patients (n = 56) and recurrent CRC (n = 16) was studied as well as colon mucosa samples from healthy subjects (n = 76). Furthermore, mtDNA copy number was assessed in carcinomas of 693 CRC cases identified from the population-based Netherlands Cohort Study (NLCS). MtDNA copy number was significantly lower in carcinoma tissue (P = 0.011) and adjacent tissue (P < 0.001) compared to earlier resected adenoma tissue and in primary CRC tissue compared to recurrent CRC tissue (P = 0.011). Within both study populations, mtDNA copy number was significantly lower in mutated BRAF (P = 0.027 and P = 0.006) and in microsatellite unstable (MSI) tumors (P = 0.033 and P < 0.001) and higher in KRAS mutated tumors (P = 0.004). Furthermore, the association between mtDNA and survival seemed to follow an inverse U-shape with the highest HR observed in the second quintile of mtDNA copy number (HR = 1.70, 95% CI = 1.18, 2.44) compared to the first quintile. These results might reflect an association of mtDNA copy number with various malignant processes in cancer cells and warrants further research on tumor energy metabolism in CRC prognosis. [ABSTRACT FROM AUTHOR]

The article presents a study that investigates use of DNA from nails for genetic analyses in epidemiologic studies. The study involves using toenails as a source of genomic DNA for genotyping a limited set of 10 single-nucleotide polymorphisms. Further the study reveals that nails can serve as better DNA source in terms of ease and costs of obtaining and storing the samples.

The article discusses a study conducted to investigate the body size, physical activity and early-life energy restriction in the context of colorectal tumors while examining their association with methylated insulin-like growth factor-binding protein (IGFBP) genes. It compared the highest sex-specific tertiles with lowest sex-specific tertiles of adult body mass index. It concluded that body size may contribute to the development of IGFBP gene-methylated colorectal tumors.

Background & Aims: Several automated programs have been developed to facilitate body composition analysis of images from abdominal computed tomography (CT) scans. External validation in patients with colorectal cancer is necessary for use in research and clinical practice. Our aim was to validate an automatic method (AutoMATiCA) of segmenting CT images at the third lumbar level (L3) from patients with colorectal cancer, by comparing with manual segmentation., Methods: Diagnostic abdominal CT scans of consecutive patients with stage I-III colorectal cancer were analysed to measure cross-sectional areas and tissue densities of skeletal muscle and intra-muscular, visceral, and subcutaneous adipose tissue. Trained analysts performed manual segmentation of L3 CT images using SliceOmatic. Automatic segmentation was performed using AutoMATiCA, an open-source software. The Dice similarity coefficient (DSC) was calculated to assess segmentation accuracy. Agreement of automatic with manual segmentation was evaluated using intra-class correlation coefficients (ICCs) and Bland-Altman plots with limits of agreement., Results: A total of 292 scans were included, of which 62% were from male patients. The agreement of AutoMATiCA with the manual segmentation was excellent, with median DSC values ranging from 0.900 to 0.991 and ICCs above 0.95 for all segmented areas. No systematic deviations were observed in Bland-Altman plots for all segmented areas, with overall narrow limits of agreement., Conclusions: AutoMATiCA provides an accurate segmentation of abdominal CT images from patients with colorectal cancer. Our findings support its use as a highly efficient automated tool for body composition analysis in research and potentially also in clinical practice., Competing Interests: Declaration of competing interest Judith de Vos-Geelen has served as a consultant for Amgen, AstraZeneca, MSD, Pierre Fabre, and Servier, and has received institutional research funding from Servier. All outside the submitted work., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: Previous studies found no or weak positive associations between height and lung cancer (LC) risk, with differences between sexes. Few studies stratified the association by smoking status and LC subtype. This prospective study investigated the association between height and risks of overall LC and LC subtypes (i.e., adenocarcinoma, squamous cell carcinoma, small cell carcinoma, large cell carcinoma) in Dutch men and women, with comprehensive adjustment for smoking, and stratified by smoking status., Materials and Methods: Data originate from 120,852 Dutch participants aged 55-69 in 1986 in the Netherlands Cohort Study. Self-reported height and potential confounders were collected at baseline. After 20.3 years of follow-up, 3318 LC cases (2765 men; 553 women) and 4314 subcohort members were included in the multivariable Cox regression analysis., Results: There were no significant associations between height and risks of overall LC and LC subtypes in men and women, except for an increased adenocarcinoma risk in taller women (HR quartile4 vs quartile1 =1.62, 95% CI: 1.02-2.55, P trend =0.031). This positive association was borderline statistically significant in female current smokers only when stratifying on smoking status. No interaction by smoking status was shown in women for any LC risk. In men, smoking modified the association between height and risks of overall LC, large cell and squamous cell carcinoma, with the p-values for interaction of 0.037, 0.007 and 0.050, respectively., Conclusion: Positive associations between height and LC subtypes were predominantly seen in smokers. Further studies should focus on LC subtypes and stratify the association by smoking status., Competing Interests: Declaration of Competing Interest None, (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We empirically investigated genomic clusters associated with both height and postmenopausal breast cancer (BC) or colorectal cancer (CRC) (or both) in the Netherlands Cohort Study to unravel shared underlying mechanisms between height and these cancers. The Netherlands Cohort Study (1986-2006) includes 120,852 participants (case-cohort study: nsubcohort = 5,000; 20.3 years of follow-up). Variants in clusters on chromosomes 2, 4, 5, 6 (2 clusters), 10, and 20 were genotyped using toenail DNA. Cluster-specific genetic risk scores were modeled in relation to height and postmenopausal BC and CRC risk using age-adjusted linear regression and multivariable-adjusted Cox regression, respectively. Only the chromosome 10 cluster risk score was associated with all 3 phenotypes in the same sex (women); that is, it was associated with increased height (βcontinuous = 0.34, P = 0.014), increased risk of hormone-receptor-positive BC (for estrogen-receptor-positive BC, hazard ratio (HRcontinuous score) = 1.10 (95% confidence interval (CI): 1.02, 1.20); for progesterone-receptor-positive BC, HRcontinuous score = 1.15 (95% CI: 1.04, 1.26)), and increased risk of distal colon (HRcontinuous score = 1.13, 95% CI: 1.01, 1.27) and rectal (HRcontinuous score = 1.14, 95% CI: 0.99, 1.30) cancer. The chromosome 10 cluster variants were all annotated to the zinc finger MIZ-type containing 1 gene (ZMIZ1), which is involved in androgen receptor activity. This suggests that hormone-related growth mechanisms could influence both height and postmenopausal BC and CRC., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The mTOR-PI3K-Akt pathway influences cell metabolism and (malignant) cell growth. We generated sex-specific polygenic risk scores capturing natural variation in 7 out of 10 top-ranked genes in this pathway. We studied the scores directly and in interaction with energy balance-related factors (body mass index (BMI), trouser/skirt size, height, physical activity, and early life energy restriction) in relation to colorectal cancer (CRC) risk in the Netherlands Cohort Study (NLCS) (n=120,852). The NLCS has a case-cohort design and 20.3 years of follow-up. Participants completed a baseline questionnaire on diet and cancer in 1986 when 55-69 years old. ~75% of the cohort returned toenail clippings used for DNA isolation and genotyping (n subcohort=3,793, n cases=3,464). To generate the scores, the dataset was split in two and risk alleles were defined and weighted based on sex-specific associations with CRC risk in the other dataset half, because there were no SNPs in the top-ranked genes associated with CRC risk in previous genome-wide association studies at a significance level p<1*10 -5 ., Results: Cox regression analyses showed positive associations between the sex-specific polygenic risk scores and colon but not rectal cancer risk in men and women, with hazard ratios for continuously modeled scores close to 1.10. There was no modifying effect observed of the scores on associations between the energy balance-related factors and CRC risk. However, BMI (in men), non-occupational physical activity (in women), and height (in men and women) were associated with the risk of CRC, in particular (proximal and distal) colon cancer, in the direction as expected in the lower tertiles of the sex-specific polygenic risk scores., Conclusions: Current data suggest that the mTOR-PI3K-Akt pathway may be involved in colon cancer development. This study thereby sheds more light on colon cancer etiology through use of genetic variation in the mTOR-PI3K-Akt pathway., (© 2022. The Author(s).)

Genetic variation in the insulin-like growth factor (IGF) pathway may further increase the risk of colorectal cancer (CRC) associated with type 2 diabetes mellitus (T2DM). Joint effects of T2DM and genetic variation in the IGF pathway on CRC risk can increase mechanistic insights. Participants from the Netherlands Cohort Study (n = 120, 852) completed a baseline questionnaire in 1986 when 55-69 years old (case-cohort, n subcohort  = 5,000, n cases  = 3,441 after 16.3 years follow-up). Self-reported DM at baseline with onset at ≥30 years was classified as T2DM. Eighteen single nucleotide polymorphisms (SNPs) from the IGF pathway were aggregated in a genetic risk score (GRS). Cox proportional hazard ratios (HRs) for CRC were estimated according to combinations of T2DM status with GRS tertiles and categories of an IGF1 19-CA repeat polymorphism. Baseline T2DM prevalence was 3.1% in subcohort members and 3.8% in CRC cases. Comparison of combined categories with non-T2DM individuals in the lowest GRS tertile as reference showed that those in the highest GRS tertiles with and without T2DM had significantly increased CRC risks, particularly those with T2DM (HR = 2.28, 95% CI: 1.11, 4.66). As compared to IGF1 19-CA wild-type carriers without T2DM, carrying two IGF1 19-CA variant repeat alleles were associated with a significantly decreased CRC risk in those without T2DM (HR = 0.76, 95% CI: 0.63-0.91). This association was absent when T2DM was present. Our study of joint effects indicated that the presence of unfavorable alleles in the IGF pathway may further increase the risk of CRC associated with T2DM., (© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

The energy restriction (ER)-colorectal cancer (CRC) association is inconsistent in literature. To strengthen the biological plausibility of the ER-CRC association, we investigated whether genetic variation in the insulin-like growth factor (IGF) pathway, a putative underlying mechanism, modulated this association in the Netherlands Cohort Study. Participants completed a questionnaire (n = 120,852) and provided toenail clippings for DNA (∼75%) at baseline. Individuals living in a Western city during the Hunger Winter (1944-45) or Western rural versus non-Western area were exposed to (severe) ER at young age. Genotyping was performed for 3,768 subcohort members and 2,580 CRC cases (case-cohort with 16.3 years follow-up). Cox hazard ratios for CRC were estimated across combined categories of ER and a genetic sum score of unfavorable alleles based on 18 single nucleotide polymorphisms in IGF-related genes and ER and an IGF1 19-CA repeat polymorphism. The reference included ER exposed individuals, so that increased hazard ratios were expected in higher combined categories for calculating relative excess risks due to interaction (additive interactions). Wald tests for multiplicative interactions were also performed. Multiplicative and additive interactions were nonsignificant. Combined ER-genetic sum score categories showed increasing CRC risks in men, but confidence intervals were wide. Women carrying two variant IGF1 19-CA repeat alleles versus those carrying two wild type IGF1 19-CA repeat alleles were at an ∼50% decreased CRC risk, irrespective of ER exposure. In conclusion, data indicate that the IGF pathway might be involved in the ER-CRC association in men, but not women, although interactions were nonsignificant, hampering definite conclusions., (© 2016 UICC.)

Dietary flavonoids are hypothesized to be protective against colorectal cancer, yet findings have been inconsistent. We examined the association of dietary flavonol, flavone and catechin intake with colorectal cancer endpoints within the Netherlands Cohort Study (NLCS). In addition, we explored whether body mass index (BMI) may be an effect modifier of this association. The NLCS includes 120,852 men and women who were 55-69 years and completed a self-administered questionnaire at baseline in 1986. A case-cohort approach was used for data processing and analysis. After 13.3 years, 1,444 male and 1,041 female colorectal cancer cases were available for estimation of hazard ratios and 95% confidence intervals for quintiles of flavonoid intake. After adjustment for potential confounders, no association of total flavonol and flavone intake and total catechin intake with colorectal cancer endpoints was observed. Analyses stratified for BMI showed significant inverse trends in the association of total catechin intake, (+)-catechin intake and (-)-epicatechin intake with rectal cancer in men with a BMI>or=25 kg/m2 and in the association of total catechin intake and intake of kaempferol, myricetin and all individual catechins with colorectal cancer, in particular colon cancer, in women with a BMI<25 kg/m2. In conclusion, our findings generally do not support an association of dietary flavonol, flavone and catechin intake with colorectal cancer endpoints. Dietary catechin intake may be associated with a decreased rectal cancer risk in overweight men. Dietary flavonol and catechin intake may be associated with a decreased colorectal cancer risk in normal weight women., (Copyright (c) 2009 UICC.)