Energy balance-related factors in childhood and adolescence and risk of colorectal cancer expressing different levels of proteins involved in the Warburg-effect.

Early-life (childhood to adolescence) energy balance-related factors (height, energy restriction, BMI) have been associated with adult colorectal cancer (CRC) risk. Warburg-effect activation via PI3K/Akt-signaling might explain this link. We investigated whether early-life energy balance-related factors were associated with risk of Warburg-subtypes in CRC. We used immunohistochemistry for six proteins involved in the Warburg-effect (LDHA, GLUT1, MCT4, PKM2, P53, and PTEN) on tissue microarrays of 2399 incident CRC cases from the prospective Netherlands Cohort Study (NLCS). 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 height, energy restriction proxies (exposure to Dutch Hunger Winter; Second World War [WWII]; Economic Depression) and adolescent BMI with Warburg-subtypes in CRC. Height was positively associated with colon cancer in men, regardless of Warburg-subtypes, and with Warburg-low colon and Warburg-moderate rectal cancer in women. Energy restriction during the Dutch Hunger Winter was inversely associated with colon cancer in men, regardless of Warburg-subtypes. In women, energy restriction during the Hunger Winter and WWII was inversely associated with Warburg-low colon cancer, whereas energy restriction during the Economic Depression was positively associated with Warburg-high colon cancer. Adolescent BMI was positively associated with Warburg-high colon cancer in men, and Warburg-moderate rectal cancer in women. In conclusion, the Warburg-effect seems to be involved in associations of adolescent BMI with colon cancer in men, and of energy restriction during the Economic Depression with colon cancer in women. Further research is needed to validate these results.

Metabolic and Risk Profiles of Lean and Non-Lean Hepatic Steatosis among US Adults.

Hepatic steatosis can occur in lean individuals, while its metabolic and risk profiles remain unclear. We aimed to characterize the clinical and risk profiles of lean and non-lean steatosis. This cross-sectional study included 1610 patients with transient elastography-assessed steatosis. The metabolic and risk profiles were compared. Compared to their non-lean counterparts, lean subjects with steatosis had a lower degree of fibrosis (F0-F1: 91.9% vs. 80.9%), had a lower prevalence of diabetes (27.9% vs. 32.8%), dyslipidemia (54.7% vs. 60.2%) and hypertension (50.0% vs. 51.3%), and had higher levels of high-density lipoprotein cholesterol while lower fasting insulin and homeostatic model assessment for insulin resistance (all p < 0.05). Of the 16 potential risk factors, being Hispanic was associated with higher odds of non-lean steatosis but not with lean steatosis (odds ratio (OR): 2.07 vs. 0.93), while excessive alcohol consumption had a different trend in the ratio (OR: 1.47 vs.6.65). Higher waist-to-hip ratio (OR: 7.48 vs. 2.45), and higher waist circumference (OR: 1.14 vs. 1.07) showed a stronger positive association with lean steatosis than with non-lean steatosis (all Pheterogeneity < 0.05). Although lean individuals with steatosis presented a healthier metabolic profile, both lean and non-lean steatosis had a significant proportion of metabolic derangements. In addition, the etiological heterogeneity between lean and non-lean steatosis may exist.

Energy balance-related factors and risk of colorectal cancer based on KRAS, PIK3CA, and BRAF mutations and MMR status.

INTRODUCTION: KRAS mutations (KRASmut), PIK3CAmut, BRAFmut, and mismatch repair deficiency (dMMR) have been associated with the Warburg-effect. We previously observed differential associations between energy balance-related factors (BMI, clothing-size, physical activity) and colorectal cancer (CRC) subtypes based on the Warburg-effect. We now investigated whether associations between energy balance-related factors and risk of CRC differ between subgroups based on mutation and MMR status. METHODS: Information on molecular features was available for 2349 incident CRC cases within the Netherlands Cohort Study (NLCS), with complete covariate data available for 1934 cases and 3911 subcohort members. Multivariable-adjusted Cox-regression was used to estimate associations of energy balance-related factors with risk of CRC based on individual molecular features (KRASmut; PIK3CAmut; BRAFmut; dMMR) and combinations thereof (all-wild-type + MMR-proficient (pMMR); any-mutation/dMMR). RESULTS: In men, BMI and clothing-size were positively associated with risk of colon, but not rectal cancer, regardless of molecular features subgroups; the strongest associations were observed for PIK3CAmut colon cancer. In women, however, BMI and clothing-size were only associated with risk of KRASmut colon cancer (p-heterogeneityKRASmut versus all-wild-type+pMMR = 0.008). Inverse associations of non-occupational physical activity with risk of colon cancer were strongest for any-mutation/dMMR tumors in men and women, and specifically for PIK3CAmut tumors in women. Occupational physical activity was inversely associated with both combination subgroups of colon cancer in men. CONCLUSION: In men, associations did not vary according to molecular features. In women, a role of KRAS mutations in the etiological pathway between adiposity and colon cancer is suggested, and of PIK3CA mutations between physical activity and colon cancer.

Etiological heterogeneity of symptom dimensions of adolescent depression.

The aim was to investigate the underlying factor structure of adolescent depression and etiological heterogeneity in the symptom dimensions of adolescent depression. The sample included 842 pairs of same-sex adolescent twins, among which 613 pairs were monozygotic twins and 229 pairs were dizygotic twins. The ages of the participants ranged from 11 to 17 years (M = 13.64, SD = 1.80). Adolescents' depressive symptoms were assessed using the self-reported Children's Depression Inventory. Exploratory and confirmatory factor analyses were used to explore the factor structure of youth depression and twin genetic analyses were employed to estimate genetic and environmental influences on the derived dimensions. Results showed that adolescent depression encompassed five correlated dimensions: dysphoria mood, somatic symptoms, study and externalizing problems, anhedonia symptoms, and cognitive symptoms. These five symptom dimensions had heterogeneous etiologies: Dysphoria mood, somatic symptoms, and cognitive symptoms were moderately heritable (heritability ranged from 33 to 40%), whereas study and externalizing problems, and anhedonia symptoms were mainly environmentally influenced with minimal genetic basis. Our findings supported the multidimensionality of adolescent depression and the etiological heterogeneity of these symptom dimensions.