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

Abstract

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 Warburgmoderate 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.

Energy balance‐related factors in childhood and adolescence and risk of colorectal cancer based on KRAS, PIK3CA, and BRAF mutations and MMR status

“…The Warburg effect might thus potentially play a role in the etiological pathway between early adult BMI and colon cancer. These results are partly in line with our previous study on Warburg subtypes in CRC,10…”

“…KRAS mut , PIK3CA mut , BRAF mut , and dMMR have all been associated with the Warburg effect 11,16–19 . We previously reported differential associations between early‐life energy balance‐related factors and CRC subtypes based on the expression of proteins involved in the Warburg effect 10 . Using data from a large prospective cohort study, we now investigated associations between early‐life energy balance‐related factors and the risk of CRC subgroups based on KRAS mut , PIK3CA mut , BRAF mut , and MMR status.…”

“…We have previously reported differential associations of early-life energy balance-related factors with CRC risk based on expression levels of proteins involved in the Warburg effect. 10 It has been suggested that the Warburg effect, which is characterized by increased aerobic glycolysis, [11][12][13] may play an important role in carcinogenesis. 14,15 Mutations in oncogenes such as KRAS, PIK3CA, and BRAF as well as the presence of DNA mismatch repair (MMR) deficiency have been associated with the presence of the Warburg effect.…”

“…Mechanisms underlying these long‐term effects of early‐life energy balance‐related factors are currently unknown. We have previously reported differential associations of early‐life energy balance‐related factors with CRC risk based on expression levels of proteins involved in the Warburg effect 10 …”

“…11,[16][17][18][19] We previously reported differential associations between early-life energy balance-related factors and CRC subtypes based on the expression of proteins involved in the Warburg effect 10. Using data from a large prospective cohort study,…”