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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]

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. [ABSTRACT FROM AUTHOR]

Previous research has suggested that the expression of proteins related to the Warburg effect may have prognostic value in colorectal cancer (CRC), but results remain inconsistent. Our objective was to investigate the relationship between Warburg‐subtypes and patient survival in a large population‐based series of CRC patients. In the present study, we investigated the expression of six proteins related to the Warburg effect (LDHA, GLUT1, MCT4, PKM2, p53, PTEN) by immunohistochemistry on tissue microarrays (TMAs) from 2,399 incident CRC patients from the prospective Netherlands Cohort Study. Expression levels of the six proteins were combined into a pathway‐based sum‐score and patients were categorised into three Warburg‐subtypes (low/moderate/high). The associations between Warburg‐subtypes and CRC‐specific and overall survival were investigated using Kaplan–Meier curves and Cox regression models. CRC patients were classified as Warburg‐low (n = 695, 29.0%), Warburg‐moderate (n = 858, 35.8%) or Warburg‐high (n = 841, 35.1%). Patients with Warburg‐high CRC had the poorest CRC‐specific [hazard ratio (HR) 1.17; 95% CI 1.00–1.38] and overall survival (HR 1.19; 95% CI 1.05–1.35), independent of known prognostic factors. In stratified analyses, this was particularly true for patients with tumour‐node‐metastasis (TNM) stage III CRC (HRCRC‐specific 1.45; 95% CI 1.10–1.92 and HRoverall 1.47; 95% CI 1.15–1.87), and cancers located in the rectum (HRoverall 1.56; 95% CI 1.15–2.13). To our knowledge, this is the first study to identify the prognostic value of immunohistochemistry‐based Warburg‐subtypes in CRC. Our data suggest that Warburg‐subtypes are related to potentially important differences in CRC survival. Further research is required to validate our findings and to investigate the potential clinical utility of these Warburg‐subtypes in CRC. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) remains one of the most prevalent and deadly cancers worldwide. The tumour-node-metastasis stage (TNM) is currently the most clinically important tool to predict prognosis for CRC patients. However, patients with the same TNM stage can have different prognoses. The metabolic status of tumour cells (Warburg-subtype) has been proposed as potential prognostic factor in CRC. However, potential biological mechanisms underlying the relationship between Warburg-subtype and prognosis have not been investigated in detail. One potential mechanism could be that the metabolic status of tumour cells affects the tumour microenvironment (TME). Our objective was to investigate the relationship between Warburg-subtypes and the TME. Haematoxylin/Eosin stained tumour tissue microarray cores from 2171 CRC patients from the Netherlands Cohort Study were semi quantitatively assessed for tumour infiltrating lymphocytes (TILs) and relative tumour stroma content. 5745 cores were assessed by putting each core in one of four categories for both TILs and stroma. The relationship between Warburg-subtype, TILs, and tumour stroma content was investigated. The frequency of CRC in the different TIL categories was (n, %): very low (2538, 44.2), low (2463, 42.9), high (722, 12.6), and very high (22, 0.4). The frequency of CRC in the different tumour stroma content categories was: ≤ 25% (2755, 47.9), > 25% ≤ 50% (1553, 27) > 50% ≤ 75% (905, 15.8), and > 75% (532, 9.3). There was neither an association between Warburg-subtype and tumour stroma content (p = 0.229) nor between Warburg-subtype and TILs (p = 0.429). This is the first study to investigate the relationship between Warburg-subtypes and the TME in a large population-based series of CRC patients. Our data suggest that the prognostic value of Warburg-subtypes cannot be directly attributed to differences in TILs or tumour stroma content. Our results require confirmation in an independent series. [ABSTRACT FROM AUTHOR]