Energy Balance-Related Factors and Risk of Colorectal Cancer Expressing Different Levels of Proteins Involved in the Warburg Effect

Josien C A Jenniskens; Kelly Offermans; Colinda C J M Simons; Iryna Samarska; Gregorio E Fazzi; Kim M Smits; Leo J Schouten; Matty P Weijenberg; Heike I Grabsch; Piet A van den Brandt

doi:10.1158/1055-9965.epi-21-0678

Energy Balance-Related Factors and Risk of Colorectal Cancer Expressing Different Levels of Proteins Involved in the Warburg Effect

Josien C A Jenniskens, Kelly Offermans, Colinda C J M Simons, Iryna Samarska, Gregorio E Fazzi, Kim M Smits, Leo J Schouten, Matty P Weijenberg, Heike I Grabsch^*, Piet A van den Brandt^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

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 (n total = 120,852; n subcohort = 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 (P heterogeneity = 0.192). In women, clothing size was positively associated with Warburg-low and Warburg-high colon cancer (P heterogeneity = 0.005). Nonoccupational physical activity was inversely associated with Warburg-low and Warburg-moderate colon cancer in women (P heterogeneity = 0.045), but positively associated with Warburg-high rectal cancer in men (P heterogeneity = 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.

IMPACT: Further research is needed to reproduce these results and investigate possible additional mechanisms.

Original language	English
Pages (from-to)	633-646
Number of pages	14
Journal	Cancer Epidemiology Biomarkers & Prevention
Volume	31
Issue number	3
Early online date	21 Dec 2021
DOIs	https://doi.org/10.1158/1055-9965.epi-21-0678
Publication status	Published - Mar 2022

Keywords

ADIPONECTIN
ASSOCIATIONS
BODY-MASS INDEX
COHORT
COLON-CANCER
INSULIN
METAANALYSIS
MOLECULAR PATHOLOGICAL EPIDEMIOLOGY
OBESITY
PHYSICAL-ACTIVITY
PREVENTION

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10.1158/1055-9965.epi-21-0678

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Jenniskens, J. C. A., Offermans, K., Simons, C. C. J. M., Samarska, I., Fazzi, G. E., Smits, K. M., Schouten, L. J., Weijenberg, M. P., Grabsch, H. I., & van den Brandt, P. A. (2022). Energy Balance-Related Factors and Risk of Colorectal Cancer Expressing Different Levels of Proteins Involved in the Warburg Effect. Cancer Epidemiology Biomarkers & Prevention, 31(3), 633-646. https://doi.org/10.1158/1055-9965.epi-21-0678

@article{63d5b39af8a24cb9af95faad197e8319,

title = "Energy Balance-Related Factors and Risk of Colorectal Cancer Expressing Different Levels of Proteins Involved in the Warburg Effect",

abstract = "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 (n total = 120,852; n subcohort = 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 (P heterogeneity = 0.192). In women, clothing size was positively associated with Warburg-low and Warburg-high colon cancer (P heterogeneity = 0.005). Nonoccupational physical activity was inversely associated with Warburg-low and Warburg-moderate colon cancer in women (P heterogeneity = 0.045), but positively associated with Warburg-high rectal cancer in men (P heterogeneity = 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.IMPACT: Further research is needed to reproduce these results and investigate possible additional mechanisms.",

keywords = "ADIPONECTIN, ASSOCIATIONS, BODY-MASS INDEX, COHORT, COLON-CANCER, INSULIN, METAANALYSIS, MOLECULAR PATHOLOGICAL EPIDEMIOLOGY, OBESITY, PHYSICAL-ACTIVITY, PREVENTION",

author = "Jenniskens, {Josien C A} and Kelly Offermans and Simons, {Colinda C J M} and Iryna Samarska and Fazzi, {Gregorio E} and Smits, {Kim M} and Schouten, {Leo J} and Weijenberg, {Matty P} and Grabsch, {Heike I} and {van den Brandt}, {Piet A}",

note = "{\textcopyright}2021 American Association for Cancer Research.",

year = "2022",

month = mar,

doi = "10.1158/1055-9965.epi-21-0678",

language = "English",

volume = "31",

pages = "633--646",

journal = "Cancer Epidemiology Biomarkers & Prevention",

issn = "1055-9965",

publisher = "American Association for Cancer Research Inc.",

number = "3",

}

Jenniskens, JCA, Offermans, K , Simons, CCJM , Samarska, I , Fazzi, GE , Smits, KM , Schouten, LJ , Weijenberg, MP , Grabsch, HI & van den Brandt, PA 2022, 'Energy Balance-Related Factors and Risk of Colorectal Cancer Expressing Different Levels of Proteins Involved in the Warburg Effect', Cancer Epidemiology Biomarkers & Prevention, vol. 31, no. 3, pp. 633-646. https://doi.org/10.1158/1055-9965.epi-21-0678

Energy Balance-Related Factors and Risk of Colorectal Cancer Expressing Different Levels of Proteins Involved in the Warburg Effect. / Jenniskens, Josien C A; Offermans, Kelly ; Simons, Colinda C J M et al.
In: Cancer Epidemiology Biomarkers & Prevention, Vol. 31, No. 3, 03.2022, p. 633-646.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Energy Balance-Related Factors and Risk of Colorectal Cancer Expressing Different Levels of Proteins Involved in the Warburg Effect

AU - Jenniskens, Josien C A

AU - Offermans, Kelly

AU - Simons, Colinda C J M

AU - Samarska, Iryna

AU - Fazzi, Gregorio E

AU - Smits, Kim M

AU - Schouten, Leo J

AU - Weijenberg, Matty P

AU - Grabsch, Heike I

AU - van den Brandt, Piet A

PY - 2022/3

Y1 - 2022/3

N2 - 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 (n total = 120,852; n subcohort = 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 (P heterogeneity = 0.192). In women, clothing size was positively associated with Warburg-low and Warburg-high colon cancer (P heterogeneity = 0.005). Nonoccupational physical activity was inversely associated with Warburg-low and Warburg-moderate colon cancer in women (P heterogeneity = 0.045), but positively associated with Warburg-high rectal cancer in men (P heterogeneity = 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.IMPACT: Further research is needed to reproduce these results and investigate possible additional mechanisms.

AB - 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 (n total = 120,852; n subcohort = 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 (P heterogeneity = 0.192). In women, clothing size was positively associated with Warburg-low and Warburg-high colon cancer (P heterogeneity = 0.005). Nonoccupational physical activity was inversely associated with Warburg-low and Warburg-moderate colon cancer in women (P heterogeneity = 0.045), but positively associated with Warburg-high rectal cancer in men (P heterogeneity = 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.IMPACT: Further research is needed to reproduce these results and investigate possible additional mechanisms.

KW - ADIPONECTIN

KW - ASSOCIATIONS

KW - BODY-MASS INDEX

KW - COHORT

KW - COLON-CANCER

KW - INSULIN

KW - METAANALYSIS

KW - MOLECULAR PATHOLOGICAL EPIDEMIOLOGY

KW - OBESITY

KW - PHYSICAL-ACTIVITY

KW - PREVENTION

U2 - 10.1158/1055-9965.epi-21-0678

DO - 10.1158/1055-9965.epi-21-0678

M3 - Article

C2 - 34933957

SN - 1055-9965

VL - 31

SP - 633

EP - 646

JO - Cancer Epidemiology Biomarkers & Prevention

JF - Cancer Epidemiology Biomarkers & Prevention

IS - 3

ER -