Body size and risk of colorectal cancer molecular defined subtypes and pathways: Mendelian randomization analyses

Nikos Papadimitriou; Conghui Qu; Tabitha A. Harrison; Alaina M. Bever; Richard M. Martin; Konstantinos K. Tsilidis; Polly A. Newcomb; Stephen N. Thibodeau; Christina C. Newton; Caroline Y. Um; Mireia Obón-Santacana; Victor Moreno; Hermann Brenner; Marko Mandic; Jenny Chang-Claude; Michael Hoffmeister; Andrew J. Pellatt; Robert E. Schoen; Sophia Harlid; Shuji Ogino; Tomotaka Ugai; Daniel D. Buchanan; Brigid M. Lynch; Stephen B. Gruber; Yin Cao; Li Hsu; Jeroen R. Huyghe; Yi Lin; Robert S. Steinfelder; Wei Sun; Bethany Van Guelpen; Syed H. Zaidi; Amanda E. Toland; Sonja I. Berndt; Wen Yi Huang; Elom K. Aglago; David A. Drew; Amy J. French; Peter Georgeson; Marios Giannakis; Meredith Hullar; Johnathan A. Nowak; Claire E. Thomas; Loic Le Marchand; Iona Cheng; Steven Gallinger; Mark A. Jenkins; Marc J. Gunter; Peter T. Campbell; Ulrike Peters; Mingyang Song; Amanda I. Phipps; Neil Murphy

doi:10.1016/j.ebiom.2024.105010

Body size and risk of colorectal cancer molecular defined subtypes and pathways: Mendelian randomization analyses

Nikos Papadimitriou, Conghui Qu, Tabitha A. Harrison, Alaina M. Bever, Richard M. Martin, Konstantinos K. Tsilidis, Polly A. Newcomb, Stephen N. Thibodeau, Christina C. Newton, Caroline Y. Um, Mireia Obón-Santacana, Victor Moreno, Hermann Brenner, Marko Mandic, Jenny Chang-Claude, Michael Hoffmeister, Andrew J. Pellatt, Robert E. Schoen, Sophia Harlid, Shuji OginoTomotaka Ugai, Daniel D. Buchanan, Brigid M. Lynch, Stephen B. Gruber, Yin Cao, Li Hsu, Jeroen R. Huyghe, Yi Lin, Robert S. Steinfelder, Wei Sun, Bethany Van Guelpen, Syed H. Zaidi, Amanda E. Toland, Sonja I. Berndt, Wen Yi Huang, Elom K. Aglago, David A. Drew, Amy J. French, Peter Georgeson, Marios Giannakis, Meredith Hullar, Johnathan A. Nowak, Claire E. Thomas, Loic Le Marchand, Iona Cheng, Steven Gallinger, Mark A. Jenkins, Marc J. Gunter, Peter T. Campbell, Ulrike Peters, Mingyang Song, Amanda I. Phipps, Neil Murphy

Laboratory Medicine and Pathology

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

Abstract

Background: Obesity has been positively associated with most molecular subtypes of colorectal cancer (CRC); however, the magnitude and the causality of these associations is uncertain. Methods: We used Mendelian randomization (MR) to examine potential causal relationships between body size traits (body mass index [BMI], waist circumference, and body fat percentage) with risks of Jass classification types and individual subtypes of CRC (microsatellite instability [MSI] status, CpG island methylator phenotype [CIMP] status, BRAF and KRAS mutations). Summary data on tumour markers were obtained from two genetic consortia (CCFR, GECCO). Findings: A 1-standard deviation (SD:5.1 kg/m²) increment in BMI levels was found to increase risks of Jass type 1_{MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype} (odds ratio [OR]: 2.14, 95% confidence interval [CI]: 1.46, 3.13; p-value = 9 × 10⁻⁵) and Jass type 2_{non-MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype} CRC (OR: 2.20, 95% CI: 1.26, 3.86; p-value = 0.005). The magnitude of these associations was stronger compared with Jass type 4_{non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-wildtype} CRC (p-differences: 0.03 and 0.04, respectively). A 1-SD (SD:13.4 cm) increment in waist circumference increased risk of Jass type 3_{non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-mutated} (OR 1.73, 95% CI: 1.34, 2.25; p-value = 9 × 10⁻⁵) that was stronger compared with Jass type 4 CRC (p-difference: 0.03). A higher body fat percentage (SD:8.5%) increased risk of Jass type 1 CRC (OR: 2.59, 95% CI: 1.49, 4.48; p-value = 0.001), which was greater than Jass type 4 CRC (p-difference: 0.03). Interpretation: Body size was more strongly linked to the serrated (Jass types 1 and 2) and alternate (Jass type 3) pathways of colorectal carcinogenesis in comparison to the traditional pathway (Jass type 4). Funding: Cancer Research UK, National Institute for Health Research, Medical Research Council, National Institutes of Health, National Cancer Institute, American Institute for Cancer Research, Brigham and Women's Hospital, Prevent Cancer Foundation, Victorian Cancer Agency, Swedish Research Council, Swedish Cancer Society, Region Västerbotten, Knut and Alice Wallenberg Foundation, Lion's Cancer Research Foundation, Insamlingsstiftelsen, Umeå University. Full funding details are provided in acknowledgements.

Original language	English (US)
Article number	105010
Journal	EBioMedicine
Volume	101
DOIs	https://doi.org/10.1016/j.ebiom.2024.105010
State	Published - Mar 2024

Keywords

Colorectal cancer
Mendelian randomization
Molecular subtypes
Obesity

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.ebiom.2024.105010

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Papadimitriou, N., Qu, C., Harrison, T. A., Bever, A. M., Martin, R. M., Tsilidis, K. K., Newcomb, P. A., Thibodeau, S. N., Newton, C. C., Um, C. Y., Obón-Santacana, M., Moreno, V., Brenner, H., Mandic, M., Chang-Claude, J., Hoffmeister, M., Pellatt, A. J., Schoen, R. E., Harlid, S., ... Murphy, N. (2024). Body size and risk of colorectal cancer molecular defined subtypes and pathways: Mendelian randomization analyses. EBioMedicine, 101, Article 105010. https://doi.org/10.1016/j.ebiom.2024.105010

Papadimitriou, N, Qu, C, Harrison, TA, Bever, AM, Martin, RM, Tsilidis, KK, Newcomb, PA, Thibodeau, SN, Newton, CC, Um, CY, Obón-Santacana, M, Moreno, V, Brenner, H, Mandic, M, Chang-Claude, J, Hoffmeister, M, Pellatt, AJ, Schoen, RE, Harlid, S, Ogino, S, Ugai, T, Buchanan, DD, Lynch, BM, Gruber, SB, Cao, Y, Hsu, L, Huyghe, JR, Lin, Y, Steinfelder, RS, Sun, W, Van Guelpen, B, Zaidi, SH, Toland, AE, Berndt, SI, Huang, WY, Aglago, EK, Drew, DA, French, AJ, Georgeson, P, Giannakis, M, Hullar, M, Nowak, JA, Thomas, CE, Le Marchand, L, Cheng, I, Gallinger, S, Jenkins, MA, Gunter, MJ, Campbell, PT, Peters, U, Song, M, Phipps, AI & Murphy, N 2024, 'Body size and risk of colorectal cancer molecular defined subtypes and pathways: Mendelian randomization analyses', EBioMedicine, vol. 101, 105010. https://doi.org/10.1016/j.ebiom.2024.105010

@article{b5829e9c2c104745a2b998d1d766ac63,

title = "Body size and risk of colorectal cancer molecular defined subtypes and pathways: Mendelian randomization analyses",

abstract = "Background: Obesity has been positively associated with most molecular subtypes of colorectal cancer (CRC); however, the magnitude and the causality of these associations is uncertain. Methods: We used Mendelian randomization (MR) to examine potential causal relationships between body size traits (body mass index [BMI], waist circumference, and body fat percentage) with risks of Jass classification types and individual subtypes of CRC (microsatellite instability [MSI] status, CpG island methylator phenotype [CIMP] status, BRAF and KRAS mutations). Summary data on tumour markers were obtained from two genetic consortia (CCFR, GECCO). Findings: A 1-standard deviation (SD:5.1 kg/m2) increment in BMI levels was found to increase risks of Jass type 1MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype (odds ratio [OR]: 2.14, 95% confidence interval [CI]: 1.46, 3.13; p-value = 9 × 10−5) and Jass type 2non-MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype CRC (OR: 2.20, 95% CI: 1.26, 3.86; p-value = 0.005). The magnitude of these associations was stronger compared with Jass type 4non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-wildtype CRC (p-differences: 0.03 and 0.04, respectively). A 1-SD (SD:13.4 cm) increment in waist circumference increased risk of Jass type 3non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-mutated (OR 1.73, 95% CI: 1.34, 2.25; p-value = 9 × 10−5) that was stronger compared with Jass type 4 CRC (p-difference: 0.03). A higher body fat percentage (SD:8.5%) increased risk of Jass type 1 CRC (OR: 2.59, 95% CI: 1.49, 4.48; p-value = 0.001), which was greater than Jass type 4 CRC (p-difference: 0.03). Interpretation: Body size was more strongly linked to the serrated (Jass types 1 and 2) and alternate (Jass type 3) pathways of colorectal carcinogenesis in comparison to the traditional pathway (Jass type 4). Funding: Cancer Research UK, National Institute for Health Research, Medical Research Council, National Institutes of Health, National Cancer Institute, American Institute for Cancer Research, Brigham and Women's Hospital, Prevent Cancer Foundation, Victorian Cancer Agency, Swedish Research Council, Swedish Cancer Society, Region V{\"a}sterbotten, Knut and Alice Wallenberg Foundation, Lion's Cancer Research Foundation, Insamlingsstiftelsen, Ume{\aa} University. Full funding details are provided in acknowledgements.",

keywords = "Colorectal cancer, Mendelian randomization, Molecular subtypes, Obesity",

author = "Nikos Papadimitriou and Conghui Qu and Harrison, {Tabitha A.} and Bever, {Alaina M.} and Martin, {Richard M.} and Tsilidis, {Konstantinos K.} and Newcomb, {Polly A.} and Thibodeau, {Stephen N.} and Newton, {Christina C.} and Um, {Caroline Y.} and Mireia Ob{\'o}n-Santacana and Victor Moreno and Hermann Brenner and Marko Mandic and Jenny Chang-Claude and Michael Hoffmeister and Pellatt, {Andrew J.} and Schoen, {Robert E.} and Sophia Harlid and Shuji Ogino and Tomotaka Ugai and Buchanan, {Daniel D.} and Lynch, {Brigid M.} and Gruber, {Stephen B.} and Yin Cao and Li Hsu and Huyghe, {Jeroen R.} and Yi Lin and Steinfelder, {Robert S.} and Wei Sun and {Van Guelpen}, Bethany and Zaidi, {Syed H.} and Toland, {Amanda E.} and Berndt, {Sonja I.} and Huang, {Wen Yi} and Aglago, {Elom K.} and Drew, {David A.} and French, {Amy J.} and Peter Georgeson and Marios Giannakis and Meredith Hullar and Nowak, {Johnathan A.} and Thomas, {Claire E.} and {Le Marchand}, Loic and Iona Cheng and Steven Gallinger and Jenkins, {Mark A.} and Gunter, {Marc J.} and Campbell, {Peter T.} and Ulrike Peters and Mingyang Song and Phipps, {Amanda I.} and Neil Murphy",

note = "Publisher Copyright: {\textcopyright} 2024",

year = "2024",

month = mar,

doi = "10.1016/j.ebiom.2024.105010",

language = "English (US)",

volume = "101",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier BV",

}

TY - JOUR

T1 - Body size and risk of colorectal cancer molecular defined subtypes and pathways

T2 - Mendelian randomization analyses

AU - Papadimitriou, Nikos

AU - Qu, Conghui

AU - Harrison, Tabitha A.

AU - Bever, Alaina M.

AU - Martin, Richard M.

AU - Tsilidis, Konstantinos K.

AU - Newcomb, Polly A.

AU - Thibodeau, Stephen N.

AU - Newton, Christina C.

AU - Um, Caroline Y.

AU - Obón-Santacana, Mireia

AU - Moreno, Victor

AU - Brenner, Hermann

AU - Mandic, Marko

AU - Chang-Claude, Jenny

AU - Hoffmeister, Michael

AU - Pellatt, Andrew J.

AU - Schoen, Robert E.

AU - Harlid, Sophia

AU - Ogino, Shuji

AU - Ugai, Tomotaka

AU - Buchanan, Daniel D.

AU - Lynch, Brigid M.

AU - Gruber, Stephen B.

AU - Cao, Yin

AU - Hsu, Li

AU - Huyghe, Jeroen R.

AU - Lin, Yi

AU - Steinfelder, Robert S.

AU - Sun, Wei

AU - Van Guelpen, Bethany

AU - Zaidi, Syed H.

AU - Toland, Amanda E.

AU - Berndt, Sonja I.

AU - Huang, Wen Yi

AU - Aglago, Elom K.

AU - Drew, David A.

AU - French, Amy J.

AU - Georgeson, Peter

AU - Giannakis, Marios

AU - Hullar, Meredith

AU - Nowak, Johnathan A.

AU - Thomas, Claire E.

AU - Le Marchand, Loic

AU - Cheng, Iona

AU - Gallinger, Steven

AU - Jenkins, Mark A.

AU - Gunter, Marc J.

AU - Campbell, Peter T.

AU - Peters, Ulrike

AU - Song, Mingyang

AU - Phipps, Amanda I.

AU - Murphy, Neil

PY - 2024/3

Y1 - 2024/3

N2 - Background: Obesity has been positively associated with most molecular subtypes of colorectal cancer (CRC); however, the magnitude and the causality of these associations is uncertain. Methods: We used Mendelian randomization (MR) to examine potential causal relationships between body size traits (body mass index [BMI], waist circumference, and body fat percentage) with risks of Jass classification types and individual subtypes of CRC (microsatellite instability [MSI] status, CpG island methylator phenotype [CIMP] status, BRAF and KRAS mutations). Summary data on tumour markers were obtained from two genetic consortia (CCFR, GECCO). Findings: A 1-standard deviation (SD:5.1 kg/m2) increment in BMI levels was found to increase risks of Jass type 1MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype (odds ratio [OR]: 2.14, 95% confidence interval [CI]: 1.46, 3.13; p-value = 9 × 10−5) and Jass type 2non-MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype CRC (OR: 2.20, 95% CI: 1.26, 3.86; p-value = 0.005). The magnitude of these associations was stronger compared with Jass type 4non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-wildtype CRC (p-differences: 0.03 and 0.04, respectively). A 1-SD (SD:13.4 cm) increment in waist circumference increased risk of Jass type 3non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-mutated (OR 1.73, 95% CI: 1.34, 2.25; p-value = 9 × 10−5) that was stronger compared with Jass type 4 CRC (p-difference: 0.03). A higher body fat percentage (SD:8.5%) increased risk of Jass type 1 CRC (OR: 2.59, 95% CI: 1.49, 4.48; p-value = 0.001), which was greater than Jass type 4 CRC (p-difference: 0.03). Interpretation: Body size was more strongly linked to the serrated (Jass types 1 and 2) and alternate (Jass type 3) pathways of colorectal carcinogenesis in comparison to the traditional pathway (Jass type 4). Funding: Cancer Research UK, National Institute for Health Research, Medical Research Council, National Institutes of Health, National Cancer Institute, American Institute for Cancer Research, Brigham and Women's Hospital, Prevent Cancer Foundation, Victorian Cancer Agency, Swedish Research Council, Swedish Cancer Society, Region Västerbotten, Knut and Alice Wallenberg Foundation, Lion's Cancer Research Foundation, Insamlingsstiftelsen, Umeå University. Full funding details are provided in acknowledgements.

AB - Background: Obesity has been positively associated with most molecular subtypes of colorectal cancer (CRC); however, the magnitude and the causality of these associations is uncertain. Methods: We used Mendelian randomization (MR) to examine potential causal relationships between body size traits (body mass index [BMI], waist circumference, and body fat percentage) with risks of Jass classification types and individual subtypes of CRC (microsatellite instability [MSI] status, CpG island methylator phenotype [CIMP] status, BRAF and KRAS mutations). Summary data on tumour markers were obtained from two genetic consortia (CCFR, GECCO). Findings: A 1-standard deviation (SD:5.1 kg/m2) increment in BMI levels was found to increase risks of Jass type 1MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype (odds ratio [OR]: 2.14, 95% confidence interval [CI]: 1.46, 3.13; p-value = 9 × 10−5) and Jass type 2non-MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype CRC (OR: 2.20, 95% CI: 1.26, 3.86; p-value = 0.005). The magnitude of these associations was stronger compared with Jass type 4non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-wildtype CRC (p-differences: 0.03 and 0.04, respectively). A 1-SD (SD:13.4 cm) increment in waist circumference increased risk of Jass type 3non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-mutated (OR 1.73, 95% CI: 1.34, 2.25; p-value = 9 × 10−5) that was stronger compared with Jass type 4 CRC (p-difference: 0.03). A higher body fat percentage (SD:8.5%) increased risk of Jass type 1 CRC (OR: 2.59, 95% CI: 1.49, 4.48; p-value = 0.001), which was greater than Jass type 4 CRC (p-difference: 0.03). Interpretation: Body size was more strongly linked to the serrated (Jass types 1 and 2) and alternate (Jass type 3) pathways of colorectal carcinogenesis in comparison to the traditional pathway (Jass type 4). Funding: Cancer Research UK, National Institute for Health Research, Medical Research Council, National Institutes of Health, National Cancer Institute, American Institute for Cancer Research, Brigham and Women's Hospital, Prevent Cancer Foundation, Victorian Cancer Agency, Swedish Research Council, Swedish Cancer Society, Region Västerbotten, Knut and Alice Wallenberg Foundation, Lion's Cancer Research Foundation, Insamlingsstiftelsen, Umeå University. Full funding details are provided in acknowledgements.

KW - Colorectal cancer

KW - Mendelian randomization

KW - Molecular subtypes

KW - Obesity

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UR - http://www.scopus.com/inward/citedby.url?scp=85184797654&partnerID=8YFLogxK

U2 - 10.1016/j.ebiom.2024.105010

DO - 10.1016/j.ebiom.2024.105010

M3 - Article

C2 - 38350331

AN - SCOPUS:85184797654

SN - 2352-3964

VL - 101

JO - EBioMedicine

JF - EBioMedicine

M1 - 105010

ER -

Body size and risk of colorectal cancer molecular defined subtypes and pathways: Mendelian randomization analyses

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