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
N1 - Publisher Copyright:
© 2024
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
UR - http://www.scopus.com/inward/record.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 -