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