Citations 2
Associations Between Glycemic Traits and Colorectal Cancer: A Mendelian Randomization Analysis
Murphy, Neil , Song, Mingyang , Papadimitriou, Nikos , Carreras‐Torres, Robert , Langenberg, Claudia , Martin, Richard M. , Tsilidis, Konstantinos K. , Barroso, Inês , Chen, Ji , Vincent, Emma E. , Cotterchio, Michelle , Gruber, Stephen B. , Pai, Rish K. , Perez‐Cornago, Aurora , Duijnhoven, Fränzel J.B. van , Guelpen, Bethany Van , Vodička, Pavel , Wu, Anna H. , Peters, Ulrike , Gunter, Marc J. , Frayling, Timothy M , Bull, Caroline J , Vincent, Emma E , Gruber, Stephen B , Pai, R K , Perez-Cornago, Aurora , van Duijnhoven, Fränzel J B , Van Guelpen, Bethany , Wolk, Alicja , Chan, Andrew T , Gunter, Marc J , Murphy, Neil , Martin, Richard M , Song, Mingyang , Carreras-Torres, Robert , Tsilidis, Konstantinos K , Papadimitriou, Nikos , Vodicka, Pavel , Bull, Caroline J. , Newcomb, Polly A. , Wolk, Alicja , Chan, Andrew T.
JNCI: Journal of the National Cancer Institute | January 14, 2022 | Volume: 114 | Issue: 5 | Pages: 740-752
Abstract Background Glycemic traits—such as hyperinsulinemia, hyperglycemia, and type 2 diabetes—have been associated with higher colorectal cancer risk in observational studies; however, causality of these associations is uncertain. We used Mendelian randomization (MR) to estimate the causal effects of fasting insulin, 2-hour glucose, fasting glucose, glycated hemoglobin (HbA1c), and type 2 diabetes with colorectal cancer. Methods Genome-wide association study summary data were used to identify genetic variants associated with circulating levels of fasting insulin (n = 34), 2-hour glucose (n = 13), fasting glucose (n = 70), HbA1c (n = 221), and type 2 diabetes (n = 268). Using 2-sample MR, we examined these variants in relation to colorectal cancer risk (48 214 case patient and 64 159 control patients). Results In inverse-variance models, higher fasting insulin levels increased colorectal cancer risk (odds ratio [OR] per 1-SD = 1.65, 95% confidence interval [CI] = 1.15 to 2.36). We found no evidence of any effect of 2-hour glucose (OR per 1-SD = 1.02, 95% CI = 0.86 to 1.21) or fasting glucose (OR per 1-SD = 1.04, 95% CI = 0.88 to 1.23) concentrations on colorectal cancer risk. Genetic liability to type 2 diabetes (OR per 1-unit increase in log odds = 1.04, 95% CI = 1.01 to 1.07) and higher HbA1c levels (OR per 1-SD = 1.09, 95% CI = 1.00 to 1.19) increased colorectal cancer risk, although these findings may have been biased by pleiotropy. Higher HbA1c concentrations increased rectal cancer risk in men (OR per 1-SD = 1.21, 95% CI = 1.05 to 1.40), but not in women. Conclusions Our results support a causal effect of higher fasting insulin, but not glucose traits or type 2 diabetes, on increased colorectal cancer risk. This suggests that pharmacological or lifestyle interventions that lower circulating insulin levels may be beneficial in preventing colorectal tumorigenesis.
Genetic architectures of proximal and distal colorectal cancer are partly distinct
Huyghe, Jeroen R. , Harrison, Tabitha A. , Figueiredo, Jane C. , Schmit, Stephanie L. , Chen, Sai , Barfield, Richard , Cross, Amanda J. , Diergaarde, Brenda , Duggan, David , Harlid, Sophia , Imaz, Liher , Kang, Hyun Min , Levine, David , Perduca, Vittorio , Perez‐Cornago, Aurora , Slattery, Martha L. , Duijnhoven, Fränzel J.B. van , Guelpen, Bethany Van , Anderson, Kristin E. , Arnau‐Collell, Coral, Banbury, Barbara L. , Berndt, Sonja I. , Bishop, D. Timothy , Boehm, Juergen , Boeing, Heiner , Brenner, Hermann , Buch, Stephan , Burnett‐Hartman, Andrea N. , Carr, Prudence R. , Castells, Antoni , Chang‐Claude, Jenny , Curtis, Keith R. , Chapelle, Albert de la , Easton, Douglas F. , English, Dallas R. , Gala, Manish , Gallinger, Steven , Gauderman, W. James, Goodman, Phyllis J. , Grove, John, Gsur, Andrea , Gunter, Marc J. , Haile, Robert W. , Hampe, Jochen , Hoffmeister, Michael , Hsu, Wan‐Ling, Huang, Wen‐Yi , Joshi, Amit D. , Kühn, Tilman , Küry, Sébastien , Lejbkowicz, Flavio, Li, Li , Lindblom, Annika , Lindor, Noralane M. , Markowitz, Sanford D. , Moreno, Lorena , Murphy, Neil , Nassir, Rami , Offit, Kenneth, Parfrey, Patrick S. , Pearlman, Rachel , Phipps, Amanda I. , Prentice, Ross L. , Qi, Lihong , Rennert, Gad , Rennert, Hedy S., Ríboli, Elio , Schafmayer, Clemens, Seminara, Daniela, Song, Mingyang , Su, Yu‐Ru, Thibodeau, Stephen N. , Thomas, Duncan C. , Trichopoulou, Antonia , Visvanathan, Kala, Vodička, Pavel , Vodičková, Ludmila, Weigl, Korbinian , Weinstein, Stephanie J. , Woods, Michael O. , Wu, Anna H. , Nickerson, Deborah A. , Scacheri, Peter C. , Kundaje, Anshul , Casey, Graham , Gruber, Stephen B. , Hayes, Richard B. , Peters, Ulrike , Visvanathan, Kala , Brenner, Hermann , Buchanan, Daniel D , Chan, Andrew T , Gsur, Andrea , Hampe, Jochen , Hoffmeister, Michael , Huang, Wen-Yi , Jenab, Mazda , Murphy, Neil , Peters, Ulrike , Rennert, Gad , English, Dallas R , Gunter, Marc J , Haile, Robert W , Harrison, Tabitha A , Van Guelpen, Bethany , Visvanathan, Kala , Kury, Sebastien , Bishop, D Timothy , Song, Mingyang , Hayes, Richard B , Perez-Cornago, Aurora , Nassir, Rami , Kundaje, Anshul , Riboli, Elio , Vodicka, Pavel , Diergaarde, Brenda , Lindblom, Annika , Bien, Stephanie A. , Hampel, Heather , Conti, David V. , Qu, Conghui , Lin, Yi , Baron, John A. , Sakoda, Lori C. , Schumacher, Fredrick R. , Toland, Amanda Ewart , Agudo, Antonio , Albanes, Demetrius , Alonso, M. Henar , Arndt, Volker , Bassik, Michael Cory , Bezieau, Stéphane , Boutron‐Ruault, Marie‐Christine , Brezina, Stefanie , Buchanan, Daniel D. , Caan, Bette J. , Campbell, Peter T. , Castellvı́-Bel, Sergi , Chan, Andrew T. , Chanock, Stephen Jacob , Feskens, Edith J. M. , Giles, Graham G. , Grady, William M. , Hopper, John L. , Hudson, Thomas J , Jenab, Mazda , Jenkins, Mark A. , Keku, Temitope O , Kooperberg, Charles , Marchand, Loı̈c Le , Li, Christopher I , Lieb, Wolfgang , Männistö, Satu , Milne, Roger L. , Ogino, Shuji , Panico, Salvatore , Pharoah, Paul D.P. , Platz, Elizabeth A. , Potter, John D. , Raskin, Leon , Schoen, Robert E. , Tangen, Catherine M. , Ulrich, Cornelia M. , Vymetalkova, Veronika Polakova , White, Emily E. , Wolk, Alicja , Abecasis, Gonçalo R. , Hsu, Li , Moreno, Vı́ctor , Newcomb, Polly A.
Gut | February 25, 2021 | Volume: 70 | Issue: 7 | Pages: 1325-1334
Objective An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined. Design To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling. Results We identified 13 loci that reached genome-wide significance (p<5×10 −8 ) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. Conclusion Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.