Genetic architectures of proximal and distal colorectal cancer are partly distinct

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...

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Autores: Huyghe, Jeroen R., Harrison, Tabitha A., Bien, Stephanie A., Hampel, Heather, Figueiredo, Jane C., Schmit, Stephanie L., Conti, David V., Chen, Sai, Qu, Conghui, Lin, Yi, Barfield, Richard, Peters, Ulrike, Gunter, Marc J., Banbury, Barbara L., Chan, Andrew T., Harlid, Sophia, Imaz, Liher, Sakoda, Lori C., Kang, Hyun Min, Huang, Wen-yi, Boehm, Juergen, De La Chapelle, Albert, Schumacher, Fredrick R., Slattery, Martha L., Gala, Manish, Toland, Amanda E., Phipps, Amanda I., Buch, Stephan, Albanes, Demetrius, Alonso Aguado, Maria Henar, Gsur, Andrea, Anderson, Kristin, Rennert, Hedy S., Gauderman, W. James, Bassik, Michael C., Berndt, Sonja I., Hsu, Wan-ling, Bézieau, Stéphane, Haile, Robert W., Boeing, Heiner, Boutron-Ruault, Marie-Christine, Keku, Temitope O., Brenner, Hermann, Hudson, Thomas J., Buchanan, Daniel D., Burnett Hartman, Andrea, Lejbkowicz, Flavio, Caan, Bette J., Carr, Prudence R., Castells Garangou, Antoni, Lindor, Noralane M., Castellví Bel, Sergi, Chang Claude, Jenny, Chanock, Stephen J., Moreno, Lorena, Curtis, Keith R., Easton, Douglas F., English, Dallas R., Giles, Graham G., Feskens, Edith J. M., Su, Yu-ru, Kooperberg, Charles, Ogino, Shuji, Goodman, Phyllis J., Grady, William M., Pharoah, Paul D. P., Grove, John S., Cross, Amanda J., Li, Christopher I., Hampe, Jochen, Hoffmeister, Michael, Rennert, Gad, Hopper, John L., Perduca, Vittorio, Platz, Elizabeth A., Jenab, Mazda, Jenkins, Mark A., Song, Mingyang, Joshi, Amit D., Riboli, Elio, Kühn, Tilman, Küry, Sébastien, Ulrich, Cornelia M., Le Marchand, Loic, Tangen, Catherine M., Li, Li, Lieb, Wolfgang, Weigl, Korbinian, Lindblom, Annika, Männistö, Satu, Markowitz, Sanford D., Wu, Anna H., Milne, Roger L., Murphy, Neil, Nassir, Rami, Kundaje, Anshul, Offit, Kenneth, Panico, Salvatore, Parfrey, Patrick S., Potter, John D., Pearlman, Rachel, Van Guelpen, Bethany, Visvanathan, Kala, Moreno Aguado, Víctor, Prentice, Ross L., Qi, Lihong, Baron, John A., Raskin, Leon, Arndt, Volker, Weinstein, Stephanie J., Schafmayer, Clemens, Schoen, Robert E., Levine, David M., Seminara, Daniela, Gallinger, Steven, Diergaarde, Brenda, Thibodeau, Stephen N., Thomas, Duncan C., Van Duijnhoven, Fränzel J. B., Trichopoulou, Antonia, Pérez Cornago, Aurora, Vodicka, Pavel, Vodickova, Ludmila, Arnau Collell, Coral, Vymetalkova, Veronika, Agudo, Antonio, White, Emily, Wolk, Alicja, Bishop, D. Timothy, Woods, Michael O., Abecasis, Gonçalo R., Nickerson, Deborah A., Brezina, Stefanie, Scacheri, Peter C., Casey, Graham, Gruber, Stephen B., Campbell, Peter T., Hsu, Li, Hayes, Richard B., Newcomb, Polly A., Duggan, David
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/179342
Acceso en línea:https://hdl.handle.net/2445/179342
Access Level:acceso abierto
Palabra clave:Medicina preventiva
Càncer colorectal
Genètica
Preventive medicine
Colorectal cancer
Genetics
Descripción
Sumario: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.

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