@article{3029824,
    title = "Genetic architectures of proximal and distal colorectal cancer are
partly distinct",
    author = "Huyghe, Jeroen R. and Harrison, Tabitha A. and Bien, Stephanie A. and and Hampel, Heather and Figueiredo, Jane C. and Schmit, Stephanie L. and and Conti, V, David and Chen, Sai and Qu, Conghui and Lin, Yi and Barfield, and Richard and Baron, John A. and Cross, Amanda J. and Diergaarde, Brenda and and Duggan, David and Harlid, Sophia and Imaz, Liher and Kang, Hyun Min and and Levine, David M. and Perduca, Vittorio and Perez-Cornago, Aurora and and Sakoda, Lori C. and Schumacher, Fredrick R. and Slattery, Martha L. and and Toland, Amanda E. and van Duijnhoven, Franzel J. B. and Van Guelpen, and Bethany and Agudo, Antonio and Albanes, Demetrius and Alonso, M. Henar and and Anderson, Kristin and Arnau-Collell, Coral and Arndt, Volker and and Banbury, Barbara L. and Bassik, Michael C. and Berndt, I, Sonja and and Bezieau, Stephane and Bishop, D. Timothy and Boehm, Juergen and Boeing, and Heiner and Boutron-Ruault, Marie-Christine and Brenner, Hermann and and Brezina, Stefanie and Buch, Stephan and Buchanan, Daniel D. and and Burnett-Hartman, Andrea and Caan, Bette J. and Campbell, Peter T. and and Carr, Prudence R. and Castells, Antoni and Castellvi-Bel, Sergi and and Chan, Andrew T. and Chang-Claude, Jenny and Chanock, Stephen J. and and Curtis, Keith R. and de la Chapelle, Albert and Easton, Douglas F. and and English, Dallas R. and Feskens, Edith J. M. and Gala, Manish and and Gallinger, Steven J. and Gauderman, W. James and Giles, Graham G. and and Goodman, Phyllis J. and Grady, William M. and Grove, John S. and Gsur, and Andrea and Gunter, Marc J. and Haile, Robert W. and Hampe, Jochen and and Hoffmeister, Michael and Hopper, John L. and Hsu, Wan-Ling and Huang, and Wen-Yi and Hudson, Thomas J. and Jenab, Mazda and Jenkins, Mark A. and and Joshi, Amit D. and Keku, Temitope O. and Kooperberg, Charles and Kuhn, and Tilman and Kury, Sebastien and Le Marchand, Loic and Lejbkowicz, Flavio and and Li, I, Christopher and Li, Li and Lieb, Wolfgang and Lindblom, and Annika and Lindor, Noralane M. and Mannisto, Satu and Markowitz, Sanford and D. and Milne, Roger L. and Moreno, Lorena and Murphy, Neil and Nassir, and Rami and Offit, Kenneth and Ogino, Shuji and Panico, Salvatore and and Parfrey, Patrick S. and Pearlman, Rachel and Pharoah, Paul D. P. and and Phipps, I, Amanda and Platz, Elizabeth A. and Potter, John D. and and Prentice, Ross L. and Qi, Lihong and Raskin, Leon and Rennert, Gad and and Rennert, Hedy S. and Riboli, Elio and Schafmayer, Clemens and Schoen, and Robert E. and Seminara, Daniela and Song, Mingyang and Su, Yu-Ru and and Tangen, Catherine M. and Thibodeau, Stephen N. and Thomas, Duncan C. and and Trichopoulou, Antonia and Ulrich, Cornelia M. and Visvanathan, Kala and and Vodicka, Pavel and Vodickova, Ludmila and Vymetalkova, Veronika and and Weigl, Korbinian and Weinstein, Stephanie J. and White, Emily and Wolk, and Alicja and Woods, Michael O. and Wu, Anna H. and Abecasis, Goncalo R. and and Nickerson, Deborah A. and Scacheri, Peter C. and Kundaje, Anshul and and Casey, Graham and Gruber, Stephen B. and Hsu, Li and Moreno, Victor and and Hayes, Richard B. and Newcomb, Polly A. and Peters, Ulrike",
    journal = "Gut Pathogens",
    year = "2021",
    volume = "70",
    number = "7",
    pages = "1325-1334",
    publisher = "BMJ Publishing Group",
    issn = "1757-4749",
    doi = "10.1136/gutjnl-2020-321534",
    abstract = "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<5x10(-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."
}