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