Ερευνητικό υλικό ΕΚΠΑ

Genetic architectures of proximal and distal colorectal cancer are
partly distinct

Αγγλικά

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.

2021

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

Gut Pathogens

BMJ Publishing Group

70

7

1325-1334

https://doi.org/10.1136/gutjnl-2020-321534

10.1136/gutjnl-2020-321534

https://pergamos.lib.uoa.gr/uoa/dl/object/3029824