Genetic architectures of proximal and distal colorectal cancer are partly distinct

TY - JOUR

T1 - Genetic architectures of proximal and distal colorectal cancer are partly distinct

AU - Huyghe, Jeroen R

AU - Harrison, Tabitha A

AU - Bien, Stephanie A

AU - Hampel, Heather

AU - Figueiredo, Jane C

AU - Schmit, Stephanie L

AU - Conti, David V

AU - Chen, Sai

AU - Qu, Conghui

AU - Lin, Yi

AU - Barfield, Richard

AU - Baron, John A

AU - Cross, Amanda J

AU - Diergaarde, Brenda

AU - Duggan, David

AU - Harlid, Sophia

AU - Imaz, Liher

AU - Kang, Hyun Min

AU - Levine, David M

AU - Perduca, Vittorio

AU - Perez-Cornago, Aurora

AU - Sakoda, Lori C

AU - Schumacher, Fredrick R

AU - Slattery, Martha L

AU - Toland, Amanda E

AU - van Duijnhoven, Fränzel J B

AU - Van Guelpen, Bethany

AU - Agudo, Antonio

AU - Albanes, Demetrius

AU - Alonso, M Henar

AU - Anderson, Kristin

AU - Arnau-Collell, Coral

AU - Arndt, Volker

AU - Banbury, Barbara L

AU - Bassik, Michael C

AU - Berndt, Sonja I

AU - Bézieau, Stéphane

AU - Bishop, D Timothy

AU - Boehm, Juergen

AU - Boeing, Heiner

AU - Boutron-Ruault, Marie-Christine

AU - Brenner, Hermann

AU - Brezina, Stefanie

AU - Buch, Stephan

AU - Buchanan, Daniel D

AU - Burnett-Hartman, Andrea

AU - Caan, Bette J

AU - Campbell, Peter T

AU - Carr, Prudence R

AU - Castells, Antoni

AU - Castellví-Bel, Sergi

AU - Chan, Andrew T

AU - Chang-Claude, Jenny

AU - Chanock, Stephen J

AU - Curtis, Keith R

AU - de la Chapelle, Albert

AU - Easton, Douglas F

AU - English, Dallas R

AU - Feskens, Edith J M

AU - Gala, Manish

AU - Gallinger, Steven J

AU - Gauderman, W James

AU - Giles, Graham G

AU - Goodman, Phyllis J

AU - Grady, William M

AU - Grove, John S

AU - Gsur, Andrea

AU - Gunter, Marc J

AU - Haile, Robert W

AU - Hampe, Jochen

AU - Hoffmeister, Michael

AU - Hopper, John L

AU - Hsu, Wan-Ling

AU - Huang, Wen-Yi

AU - Hudson, Thomas J

AU - Jenab, Mazda

AU - Jenkins, Mark A

AU - Joshi, Amit D

AU - Keku, Temitope O

AU - Kooperberg, Charles

AU - Kühn, Tilman

AU - Küry, Sébastien

AU - Le Marchand, Loic

AU - Lejbkowicz, Flavio

AU - Li, Christopher I

AU - Li, Li

AU - Lieb, Wolfgang

AU - Lindblom, Annika

AU - Lindor, Noralane M

AU - Männistö, Satu

AU - Markowitz, Sanford D

AU - Milne, Roger L

AU - Moreno, Lorena

AU - Murphy, Neil

AU - Nassir, Rami

AU - Offit, Kenneth

AU - Ogino, Shuji

AU - Panico, Salvatore

AU - Parfrey, Patrick S

AU - Pearlman, Rachel

AU - Pharoah, Paul D P

AU - Phipps, Amanda I

AU - Platz, Elizabeth A

AU - Potter, John D

AU - Prentice, Ross L

AU - Qi, Lihong

AU - Raskin, Leon

AU - Rennert, Gad

AU - Rennert, Hedy S

AU - Riboli, Elio

AU - Schafmayer, Clemens

AU - Schoen, Robert E

AU - Seminara, Daniela

AU - Song, Mingyang

AU - Su, Yu-Ru

AU - Tangen, Catherine M

AU - Thibodeau, Stephen N

AU - Thomas, Duncan C

AU - Trichopoulou, Antonia

AU - Ulrich, Cornelia M

AU - Visvanathan, Kala

AU - Vodicka, Pavel

AU - Vodickova, Ludmila

AU - Vymetalkova, Veronika

AU - Weigl, Korbinian

AU - Weinstein, Stephanie J

AU - White, Emily

AU - Wolk, Alicja

AU - Woods, Michael O

AU - Wu, Anna H

AU - Abecasis, Goncalo R

AU - Nickerson, Deborah A

AU - Scacheri, Peter C

AU - Kundaje, Anshul

AU - Casey, Graham

AU - Gruber, Stephen B

AU - Hsu, Li

AU - Moreno, Victor

AU - Hayes, Richard B

AU - Newcomb, Polly A

N1 - © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

PY - 2021/7

Y1 - 2021/7

N2 - 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.

AB - 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.

U2 - 10.1136/gutjnl-2020-321534

DO - 10.1136/gutjnl-2020-321534

M3 - SCORING: Journal article

C2 - 33632709

VL - 70

SP - 1325

EP - 1334

JO - GUT

JF - GUT

SN - 0017-5749

IS - 7

ER -