Genetic architectures of proximal and distal colorectal cancer are partly distinct
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Genetic architectures of proximal and distal colorectal cancer are partly distinct. / 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; Baron, John A; Cross, Amanda J; Diergaarde, Brenda; Duggan, David; Harlid, Sophia; Imaz, Liher; Kang, Hyun Min; Levine, David M; Perduca, Vittorio; Perez-Cornago, Aurora; Sakoda, Lori C; Schumacher, Fredrick R; Slattery, Martha L; Toland, Amanda E; van Duijnhoven, Fränzel J B; Van Guelpen, Bethany; Agudo, Antonio; Albanes, Demetrius; Alonso, M Henar; Anderson, Kristin; Arnau-Collell, Coral; Arndt, Volker; Banbury, Barbara L; Bassik, Michael C; Berndt, Sonja I; Bézieau, Stéphane; Bishop, D Timothy; Boehm, Juergen; Boeing, Heiner; Boutron-Ruault, Marie-Christine; Brenner, Hermann; Brezina, Stefanie; Buch, Stephan; Buchanan, Daniel D; Burnett-Hartman, Andrea; Caan, Bette J; Campbell, Peter T; Carr, Prudence R; Castells, Antoni; Castellví-Bel, Sergi; Chan, Andrew T; Chang-Claude, Jenny; Chanock, Stephen J; Curtis, Keith R; de la Chapelle, Albert; Easton, Douglas F; English, Dallas R; Feskens, Edith J M; Gala, Manish; Gallinger, Steven J; Gauderman, W James; Giles, Graham G; Goodman, Phyllis J; Grady, William M; Grove, John S; Gsur, Andrea; Gunter, Marc J; Haile, Robert W; Hampe, Jochen; Hoffmeister, Michael; Hopper, John L; Hsu, Wan-Ling; Huang, Wen-Yi; Hudson, Thomas J; Jenab, Mazda; Jenkins, Mark A; Joshi, Amit D; Keku, Temitope O; Kooperberg, Charles; Kühn, Tilman; Küry, Sébastien; Le Marchand, Loic; Lejbkowicz, Flavio; Li, Christopher I; Li, Li; Lieb, Wolfgang; Lindblom, Annika; Lindor, Noralane M; Männistö, Satu; Markowitz, Sanford D; Milne, Roger L; Moreno, Lorena; Murphy, Neil; Nassir, Rami; Offit, Kenneth; Ogino, Shuji; Panico, Salvatore; Parfrey, Patrick S; Pearlman, Rachel; Pharoah, Paul D P; Phipps, Amanda I; Platz, Elizabeth A; Potter, John D; Prentice, Ross L; Qi, Lihong; Raskin, Leon; Rennert, Gad; Rennert, Hedy S; Riboli, Elio; Schafmayer, Clemens; Schoen, Robert E; Seminara, Daniela; Song, Mingyang; Su, Yu-Ru; Tangen, Catherine M; Thibodeau, Stephen N; Thomas, Duncan C; Trichopoulou, Antonia; Ulrich, Cornelia M; Visvanathan, Kala; Vodicka, Pavel; Vodickova, Ludmila; Vymetalkova, Veronika; Weigl, Korbinian; Weinstein, Stephanie J; White, Emily; Wolk, Alicja; Woods, Michael O; Wu, Anna H; Abecasis, Goncalo R; Nickerson, Deborah A; Scacheri, Peter C; Kundaje, Anshul; Casey, Graham; Gruber, Stephen B; Hsu, Li; Moreno, Victor; Hayes, Richard B; Newcomb, Polly A.
in: GUT, Jahrgang 70, Nr. 7, 07.2021, S. 1325-1334.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -