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@article{Huyghe:2021:10.1136/gutjnl-2020-321534,
author = {Huyghe, JR and Harrison, TA and Bien, SA and Hampel, H and Figueiredo, JC and Schmit, SL and Conti, DV and Chen, S and Qu, C and Lin, Y and Barfield, R and Baron, JA and Cross, AJ and Diergaarde, B and Duggan, D and Harlid, S and Imaz, L and Kang, HM and Levine, DM and Perduca, V and Perez-Cornago, A and Sakoda, LC and Schumacher, FR and Slattery, ML and Toland, AE and van, Duijnhoven FJB and Van, Guelpen B and Agudo, A and Albanes, D and Alonso, MH and Anderson, K and Arnau-Collell, C and Arndt, V and Banbury, BL and Bassik, MC and Berndt, SI and Bézieau, S and Bishop, DT and Boehm, J and Boeing, H and Boutron-Ruault, M-C and Brenner, H and Brezina, S and Buch, S and Buchanan, DD and Burnett-Hartman, A and Caan, BJ and Campbell, PT and Carr, PR and Castells, A and Castellví-Bel, S and Chan, AT and Chang-Claude, J and Chanock, SJ and Curtis, KR and de, la Chapelle A and Easton, DF and English, DR and Feskens, EJM and Gala, M and Gallinger, SJ and Gauderman, WJ and Giles, GG and Goodman},
doi = {10.1136/gutjnl-2020-321534},
journal = {Gut},
pages = {1325--1334},
title = {Genetic architectures of proximal and distal colorectal cancer are partly distinct},
url = {http://dx.doi.org/10.1136/gutjnl-2020-321534},
volume = {70},
year = {2021}
}

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TY  - JOUR
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.
AU  - Huyghe,JR
AU  - Harrison,TA
AU  - Bien,SA
AU  - Hampel,H
AU  - Figueiredo,JC
AU  - Schmit,SL
AU  - Conti,DV
AU  - Chen,S
AU  - Qu,C
AU  - Lin,Y
AU  - Barfield,R
AU  - Baron,JA
AU  - Cross,AJ
AU  - Diergaarde,B
AU  - Duggan,D
AU  - Harlid,S
AU  - Imaz,L
AU  - Kang,HM
AU  - Levine,DM
AU  - Perduca,V
AU  - Perez-Cornago,A
AU  - Sakoda,LC
AU  - Schumacher,FR
AU  - Slattery,ML
AU  - Toland,AE
AU  - van,Duijnhoven FJB
AU  - Van,Guelpen B
AU  - Agudo,A
AU  - Albanes,D
AU  - Alonso,MH
AU  - Anderson,K
AU  - Arnau-Collell,C
AU  - Arndt,V
AU  - Banbury,BL
AU  - Bassik,MC
AU  - Berndt,SI
AU  - Bézieau,S
AU  - Bishop,DT
AU  - Boehm,J
AU  - Boeing,H
AU  - Boutron-Ruault,M-C
AU  - Brenner,H
AU  - Brezina,S
AU  - Buch,S
AU  - Buchanan,DD
AU  - Burnett-Hartman,A
AU  - Caan,BJ
AU  - Campbell,PT
AU  - Carr,PR
AU  - Castells,A
AU  - Castellví-Bel,S
AU  - Chan,AT
AU  - Chang-Claude,J
AU  - Chanock,SJ
AU  - Curtis,KR
AU  - de,la Chapelle A
AU  - Easton,DF
AU  - English,DR
AU  - Feskens,EJM
AU  - Gala,M
AU  - Gallinger,SJ
AU  - Gauderman,WJ
AU  - Giles,GG
AU  - Goodman,PJ
AU  - Grady,WM
AU  - Grove,JS
AU  - Gsur,A
AU  - Gunter,MJ
AU  - Haile,RW
AU  - Hampe,J
AU  - Hoffmeister,M
AU  - Hopper,JL
AU  - Hsu,W-L
AU  - Huang,W-Y
AU  - Hudson,TJ
AU  - Jenab,M
AU  - Jenkins,MA
AU  - Joshi,AD
AU  - Keku,TO
AU  - Kooperberg,C
AU  - Kühn,T
AU  - Küry,S
AU  - Le,Marchand L
AU  - Lejbkowicz,F
AU  - Li,CI
AU  - Li,L
AU  - Lieb,W
AU  - Lindblom,A
AU  - Lindor,NM
AU  - Männistö,S
AU  - Markowitz,SD
AU  - Milne,RL
AU  - Moreno,L
AU  - Murphy,N
AU  - Nassir,R
AU  - Offit,K
AU  - Ogino,S
AU  - Panico,S
AU  - Parfrey,PS
AU  - Pearlman,R
AU  - Pharoah,PDP
AU  - Phipps,AI
AU  - Platz,EA
AU  - Potter,JD
AU  - Prentice,RL
AU  - Qi,L
AU  - Raskin,L
AU  - Rennert,G
AU  - Rennert,HS
AU  - Riboli,E
AU  - Schafmayer,C
AU  - Schoen,RE
AU  - Seminara,D
AU  - Song,M
AU  - Su,Y-R
AU  - Tangen,CM
AU  - Thibodeau,SN
AU  - Thomas,DC
AU  - Trichopoulou,A
AU  - Ulrich,CM
AU  - Visvanathan,K
AU  - Vodicka,P
AU  - Vodickova,L
AU  - Vymetalkova,V
AU  - Weigl,K
AU  - Weinstein,SJ
AU  - White,E
AU  - Wolk,A
AU  - Woods,MO
AU  - Wu,AH
AU  - Abecasis,GR
AU  - Nickerson,DA
AU  - Scacheri,PC
AU  - Kundaje,A
AU  - Casey,G
AU  - Gruber,SB
AU  - Hsu,L
AU  - Moreno,V
AU  - Hayes,RB
AU  - Newcomb,PA
AU  - Peters,U
DO  - 10.1136/gutjnl-2020-321534
EP  - 1334
PY  - 2021///
SN  - 0017-5749
SP  - 1325
TI  - Genetic architectures of proximal and distal colorectal cancer are partly distinct
T2  - Gut
UR  - http://dx.doi.org/10.1136/gutjnl-2020-321534
UR  - https://www.ncbi.nlm.nih.gov/pubmed/33632709
UR  - http://hdl.handle.net/10044/1/90216
VL  - 70
ER  -

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