Abstract
Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.
| Original language | English |
|---|---|
| Journal | Nature Genetics |
| Volume | 55 |
| Pages (from-to) | 89-99 |
| ISSN | 1061-4036 |
| DOIs | |
| Publication status | Published - Jan 2023 |
Keywords
- Colorectal Neoplasms/genetics
- East Asian People/genetics
- European People/genetics
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Humans
- Multiomics
- Polymorphism, Single Nucleotide/genetics
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In: Nature Genetics, Vol. 55, 01.2023, p. 89-99.
Research output: Contribution to journal › Journal article › Research › peer-review
TY - JOUR
T1 - Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries
AU - Fernandez-Rozadilla, Ceres
AU - Timofeeva, Maria
AU - Chen, Zhishan
AU - Law, Philip
AU - Thomas, Minta
AU - Schmit, Stephanie
AU - Díez-Obrero, Virginia
AU - Hsu, Li
AU - Fernandez-Tajes, Juan
AU - Palles, Claire
AU - Sherwood, Kitty
AU - Briggs, Sarah
AU - Svinti, Victoria
AU - Donnelly, Kevin
AU - Farrington, Susan
AU - Blackmur, James
AU - Vaughan-Shaw, Peter
AU - Shu, Xiao ou
AU - Long, Jirong
AU - Cai, Qiuyin
AU - Guo, Xingyi
AU - Lu, Yingchang
AU - Broderick, Peter
AU - Studd, James
AU - Huyghe, Jeroen
AU - Harrison, Tabitha
AU - Conti, David
AU - Dampier, Christopher
AU - Devall, Mathew
AU - Schumacher, Fredrick
AU - Melas, Marilena
AU - Rennert, Gad
AU - Obón-Santacana, Mireia
AU - Martín-Sánchez, Vicente
AU - Moratalla-Navarro, Ferran
AU - Oh, Jae Hwan
AU - Kim, Jeongseon
AU - Jee, Sun Ha
AU - Jung, Keum Ji
AU - Kweon, Sun Seog
AU - Shin, Min Ho
AU - Shin, Aesun
AU - Ahn, Yoon Ok
AU - Kim, Dong Hyun
AU - Oze, Isao
AU - Wen, Wanqing
AU - Matsuo, Keitaro
AU - Matsuda, Koichi
AU - Tanikawa, Chizu
AU - Ren, Zefang
AU - Gao, Yu Tang
AU - Jia, Wei Hua
AU - Hopper, John
AU - Jenkins, Mark
AU - Win, Aung Ko
AU - Pai, Rish
AU - Figueiredo, Jane
AU - Haile, Robert
AU - Gallinger, Steven
AU - Woods, Michael
AU - Newcomb, Polly
AU - Duggan, David
AU - Cheadle, Jeremy
AU - Kaplan, Richard
AU - Maughan, Timothy
AU - Kerr, Rachel
AU - Kerr, David
AU - Kirac, Iva
AU - Böhm, Jan
AU - Mecklin, Lukka Pekka
AU - Jousilahti, Pekka
AU - Knekt, Paul
AU - Aaltonen, Lauri
AU - Rissanen, Harri
AU - Pukkala, Eero
AU - Eriksson, Johan
AU - Cajuso, Tatiana
AU - Hänninen, Ulrika
AU - Kondelin, Johanna
AU - Palin, Kimmo
AU - Tanskanen, Tomas
AU - Renkonen-Sinisalo, Laura
AU - Zanke, Brent
AU - Männistö, Satu
AU - Albanes, Demetrius
AU - Weinstein, Stephanie
AU - Ruiz-Narvaez, Edward
AU - Palmer, Julie
AU - Buchanan, Daniel
AU - Platz, Elizabeth
AU - Visvanathan, Kala
AU - Ulrich, Cornelia
AU - Siegel, Erin
AU - Brezina, Stefanie
AU - Gsur, Andrea
AU - Campbell, Peter
AU - Chang-Claude, Jenny
AU - Hoffmeister, Michael
AU - Brenner, Hermann
AU - Slattery, Martha
AU - Potter, John
AU - Tsilidis, Konstantinos
AU - Schulze, Matthias
AU - Gunter, Marc
AU - Murphy, Neil
AU - Castells, Antoni
AU - Castellví-Bel, Sergi
AU - Moreira, Leticia
AU - Arndt, Volker
AU - Shcherbina, Anna
AU - Stern, Mariana
AU - Pardamean, Bens
AU - Bishop, Timothy
AU - Giles, Graham
AU - Southey, Melissa
AU - Idos, Gregory
AU - McDonnell, Kevin
AU - Abu-Ful, Zomoroda
AU - Greenson, Joel
AU - Shulman, Katerina
AU - Lejbkowicz, Flavio
AU - Offit, Kenneth
AU - Su, Yu Ru
AU - Steinfelder, Robert
AU - Keku, Temitope
AU - van Guelpen, Bethany
AU - Hudson, Thomas
AU - Hampel, Heather
AU - Pearlman, Rachel
AU - Berndt, Sonja
AU - Hayes, Richard
AU - Martinez, Marie Elena
AU - Thomas, Sushma
AU - Corley, Douglas
AU - Pharoah, Paul
AU - Larsson, Susanna
AU - Yen, Yun
AU - Lenz, Heinz Josef
AU - White, Emily
AU - Li, Li
AU - Doheny, Kimberly
AU - Pugh, Elizabeth
AU - Shelford, Tameka
AU - Chan, Andrew
AU - Cruz-Correa, Marcia
AU - Lindblom, Annika
AU - Hunter, David
AU - Joshi, Amit
AU - Schafmayer, Clemens
AU - Scacheri, Peter
AU - Kundaje, Anshul
AU - Nickerson, Deborah
AU - Schoen, Robert
AU - Hampe, Jochen
AU - Stadler, Zsofia
AU - Vodicka, Pavel
AU - Vodickova, Ludmila
AU - Vymetalkova, Veronika
AU - Papadopoulos, Nickolas
AU - Edlund, Chistopher
AU - Gauderman, William
AU - Thomas, Duncan
AU - Shibata, David
AU - Toland, Amanda
AU - Markowitz, Sanford
AU - Kim, Andre
AU - Chanock, Stephen
AU - van Duijnhoven, Franzel
AU - Feskens, Edith
AU - Sakoda, Lori
AU - Gago-Dominguez, Manuela
AU - Wolk, Alicja
AU - Naccarati, Alessio
AU - Pardini, Barbara
AU - FitzGerald, Liesel
AU - Lee, Soo Chin
AU - Ogino, Shuji
AU - Bien, Stephanie
AU - Kooperberg, Charles
AU - Li, Christopher
AU - Lin, Yi
AU - Prentice, Ross
AU - Qu, Conghui
AU - Bézieau, Stéphane
AU - Tangen, Catherine
AU - Mardis, Elaine
AU - Yamaji, Taiki
AU - Sawada, Norie
AU - Iwasaki, Motoki
AU - Haiman, Christopher
AU - Le Marchand, Loic
AU - Wu, Anna
AU - Qu, Chenxu
AU - McNeil, Caroline
AU - Coetzee, Gerhard
AU - Hayward, Caroline
AU - Deary, Ian
AU - Harris, Sarah
AU - Theodoratou, Evropi
AU - Reid, Stuart
AU - Walker, Marion
AU - Ooi, Li Yin
AU - Moreno, Victor
AU - Casey, Graham
AU - Gruber, Stephen
AU - Tomlinson, Ian
AU - Zheng, Wei
AU - Dunlop, Malcolm
AU - Houlston, Richard
AU - Peters, Ulrike
N1 - Funding Information: At the Institute of Cancer Research, this work was supported by Cancer Research UK (CRUK, grant no. C1298/A25514 to R.S.H.). Additional support was provided by the National Cancer Research Network. In Edinburgh, the work was supported by program grant funding from CRUK (grant nos. C348/A12076 to M.G.D. and C6199/A16459 to I.T.), EU European Research Council Advanced Grant EVOCAN, and the infrastructure and staffing of the Edinburgh CRUK Cancer Research Centre. C.F.R. was supported by a Marie Sklodowska-Curie Intra-European Fellowship Action (grant no. IEF-301077) for the INTERMPHEN project and received considerable help from many staff in the Department of Endoscopy at the John Radcliffe Hospital in Oxford. Support from the European Union (grant nos. FP7/207–2013 and 258236), FP7 collaborative project SYSCOL and COST Actions EuColonGene and TransColonCan are also acknowledged (grant nos. BM1206 and CA17118 to I.T.). We are grateful to many colleagues within UK clinical genetics departments (for CORGI) and to many collaborators who participated in the VICTOR, QUASAR2 and SCOT trials. We also thank colleagues from the UK National Cancer Research Network (for NSCCG). IT acknowledges funding from CRUK program grant no. C6199/A27327. The work at Vanderbilt University Medical Center was supported by US National Institutes of Health (NIH; grant nos. R01CA188214, R37CA070867, UM1CA182910, R01CA124558, R01CA158473 and R01CA148667), as well as Anne Potter Wilson Chair funds from the Vanderbilt University School of Medicine (to W.Z.). Sample preparation and genotyping assays at Vanderbilt University were conducted at the Survey and Biospecimen Shared Resources and Vanderbilt Microarray Shared Resource, supported in part by the Vanderbilt-Ingram Cancer Center (grant no. P30CA068485). Statistical analyses were performed on servers maintained by the Advanced Computing Center for Research and Education (ACCRE) at Vanderbilt University. Genetics and Epidemiology of Colorectal Cancer Consortium (GECCC), National Cancer Institute (NCI), NIH, US Department of Health and Human Services provided grant nos. U01 CA164930, U01 CA137088, R01 CA059045, R01201407 and R01CA206279. Genotyping services were provided by the Center for Inherited Disease Research (CIDR) contract no. HHSN268201200008I. This research was funded in part through the NIH/NCI Cancer Center support grant no. P30 CA015704. Scientific Computing Infrastructure at the Fred Hutchinson Cancer Research Center was funded by ORIP grant no. S10OD028685 (to U.P.). The Colorectal Cancer Transdisciplinary (CORECT) study was supported by the NCI/NIH, US Department of Health and Human Services (grant nos. U19 CA148107, R01 CA81488, P30 CA014089, R01 CA197350, P01 CA196569 and R01 CA201407) and National Institutes of Environmental Health Sciences, NIH (grant no. T32 ES013678). The Colon Cancer Family Registry (CCFR) participant recruitment and collection of data and biospecimens used in the present study were supported by the NCI, NIH (grant no. U01 CA167551). OFCCR was supported through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (grant no. U01 CA074783). The content of this manuscript does not necessarily reflect the views or policies of the NCI or any of the collaborating centers in the CCFR, and the mention of trade names, commercial products or organizations does not imply endorsement by the US Government, any cancer registry or the CCFR. Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2023/1
Y1 - 2023/1
N2 - Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.
AB - Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.
KW - Colorectal Neoplasms/genetics
KW - East Asian People/genetics
KW - European People/genetics
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study
KW - Humans
KW - Multiomics
KW - Polymorphism, Single Nucleotide/genetics
UR - https://doi.org/10.1038/s41588-023-01334-w
U2 - 10.1038/s41588-022-01222-9
DO - 10.1038/s41588-022-01222-9
M3 - Journal article
C2 - 36539618
AN - SCOPUS:85144441436
SN - 1061-4036
VL - 55
SP - 89
EP - 99
JO - Nature Genetics
JF - Nature Genetics
ER -