Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries

被引：113

作者：

Fernandez-Rozadilla, Ceres ^{[1
,2
]}

Timofeeva, Maria ^{[3
,4
]}

Chen, Zhishan ^{[5
]}

Law, Philip ^{[6
]}

Thomas, Minta ^{[7
]}

Bien, Stephanie ^{[7
,8
,9
]}

Diez-Obrero, Virginia ^{[10
]}

Li, Li ^{[7
,14
,21
]}

Fernandez-Tajes, Juan ^{[1
]}

Palles, Claire ^{[15
]}

Sherwood, Kitty ^{[1
]}

Harris, Sarah ^{[16
,187
]}

Svinti, Victoria ^{[3
]}

McDonnell, Kevin ^{[3
,24
,25
,109
,110
]}

Farrington, Susan ^{[3
]}

Studd, James ^{[3
,6
]}

Vaughan-Shaw, Peter ^{[3
]}

Shu, Xiao-ou ^{[5
]}

Long, Jirong ^{[5
]}

Cai, Qiuyin ^{[5
]}

Guo, Xingyi ^{[5
,17
]}

Lu, Yingchang ^{[5
]}

Scacheri, Peter ^{[6
,145
]}

Studd, James ^{[3
,6
]}

Huyghe, Jeroen ^{[7
]}

Harrison, Tabitha ^{[7
]}

Shibata, David ^{[18
,53
,138
,143
,158
]}

Haiman, Christopher ^{[19
,181
]}

Devall, Mathew ^{[19
]}

Schumacher, Fredrick ^{[20
,21
]}

Melas, Marilena ^{[22
]}

Rennert, Gad ^{[23
,24
,25
]}

Obon-Santacana, Mireia ^{[10
,11
,26
]}

Martin-Sanchez, Vicente ^{[12
,27
]}

Moratalla-Navarro, Ferran ^{[10
,11
,12
,13
]}

Oh, Jae Hwan ^{[28
]}

Kim, Jeongseon ^{[29
]}

Jee, Sun Ha ^{[30
]}

Jung, Keum Ji ^{[31
]}

Kweon, Sun-Seog ^{[31
]}

Shin, Min-Ho ^{[31
]}

Shin, Aesun ^{[32
,33
]}

Ahn, Yoon-Ok ^{[32
]}

Kim, Dong-Hyun ^{[34
]}

Oze, Isao ^{[35
]}

Wen, Wanqing ^{[5
]}

Matsuo, Keitaro ^{[36
,37
]}

Matsuda, Koichi ^{[38
]}

Tanikawa, Chizu ^{[39
]}

Ren, Zefang ^{[40
]}

机构：

[1] Univ Edinburgh, Inst Genom & Canc, Edinburgh Canc Res Ctr, Edinburgh, Midlothian, Scotland

[2] Inst Invest Sanitaria Santiago, Genom Med Grp, Santiago De Compostela, Spain

[3] Univ Edinburgh, Inst Genet & Canc, Med Res Council Human Genet Unit, Colon Canc Genet Grp, Edinburgh, Midlothian, Scotland

[4] Univ Southern Denmark, Danish Inst Adv Study, Dept Publ Hlth, Odense, Denmark

[5] Vanderbilt Univ, Med Ctr, Dept Med, Div Epidemiol,Vanderbilt Ingram Canc Ctr,Vanderbi, Nashville, TN 37232 USA

[6] Inst Canc Res, Div Genet & Epidemiol, London, England

[7] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA

[8] Cleveland Clin, Genom Med Inst, Cleveland, OH USA

[9] Case Comprehens Canc Ctr, Populat & Canc Prevent Program, Cleveland, OH USA

[10] Bellvitge Biomed Res Inst, ONCOBELL Program, Colorectal Canc Grp, Barcelona, Spain

[11] Catalan Inst Oncol, Oncol Data Analyt Program, Barcelona, Spain

[12] Consortium Biomed Res Epidemiol & Publ Hlth, Madrid, Spain

[13] Univ Barcelona, Fac Med, Dept Clin Sci, Barcelona, Spain

[14] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA USA

[15] Univ Birmingham, Inst Canc & Genom Sci, Coll Med & Dent Sci, Birmingham, W Midlands, England

[16] Univ Oxford, Dept Publ Hlth, Richard Doll Bldg, Oxford, England

[17] Vanderbilt Univ, Dept Biomed Informat, Sch Med, Nashville, TN USA

[18] Univ Southern Calif, USC Norris Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA

[19] Univ Virginia, Ctr Publ Hlth Genom, Dept Publ Hlth Sci, Charlottesville, VA USA

[20] Case Western Reserve Univ, Dept Populat & Quantitat Hlth Sci, Cleveland, OH USA

[21] Case Western Reserve Univ, Case Comprehens Canc Ctr, Cleveland, OH USA

[22] Nationwide Childrens Hosp, Steve & Cindy Rasmussen Inst Genom Med, Columbus, OH USA

[23] Lady Davis Carmel Med Ctr, Dept Community Med & Epidemiol, Haifa, Israel

[24] Technion Israel Inst Technol, Ruth & Bruce Rappaport Fac Med, Haifa, Israel

[25] Clalit Natl Canc Control Ctr, Haifa, Israel

[26] Consortium Biomed Res Epidemiol & Publ Hlth, Madrid, Spain

[27] Univ Leon, Biomed Inst, Leon, Spain

[28] Natl Canc Ctr, Natl Canc Ctr Hosp, Ctr Colorectal Canc, Goyang Si, Gyeonggi Do, South Korea

[29] Natl Canc Ctr, Grad Sch Canc Sci & Policy, Dept Canc Biomed Sci, Goyang Si, Gyeonggi Do, South Korea

[30] Yonsei Univ, Grad Sch Publ Hlth, Dept Epidemiol & Hlth Promot, Seoul, South Korea

[31] Chonnam Natl Univ, Dept Prevent Med, Sch Med, Gwangju, South Korea

[32] Seoul Natl Univ, Dept Prevent Med, Coll Med, Seoul, South Korea

[33] Seoul Natl Univ, Canc Res Inst, Seoul, South Korea

[34] Hallym Univ, Dept Social & Prevent Med, Coll Med, Chunchon, South Korea

[35] Aichi Canc Ctr, Div Canc Epidemiol & Prevent, Res Inst, Nagoya, Aichi, Japan

[36] Aichi Canc Ctr, Div Mol & Clin Epidemiol, Res Inst, Nagoya, Aichi, Japan

[37] Nagoya Univ, Dept Epidemiol, Grad Sch Med, Nagoya, Aichi, Japan

[38] Univ Tokyo, Grad Sch Frontier Sci, Dept Computat Biol & Med Sci, Lab Clin Genome Sequencing, Tokyo, Japan

[39] Univ Tokyo, Inst Med Sci, Human Genome Ctr, Lab Genome Technol, Tokyo, Japan

[40] Sun Yat Sen Univ, Sch Publ Hlth, Guangzhou, Peoples R China

[41] Shanghai Jiao Tong Univ, Shanghai Canc Inst, Renji Hosp, State Key Lab Oncogenes & Related Genes,Sch Med, Shanghai, Peoples R China

[42] Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Dept Epidemiol,Shanghai Canc Inst, Shanghai, Peoples R China

[43] Sun Yat Sen Univ, Canc Ctr, State Key Lab Oncol South China, Guangzhou, Peoples R China

[44] Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne Sch Populat & Global Hlth, Melbourne, Vic, Australia

[45] Seoul Natl Univ, Dept Epidemiol, Sch Publ Hlth, Seoul, South Korea

[46] Seoul Natl Univ, Inst Hlth & Environm, Seoul, South Korea

[47] Mayo Clin Arizona, Dept Lab Med & Pathol, Scottsdale, AZ USA

[48] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Dept Med, Los Angeles, CA USA

[49] Cedars Sinai Canc Res Ctr Hlth Equ, Dept Med, Div Oncol, Los Angeles, CA USA

[50] Univ Toronto, Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada

来源：

NATURE GENETICS | 2023年 / 55卷 / 01期

基金：

欧洲研究理事会; 美国国家卫生研究院;

关键词：

LD SCORE REGRESSION; ASSOCIATION; HERITABILITY; METAANALYSIS;

D O I：

10.1038/s41588-022-01222-9

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：89 / +

页数：18

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