A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1)

被引：428

作者：

Thomas, Gilles ^{[1
]}

Jacobs, Kevin B. ^{[1
,2
,3
]}

Kraft, Peter ^{[4
]}

Yeager, Meredith ^{[1
]}

Wacholder, Sholom ^{[1
]}

Cox, David G. ^{[4
,5
,6
]}

Hankinson, Susan E. ^{[5
,6
]}

Hutchinson, Amy ^{[1
,3
]}

Wang, Zhaoming ^{[1
,3
]}

Yu, Kai ^{[1
]}

Chatterjee, Nilanjan ^{[1
]}

Garcia-Closas, Montserrat ^{[1
]}

Gonzalez-Bosquet, Jesus ^{[1
]}

Prokunina-Olsson, Ludmila ^{[1
]}

Orr, Nick

Willett, Walter C. ^{[5
,6
,7
]}

Colditz, Graham A. ^{[8
]}

Ziegler, Regina G. ^{[1
]}

Berg, Christine D. ^{[9
]}

Buys, Saundra S. ^{[10
]}

McCarty, Catherine A. ^{[11
]}

Feigelson, Heather Spencer ^{[12
]}

Calle, Eugenia E. ^{[12
]}

Thun, Michael J. ^{[12
]}

Diver, Ryan ^{[12
]}

Prentice, Ross ^{[13
]}

Jackson, Rebecca ^{[14
]}

Kooperberg, Charles ^{[13
]}

Chlebowski, Rowan ^{[15
]}

Lissowska, Jolanta ^{[16
,17
]}

Peplonska, Beata ^{[18
]}

Brinton, Louise A. ^{[1
]}

Sigurdson, Alice ^{[1
]}

Doody, Michele ^{[1
]}

Bhatti, Parveen ^{[1
]}

Alexander, Bruce H. ^{[19
]}

Buring, Julie ^{[6
,20
]}

Lee, I-Min ^{[6
,20
]}

Vatten, Lars J. ^{[21
]}

Hveem, Kristian ^{[21
]}

Kumle, Merethe ^{[22
]}

Hayes, Richard B. ^{[1
]}

Tucker, Margaret ^{[1
]}

Gerhard, Daniela S. ^{[23
]}

Fraumeni, Joseph F., Jr. ^{[1
]}

Hoover, Robert N. ^{[1
]}

Chanock, Stephen J. ^{[1
]}

Hunter, David J. ^{[1
,4
,5
,6
,7
,24
]}

机构：

[1] NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Bethesda, MD 20892 USA

[2] Bioinformed Consulting Serv, Gaithersburg, MD USA

[3] NCI, SAIC Frederick Inc, Core Genotyping Facil, Adv Technol Program, Frederick, MD 21701 USA

[4] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Mol & Genet Epidemiol, Boston, MA 02115 USA

[5] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA

[6] Harvard Univ, Sch Med, Boston, MA USA

[7] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA

[8] Washington Univ, Sch Med, St Louis, MO USA

[9] NCI, Canc Prevent Div, NIH, US Dept HHS, Bethesda, MD 20892 USA

[10] Univ Utah, Dept Internal Med, Salt Lake City, UT 84112 USA

[11] Marshfield Clin Res Fdn, Ctr Human Genet, Marshfield, WI USA

[12] Amer Canc Soc, Dept Epidemiol & Surveillance Res, Atlanta, GA 30329 USA

[13] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA

[14] Ohio State Univ, Med Ctr, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA

[15] Harbor Univ Calif Los Angeles, Med Ctr, Torrance, CA USA

[16] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland

[17] Inst Oncol, Warsaw, Poland

[18] Nofer Inst Occupat Med, Lodz, Poland

[19] Univ Minnesota, Sch Publ Hlth, Div Environm Hlth Sci, Minneapolis, MN USA

[20] Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA 02115 USA

[21] Norwegian Univ Sci & Technol, Dept Publ Hlth, N-7034 Trondheim, Norway

[22] Univ Tromso, Inst Community Med, Tromso, Norway

[23] NCI, Off Canc Genom, NIH, US Dept HHS, Bethesda, MD 20892 USA

[24] Broad Inst Harvard & MIT, Cambridge, MA USA

来源：

NATURE GENETICS | 2009年 / 41卷 / 05期

基金：

美国国家卫生研究院;

关键词：

SUSCEPTIBILITY GENE; CONFER SUSCEPTIBILITY; COMMON VARIANTS; MUTATIONS; BRCA2; LOCI;

D O I：

10.1038/ng.353

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

We conducted a three-stage genome-wide association study (GWAS) of breast cancer in 9,770 cases and 10,799 controls in the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. In stage 1, we genotyped 528,173 SNPs in 1,145 cases of invasive breast cancer and 1,142 controls. In stage 2, we analyzed 24,909 top SNPs in 4,547 cases and 4,434 controls. In stage 3, we investigated 21 loci in 4,078 cases and 5,223 controls. Two new loci achieved genome-wide significance. A pericentromeric SNP on chromosome 1p11.2 (rs11249433; P = 6.74 x 10(-10) adjusted genotype test, 2 degrees of freedom) resides in a large linkage disequilibrium block neighboring NOTCH2 and FCGR1B; this signal was stronger for estrogen-receptor-positive tumors. A second SNP on chromosome 14q24.1 (rs999737; P = 1.74 x 10(-7)) localizes to RAD51L1, a gene in the homologous recombination DNA repair pathway. We also confirmed associations with loci on chromosomes 2q35, 5p12, 5q11.2, 8q24, 10q26 and 16q12.1.

引用

页码：579 / 584

页数：6

共 27 条

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Ko, Yon-Dschun ;

Bruening, Thomas ;

Haas, Susanne ;

Doerk, Thilo ;

Schuermann, Peter ;

Hillemanns, Peter ;

Bogdanova, Natalia ;

Bremer, Michael ;

Karstens, Johann Hinrich ;

Fagerholm, Rainer ;

Aaltonen, Kirsimari ;

Aittomaki, Kristiina ;

Von Smitten, Karl ;

Blomqvist, Carl ;

Mannermaa, Arto ;

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Eskelinen, Matti ;

Tengstrom, Maria ;

Kosma, Veli-Matti ;

Kataja, Vesa ;

Chenevix-Trench, Georgia ;

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Welch, Robert ;

Hutchinson, Amy ;

Wang, Junwen ;

Yu, Kai ;

Chatterjee, Nilanjan ;

Orr, Nick ;

Willett, Walter C. ;

Colditz, Graham A. ;

Ziegler, Regina G. ;

Berg, Christine D. ;

Buys, Saundra S. ;

McCarty, Catherine A. ;

Feigelson, Heather Spencer ;

Calle, Eugenia E. ;

Thun, Michael J. ;

Hayes, Richard B. ;

Tucker, Margaret ;

Gerhard, Daniela S. ;

Fraumeni, Joseph F., Jr. ;

Hoover, Robert N. ;

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Chanock, Stephen J. .

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← 1 2 3 →

共 27 条

[1] RAD51 135G→C modifies breast cancer risk among BRCA2 mutation carriers:: Results from a combined analysis of 19 studies [J].

Antoniou, Antonis C. ;

Sinilnikova, Olga M. ;

Simard, Jacques ;

Leone, Melanie ;

Dumont, Martine ;

Neuhausen, Susan L. ;

Struewing, Jeffery P. ;

Stoppa-Lyonnet, Dominique ;

Barjhoux, Laure ;

Hughes, David J. ;

Coupier, Isabelle ;

Belotti, Muriel ;

Lasset, Christine ;

Rebbeck, Timothy R. ;

Wagner, Theresa ;

Lynch, Henry T. ;

Domchek, Susan M. ;

Nathanson, Katherine L. ;

Garber, Judy E. ;

Weitzel, Jeffrey ;

Narod, Steven A. ;

Tomlinson, Gail ;

Olopade, Olufunmilayo I. ;

Godwin, Andrew ;

Isaacs, Claudine ;

Jakubowska, Anna ;

Lubinski, Jan ;

Gronwald, Jacek ;

Gorski, Bohdan ;

Byrski, Tomasz ;

Huzarski, Tomasz ;

Peock, Susan ;

Cook, Margaret ;

Baynes, Caroline ;

Murray, Alexandra ;

Rogers, Mark ;

Daly, Peter A. ;

Dorkins, Huw ;

Schmutzler, Rita K. ;

Versmold, Beatrix ;

Engel, Christoph ;

Meindl, Alfons ;

Arnold, Norbert ;

Niederacher, Dieter ;

Deissler, Helmut ;

Spurdle, Amanda B. ;

Chen, Xiaoqing ;

Waddell, Nicola ;

Cloonan, Nicole ;

Kirchhoff, Tomas .

AMERICAN JOURNAL OF HUMAN GENETICS, 2007, 81 (06) :1186-1200

[2] Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls [J].

Burton, Paul R. ;

Clayton, David G. ;

Cardon, Lon R. ;

Craddock, Nick ;

Deloukas, Panos ;

Duncanson, Audrey ;

Kwiatkowski, Dominic P. ;

McCarthy, Mark I. ;

Ouwehand, Willem H. ;

Samani, Nilesh J. ;

Todd, John A. ;

Donnelly, Peter ;

Barrett, Jeffrey C. ;

Davison, Dan ;

Easton, Doug ;

Evans, David ;

Leung, Hin-Tak ;

Marchini, Jonathan L. ;

Morris, Andrew P. ;

Spencer, Chris C. A. ;

Tobin, Martin D. ;

Attwood, Antony P. ;

Boorman, James P. ;

Cant, Barbara ;

Everson, Ursula ;

Hussey, Judith M. ;

Jolley, Jennifer D. ;

Knight, Alexandra S. ;

Koch, Kerstin ;

Meech, Elizabeth ;

Nutland, Sarah ;

Prowse, Christopher V. ;

Stevens, Helen E. ;

Taylor, Niall C. ;

Walters, Graham R. ;

Walker, Neil M. ;

Watkins, Nicholas A. ;

Winzer, Thilo ;

Jones, Richard W. ;

McArdle, Wendy L. ;

Ring, Susan M. ;

Strachan, David P. ;

Pembrey, Marcus ;

Breen, Gerome ;

St Clair, David ;

Caesar, Sian ;

Gordon-Smith, Katherine ;

Jones, Lisa ;

Fraser, Christine ;

Green, Elain K. .

NATURE, 2007, 447 (7145) :661-678

[3]

Colditz G.A., 2006, Cancer epidemiology and prevention, V3rd, P995

[4] A common coding variant in CASP8 is associated with breast cancer risk [J].

Cox, Angela ;

Dunning, Alison M. ;

Garcia-Closas, Montserrat ;

Balasubramanian, Sabapathy ;

Reed, Malcolm W. R. ;

Pooley, Karen A. ;

Scollen, Serena ;

Baynes, Caroline ;

Ponder, Bruce A. J. ;

Chanock, Stephen ;

Lissowska, Jolanta ;

Brinton, Louise ;

Peplonska, Beata ;

Southey, Melissa C. ;

Hopper, John L. ;

McCredie, Margaret R. E. ;

Giles, Graham G. ;

Fletcher, Olivia ;

Johnson, Nichola ;

dos Santos Silva, Isabel ;

Gibson, Lorna ;

Bojesen, Stig E. ;

Nordestgaard, Borge G. ;

Axelsson, Christen K. ;

Torres, Diana ;

Hamann, Ute ;

Justenhoven, Christina ;

Brauch, Hiltrud ;

Chang-Claude, Jenny ;

Kropp, Silke ;

Risch, Angela ;

Wang-Gohrke, Shan ;

Schuermann, Peter ;

Bogdanova, Natalia ;

Doerk, Thilo ;

Fagerholm, Rainer ;

Aaltonen, Kirsimari ;

Blomqvist, Carl ;

Nevanlinna, Heli ;

Seal, Sheila ;

Renwick, Anthony ;

Stratton, Michael R. ;

Rahman, Nazneen ;

Sangrajrang, Suleeporn ;

Hughes, David ;

Odefrey, Fabrice ;

Brennan, Paul ;

Spurdle, Amanda B. ;

Chenevix-Trench, Georgia ;

Beesley, Jonathan .

NATURE GENETICS, 2007, 39 (03) :352-358

[5] Genome-wide association study identifies novel breast cancer susceptibility loci [J].

Easton, Douglas F. ;

Pooley, Karen A. ;

Dunning, Alison M. ;

Pharoah, Paul D. P. ;

Thompson, Deborah ;

Ballinger, Dennis G. ;

Struewing, Jeffery P. ;

Morrison, Jonathan ;

Field, Helen ;

Luben, Robert ;

Wareham, Nicholas ;

Ahmed, Shahana ;

Healey, Catherine S. ;

Bowman, Richard ;

Meyer, Kerstin B. ;

Haiman, Christopher A. ;

Kolonel, Laurence K. ;

Henderson, Brian E. ;

Le Marchand, Loic ;

Brennan, Paul ;

Sangrajrang, Suleeporn ;

Gaborieau, Valerie ;

Odefrey, Fabrice ;

Shen, Chen-Yang ;

Wu, Pei-Ei ;

Wang, Hui-Chun ;

Eccles, Diana ;

Evans, D. Gareth ;

Peto, Julian ;

Fletcher, Olivia ;

Johnson, Nichola ;

Seal, Sheila ;

Stratton, Michael R. ;

Rahman, Nazneen ;

Chenevix-Trench, Georgia ;

Bojesen, Stig E. ;

Nordestgaard, Borge G. ;

Axelsson, Christen K. ;

Garcia-Closas, Montserrat ;

Brinton, Louise ;

Chanock, Stephen ;

Lissowska, Jolanta ;

Peplonska, Beata ;

Nevanlinna, Heli ;

Fagerholm, Rainer ;

Eerola, Hannaleena ;

Kang, Daehee ;

Yoo, Keun-Young ;

Noh, Dong-Young ;

Ahn, Sei-Hyun .

NATURE, 2007, 447 (7148) :1087-U7

[6] A recurrent mutation in PALB2 in Finnish cancer families [J].

Erkko, Hannele ;

Xia, Bing ;

Nikkilae, Jenni ;

Schleutker, Johanna ;

Syrjaekoski, Kirsi ;

Mannermaa, Arto ;

Kallioniemi, Anne ;

Pylkas, Katri ;

Karppinen, Sanna-Maria ;

Rapakko, Katrin ;

Miron, Alexander ;

Sheng, Qing ;

Li, Guilan ;

Mattila, Henna ;

Bell, Daphne W. ;

Haber, Daniel A. ;

Grip, Mervi ;

Reiman, Mervi ;

Jukkola-Vuorinen, Arja ;

Mustonen, Aki ;

Kere, Juha ;

Aaltonen, Lauri A. ;

Kosma, Veli-Matti ;

Kataja, Vesa ;

Soini, Ylermi ;

Drapkin, Ronny I. ;

Livingston, David M. ;

Winqvist, Robert .

NATURE, 2007, 446 (7133) :316-319

[7]

Falush D, 2003, GENETICS, V164, P1567

[8] Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics [J].

Garcia-Closas, Montserrat ;

Hall, Per ;

Nevanlinna, Heli ;

Pooley, Karen ;

Morrison, Jonathan ;

Richesson, Douglas A. ;

Bojesen, Stig E. ;

Nordestgaard, Borge G. ;

Axelsson, Christen K. ;

Arias, Jose I. ;

Milne, Roger L. ;

Ribas, Gloria ;

Gonzalez-Neira, Anna ;

Benitez, Javier ;

Zamora, Pilar ;

Brauch, Hiltrud ;

Justenhoven, Christina ;

Hamann, Ute ;

Ko, Yon-Dschun ;

Bruening, Thomas ;

Haas, Susanne ;

Doerk, Thilo ;

Schuermann, Peter ;

Hillemanns, Peter ;

Bogdanova, Natalia ;

Bremer, Michael ;

Karstens, Johann Hinrich ;

Fagerholm, Rainer ;

Aaltonen, Kirsimari ;

Aittomaki, Kristiina ;

Von Smitten, Karl ;

Blomqvist, Carl ;

Mannermaa, Arto ;

Uusitupa, Matti ;

Eskelinen, Matti ;

Tengstrom, Maria ;

Kosma, Veli-Matti ;

Kataja, Vesa ;

Chenevix-Trench, Georgia ;

Spurdle, Amanda B. ;

Beesley, Jonathan ;

Chen, Xiaoqing ;

Devilee, Peter ;

Van Asperen, Christi J. ;

Jacobi, Catharina E. ;

Tollenaar, Rob A. E. M. ;

Huijts, Petra E. A. ;

Klijn, Jan G. M. ;

Chang-Claude, Jenny ;

Kropp, Silke .

PLOS GENETICS, 2008, 4 (04)

[9] Genome-wide association study provides evidence for a breast cancer risk locus at 6q22-33 [J].

Gold, Bert ;

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