Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer

被引：347

作者：

Wang, Yufei

Mckay, James D. ^{[2
]}

Rafnar, Thorunn ^{[3
]}

Wang, Zhaoming ^{[4
]}

Timofeeva, Maria N. ^{[2
]}

Broderick, Peter ^{[1
]}

Zong, Xuchen ^{[5
]}

Laplana, Marina ^{[6
]}

Wei, Yongyue ^{[7
]}

Han, Younghun ^{[8
]}

Lloyd, Amy ^{[1
]}

Delahaye-Sourdeix, Manon ^{[2
]}

Chubb, Daniel ^{[1
]}

Gaborieau, Valerie ^{[2
]}

Wheeler, William ^{[9
]}

Chatterjee, Nilanjan ^{[4
]}

Thorleifsson, Gudmar ^{[3
]}

Sulem, Patrick ^{[3
]}

Liu, Geoffrey ^{[10
]}

Kaaks, Rudolf ^{[11
,12
]}

Henrion, Marc ^{[1
]}

Kinnersley, Ben ^{[1
]}

Vallee, Maxime ^{[2
]}

LeCalvez-Kelm, Florence ^{[2
]}

Stevens, Victoria L. ^{[13
]}

Gapstur, Susan M. ^{[13
]}

Chen, Wei V. ^{[14
]}

Zaridze, David ^{[15
]}

Szeszenia-Dabrowska, Neonilia ^{[16
]}

Lissowska, Jolanta ^{[17
,18
]}

Rudnai, Peter ^{[19
]}

Fabianova, Eleonora ^{[20
]}

Mates, Dana ^{[21
]}

Bencko, Vladimir ^{[22
]}

Foretova, Lenka ^{[23
]}

Janout, Vladimir ^{[24
]}

Krokan, Hans E. ^{[25
]}

Gabrielsen, Maiken Elvestad ^{[25
]}

Skorpen, Frank ^{[26
]}

Vatten, Lars ^{[27
]}

Njolstad, Inger ^{[28
]}

Chen, Chu ^{[29
]}

Goodman, Gary ^{[29
]}

Benhamou, Simone ^{[30
]}

Vooder, Tonu ^{[31
]}

Valk, Kristjan ^{[32
]}

Nelis, Mari ^{[33
,34
]}

Metspalu, Andres ^{[33
]}

Lener, Marcin ^{[35
]}

Lubinski, Jan ^{[35
]}

机构：

[1] Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England

[2] WHO, IARC, Lyon, France

[3] Amgen Inc, deCODE Genet, Reykjavik, Iceland

[4] NCI, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA

[5] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada

[6] German Canc Res Ctr, Div Epigen & Canc Risk Factors, Heidelberg, Germany

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

[8] Dartmouth Coll, Geisel Sch Med, Dept Community & Family Med, Ctr Genom Med, Lebanon, NH 03756 USA

[9] Informat Management Serv Inc, Rockville, MD USA

[10] Univ Hlth Network, Princess Margaret Hosp, Toronto, ON, Canada

[11] DKFZ, Div Canc Epidemiol, Heidelberg, Germany

[12] TLRC H, Heidelberg, Germany

[13] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA

[14] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA

[15] Russian NN Blokhin Canc Res Ctr, Inst Carcinogenesis, Moscow, Russia

[16] Inst Occupat Med, Dept Epidemiol, Lodz, Poland

[17] M Sklodowska Curie Mem Canc Ctr, Warsaw, Poland

[18] Inst Oncol, Warsaw, Poland

[19] Natl Inst Environm Hlth, Budapest, Hungary

[20] Reg Author Publ Hlth, Banska Bystrica, Slovakia

[21] Natl Inst Publ Hlth, Bucharest, Romania

[22] Charles Univ Prague, Inst Hyg & Epidemiol, Fac Med 1, Prague, Czech Republic

[23] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic

[24] Palacky Univ, CR-77147 Olomouc, Czech Republic

[25] Norwegian Univ Sci & Technol, Dept Lab Med, Childrens & Womens Hlth, N-7034 Trondheim, Norway

[26] Norwegian Univ Sci & Technol, Fac Med, Childrens & Womens Hlth, Dept Lab Med, N-7034 Trondheim, Norway

[27] Norwegian Univ Sci & Technol, Fac Med, Dept Publ Hlth & Gen Practice, N-7034 Trondheim, Norway

[28] Univ Tromso, Dept Community Med, Tromso, Norway

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

[30] INSERM U946, Paris, France

[31] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia

[32] Univ Bergen, Dept Biomed, Bergen, Norway

[33] Inst Mol & Cell Biol, Estonian Genome Ctr, Tartu, Estonia

[34] Univ Geneva, Sch Med, Dept Genet Med & Dev, Geneva, Switzerland

[35] Pomeranian Med Univ, Int Hereditary Canc Ctr, Dept Genet & Pathol, Szczecin, Poland

[36] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England

[37] HuGeF Fdn, Unit Mol & Genet Epidemiol, Turin, Italy

[38] Catalan Inst Oncol, Canc Epidemiol Res Program, Unit Nutr Environm & Canc, Barcelona, Spain

[39] INSERM, Ctr Res Epidemiol & Populat Hlth CESP, Nutr Hormones & Womens Hlth Team, U1018, Villejuif, France

[40] Univ Paris 11, UMRS 1018, Villejuif, France

[41] Inst Gustave Roussy, Villejuif, France

[42] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands

[43] Univ Med Ctr, Dept Gastroenterol & Hepatol, Utrecht, Netherlands

[44] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA

[45] Acad Athens, Bur Epidemiol Res, Athens, Greece

[46] Hellen Hlth Fdn, Athens, Greece

[47] Univ Cambridge, Addenbrookes Hosp, Clin Gerontol Unit, Sch Clin Med, Cambridge CB2 2QQ, England

[48] Umea Univ, Dept Radiat Sci, Umea, Sverige, Sweden

[49] Univ Tromso, Fac Hlth Sci, Dept Community Med, Tromso, Norway

[50] Canc Registry Norway, Dept Res, Oslo, Norway

来源：

NATURE GENETICS | 2014年 / 46卷 / 07期

关键词：

GENOME-WIDE ASSOCIATION; COMMON GENETIC-VARIATION; POLYMORPHIC STOP CODON; SUSCEPTIBILITY LOCUS; ADENOCARCINOMA; MUTATIONS; BREAST; P63;

D O I：

10.1038/ng.3002

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

We conducted imputation to the 1000 Genomes Project of four genome-wide association studies of lung cancer in populations of European ancestry (11,348 cases and 15,861 controls) and genotyped an additional 10,246 cases and 38,295 controls for follow-up. We identified large-effect genome-wide associations for squamous lung cancer with the rare variants BRCA2 p.Lys3326X (rs11571833, odds ratio (OR) = 2.47, P = 4.74 x 10(-20)) and CHEK2 p.Ile157Thr (rs17879961, OR = 0.38, P = 1.27 x 10(-13)). We also showed an association between common variation at 3q28 (TP63, rs13314271, OR = 1.13, P = 7.22 x 10(-10)) and lung adenocarcinoma that had been previously reported only in Asians. These findings provide further evidence for inherited genetic susceptibility to lung cancer and its biological basis. Additionally, our analysis demonstrates that imputation can identify rare disease-causing variants with substantive effects on cancer risk from preexisting genome-wide association study data.

引用

页码：736 / 741

页数：6

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