A Genome-wide Association Study of Early-Onset Breast Cancer Identifies PFKM as a Novel Breast Cancer Gene and Supports a Common Genetic Spectrum for Breast Cancer at Any Age

被引：70

作者：

Ahsan, Habibul ^{[1
,2
,3
,4
,5
]}

Halpern, Jerry ^{[6
]}

Kibriya, Muhammad G. ^{[1
,2
]}

Pierce, Brandon L. ^{[1
,2
,5
]}

Tong, Lin ^{[1
,2
]}

Gamazon, Eric ^{[3
]}

McGuire, Valerie ^{[6
]}

Felberg, Anna ^{[6
]}

Shi, Jianxin ^{[11
]}

Jasmine, Farzana ^{[1
,2
]}

Roy, Shantanu ^{[1
,2
]}

Brutus, Rachelle ^{[1
,2
]}

Argos, Maria ^{[1
,2
]}

Melkonian, Stephanie ^{[1
,2
]}

Chang-Claude, Jenny ^{[19
]}

Andrulis, Irene ^{[28
]}

Hopper, John L. ^{[30
]}

John, Esther M. ^{[6
,7
,8
]}

Malone, Kathi ^{[13
]}

Ursin, Giske

Gammon, Marilie D. ^{[14
]}

Thomas, Duncan C. ^{[9
]}

Seminara, Daniela ^{[11
]}

Casey, Graham ^{[9
]}

Knight, Julia A. ^{[28
]}

Southey, Melissa C. ^{[30
,31
]}

Giles, Graham G. ^{[30
,32
]}

Santella, Regina M. ^{[15
]}

Lee, Eunjung ^{[9
]}

Conti, David ^{[9
]}

Duggan, David ^{[16
]}

Gallinger, Steve ^{[29
]}

Haile, Robert ^{[9
]}

Jenkins, Mark ^{[32
]}

Lindor, Noralane M. ^{[17
]}

Newcomb, Polly ^{[13
]}

Michailidou, Kyriaki ^{[33
]}

Apicella, Carmel ^{[30
]}

Park, Daniel J. ^{[31
]}

Peto, Julian ^{[35
]}

Fletcher, Olivia ^{[36
]}

Silva, Isabel dos Santos ^{[35
]}

Lathrop, Mark ^{[38
,39
]}

Hunter, David J. ^{[18
]}

Chanock, Stephen J. ^{[12
]}

Meindl, Alfons ^{[20
]}

Schmutzler, Rita K. ^{[22
]}

Mueller-Myhsok, Bertram ^{[21
]}

Lochmann, Magdalena ^{[20
]}

Beckmann, Lars ^{[24
]}

机构：

[1] Univ Chicago, Ctr Canc Epidemiol & Prevent, Chicago, IL 60615 USA

[2] Univ Chicago, Dept Hlth Studies, Chicago, IL 60615 USA

[3] Univ Chicago, Dept Med, Chicago, IL 60615 USA

[4] Univ Chicago, Dept Human Genet, Chicago, IL 60615 USA

[5] Univ Chicago, Ctr Comprehens Canc, Chicago, IL 60615 USA

[6] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA

[7] Stanford Canc Inst, Stanford, CA USA

[8] Canc Prevent Inst Calif, Fremont, CA USA

[9] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA

[10] Stanford Canc Inst, Palo Alto, CA USA

[11] NCI, Epidemiol & Genet Res Program, Rockville, MD USA

[12] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA

[13] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA

[14] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA

[15] Columbia Univ, Dept Environm Hlth Sci, Mailman Sch Publ Hlth, New York, NY USA

[16] Translat Genom Res Inst, Integrated Canc Genom Div, Phoenix, AZ USA

[17] Mayo Clin Arizona, Dept Hlth Sci Res, Scottsdale, AZ USA

[18] Harvard Univ, Sch Med, Program Mol & Genet Epidemiol, Boston, MA USA

[19] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany

[20] Tech Univ Munich, Div Gynaecol Tumor Genet, Clin Gynaecol & Obstet, Munich, Germany

[21] Max Planck Inst Psychiat, D-80804 Munich, Germany

[22] Univ Cologne, Dept Obstet & Gynaecol, Div Mol Gynaecooncol, D-50931 Cologne, Germany

[23] Univ Cologne, Dept Child & Adolescent Psychiat & Psychotherapy, PMV Res Grp, D-50931 Cologne, Germany

[24] Fdn Qual & Efficiency Hlth Care, Cologne, Germany

[25] Univ Clin Hamburg Eppendorf, Clin Canc Registry, Dept Canc Epidemiol, Hamburg, Germany

[26] Univ Clin Hamburg Eppendorf, Inst Med Biometr & Epidemiol, Hamburg, Germany

[27] Johannes Gutenberg Univ Mainz, Dept Psychiat, Mainz, Germany

[28] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada

[29] Mt Sinai Hosp, Zane Cohen Ctr Digest Dis, Toronto, ON M5G 1X5, Canada

[30] Univ Melbourne, Melbourne Sch Populat Hlth, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia

[31] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Melbourne, Vic, Australia

[32] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia

[33] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England

[34] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England

[35] London Sch Hyg & Trop Med, Noncommunicable Dis Epidemiol Dept, London WC1, England

[36] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England

[37] Inst Canc Res, Sect Canc Genet, Sutton, Surrey, England

[38] Ctr Natl Genotypage, Evry, France

[39] Fdn Jean Dausset CEPH, Paris, France

[40] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland

[41] Univ Helsinki, Dept Clin Genet, Helsinki, Finland

[42] Univ Helsinki, Dept Oncol, Helsinki, Finland

[43] Univ Helsinki, Dept Oncol, Helsinki, Finland

[44] Karolinska Inst, Stockholm, Sweden

[45] Genome Inst Singapore, Div Human Genet, Singapore, Singapore

[46] Vrije Univ Amsterdam Med Ctr, Div Oncogenet, Dept Clin Genet, Amsterdam, Netherlands

[47] Erasmus MC, Dept Internal Med & Epidemiol, Rotterdam, Netherlands

来源：

CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION | 2014年 / 23卷 / 04期

关键词：

SUSCEPTIBILITY LOCI; CONFER SUSCEPTIBILITY; AFRICAN-AMERICAN; FAMILY REGISTRY; OVARIAN-CANCER; RISK; FGFR2; POPULATION; VARIANTS; EPIDEMIOLOGY;

D O I：

10.1158/1055-9965.EPI-13-0340

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Early-onset breast cancer (EOBC) causes substantial loss of life and productivity, creating a major burden among women worldwide. We analyzed 1,265,548 Hapmap3 single-nucleotide polymorphisms (SNP) among a discovery set of 3,523 EOBC incident cases and 2,702 population control women ages <= 51 years. The SNPs with smallest P values were examined in a replication set of 3,470EOBC cases and 5,475 control women. We also tested EOBC association with 19,684 genes by annotating each gene with putative functional SNPs, and then combining their P values to obtain a gene-based P value. We examined the gene with smallest P value for replication in 1,145 breast cancer cases and 1,142 control women. The combined discovery and replication sets identified 72 new SNPs associated with EOBC(P < 4 x 10(-8)) located in six genomic regions previously reported to contain SNPs associated largely with later-onset breast cancer (LOBC). SNP rs2229882 and 10 other SNPs on chromosome 5q11.2 remained associated (P < 6 x 10(-4)) after adjustment for the strongest published SNPs in the region. Thirty-two of the 82 currently known LOBC SNPs were associated with EOBC (P < 0.05). Low power is likely responsible for the remaining 50 unassociated known LOBC SNPs. The gene-based analysis identified an association between breast cancer and the phosphofructokinase-muscle (PFKM) gene on chromosome 12q13.11 that met the genome-wide gene-based threshold of 2.5 x 10(-6). In conclusion, EOBC and LOBC seem to have similar genetic etiologies; the 5q11.2 region may contain multiple distinct breast cancer loci; and the PFKM gene region is worthy of further investigation. These findings should enhance our understanding of the etiology of breast cancer. (C)2014 AACR.

引用

页码：658 / 669

页数：12

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