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

Ahsan H, Halpern J, Kibriya MG, Pierce BL, Tong L, Gamazon ER, McGuire V, Felberg A, Shi J, Jasmine F, Roy S, Paul-Brutus R, Argos M, Melkonian S, Chang-Claude J, Andrulis IL, Hopper JL, John EM, Malone KE, Ursin G, Gammon MD, Thomas DC, Seminara D, Casey G, Knight JA, Southey MC, Giles GG, Santella RM, Lee E, Conti DV, Duggan D, Gallinger S, Haile RW, Jenkins MA, Lindor NM, Newcomb PA, Michailidou K, Apicella C, Park DJ, Peto J, Fletcher O, Dos Santos Silva I, Lathrop M, Hunter DJ, Chanock SJ, Meindl A, Schmutzler RK, Muller-Myhsok B, Lochmann M, Beckmann M, Hein R, Makalic E, Schmidt DF, Bui QM, Stone J, Flesch-Janys D, Dahmen N, Nevanlinna H, Aittomaki K, Blomqvist C, Hall P, Czene K, Irwanto A, Liu J, Rahman N, Turnbull C, Dunning AM, Pharoah PD, Waisfisz Q, Meijers-Heijboer HE, Uitterlinden AG, Rivadeneira F, Nicolae D, Easton DF, Cox NJ, Whittermore AS (2014) 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. Cancer Epidemiol Biomarkers Prev

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 SNPs among a discovery set of 3,523 EOBC incident case and 2,702 population control women aged <=51 years.="" the="" snps="" with="" smallest="" p-values="" were="" examined="" in="" a="" replication="" set="" of="" 3,470="" eobc="" case="" 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="" case="" and="" 1,142="" control="" women.="" the="" combined="" discovery="" and="" replication="" sets="" identified="" 72="" new="" snps="" associated="" with="" eobc=""><4x10-8) 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=""><6x10-4) after="" adjustment="" for="" the="" strongest="" published="" snps="" in="" the="" region.="" thirty-two="" of="" the="" 82="" currently="" known="" lobc="" snps="" were="" associated="" with="" eobc=""><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="" genomewide="" gene-based="" threshold="" of="" 2.5x10-in="" conclusion,="" eobc="" and="" lobc="" appear="" 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="">