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
Creators: name: Schmutzler, Rita K.
name: Cox, Nancy J.
name: Argos, Maria
name: Stone, Jennifer
name: Roy, Shantanu
name: Müller-Myhsok, Bertram
name: Meindl, Alfons
name: Nevanlinna, Heli
name: Andrulis, Irene
name: Jasmine, Farzana
name: Gallinger, Steve
name: Santella, Regina M.
name: Aittomäki, Kristiina
name: Chang-Claude, Jenny
name: Lathrop, Mark
name: Shi, Jianxin
name: Irwanto, Astrid
name: Hopper, John L.
name: Waisfisz, Quinten
name: Hall, Per
name: Beckmann, Lars
name: Thomas, Duncan C.
name: Knight, Julia A.
name: Ursin, Giske
name: Chanock, Stephen J.
name: Easton, Douglas F.
name: Flesch-Janys, Dieter
name: Whittemore, Alice S.
name: Bui, Quang Minh
name: Dahmen, Norbert
name: Melkonian, Stephanie
name: Meijers-Heijboer, Hanne
name: Blomqvist, Carl
name: Pierce, Brandon L.
name: Gammon, Marilie D.
name: Dunning, Alison M.
name: Felberg, Anna
name: Turnbull, Clare
name: Schmidt, Daniel F.
name: Rivadeneira, Fernando
name: Michailidou, Kyriaki
name: Halpern, Jerry
name: John, Esther M.
name: Malone, Kathi
name: Lochmann, Magdalena
name: Nicolae, Dan
name: Gamazon, Eric
name: Ahsan, Habibul
name: Liu, Jianjun
name: Apicella, Carmel
name: Lee, Eunjung
name: Silva, Isabel Dos Santos
name: Uitterlinden, Andre G.
name: Tong, Lin
name: Park, Daniel J.
name: Southey, Melissa C.
name: Hein, Rebecca
name: Lindor, Noralane M.
name: Casey, Graham
name: Kibriya, Muhammad G.
name: Haile, Robert
name: Czene, Kamila
name: Newcomb, Polly
name: Conti, David
name: Seminara, Daniela
name: Rahman, Nazneen
name: Pharoah, Paul
name: Fletcher, Olivia
name: Jenkins, Mark
name: Duggan, David
name: Hunter, David J.
name: Giles, Graham G.
name: Makalic, Enes
name: Brutus, Rachelle
name: Peto, Julian
name: McGuire, Valerie
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2014

description: 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 (P<4×10−8) 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<6×10−4) 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 genomewide gene-based threshold of 2.5×10−6. 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 cancer.