Title: 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.

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

Published In Cancer Epidemiol Biomarkers Prev, (2014 Apr)

Abstract: 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 3,470 EOBC 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 × 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 genome-wide gene-based threshold of 2.5 × 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.

PubMed ID: 24493630

MeSH Terms: Biomarkers, Tumor/genetics*; Breast Neoplasms/enzymology*; Breast Neoplasms/epidemiology; Breast Neoplasms/genetics*; Case-Control Studies; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Middle Aged; Phosphofructokinase-1, Muscle Type/genetics*; Polymorphism, Single Nucleotide