A Genome-wide Association Study of Early-Onset Breast Cancer IdentifiesPFKMas 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 ,   for the 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: February 2014

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 &lt; 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 &lt; 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 &lt; 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. Cancer Epidemiol Biomarkers Prev; 23(4); 658–69. ©2014 AACR.