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

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

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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 maycontain 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.

Original languageEnglish
Pages (from-to)658-669
Number of pages12
JournalCancer Epidemiology, Biomarkers & Prevention
Volume23
Issue number4
DOIs
Publication statusPublished - 2014
Externally publishedYes

Cite this

Ahsan, H., Halpern, J., Kibriya, M. G., Pierce, B. L., Tong, L., Gamazon, E., McGuire, V., Felberg, A., Shi, J., Jasmine, F., Roy, S., Brutus, R., Argos, M., Melkonian, S., Chang-Claude, J., Andrulis, I. L., Hopper, J. L., John, E. M., Malone, K. E., ... Whittemore, A. S. (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 Epidemiology, Biomarkers & Prevention, 23(4), 658-669. https://doi.org/10.1158/1055-9965.EPI-13-0340