Data from A Genome-wide Association Study of Early-Onset Breast Cancer Identifies &lt;i&gt;PFKM&lt;/i&gt; as a Novel Breast Cancer Gene and Supports a Common Genetic Spectrum for Breast Cancer at Any Age

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

doi:10.1158/1055-9965.c.6515769

Abstract

<div>AbstractEarly-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. Cancer Epidemiol Biomarkers Prev; 23(4); 658–69. ©2014 AACR.</div>

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