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

TY - JOUR

T1 - 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

AU - Ahsan, Habibul

AU - Halpern, Jerry

AU - Kibriya, Muhammad G

AU - Pierce, Brandon L

AU - Tong, Lin

AU - Gamazon, Eric

AU - McGuire, Valerie

AU - Felberg, Anna

AU - Shi, Jianxin

AU - Jasmine, Farzana

AU - Roy, Shantanu

AU - Brutus, Rachelle

AU - Argos, Maria

AU - Melkonian, Stephanie

AU - Chang-Claude, Jenny

AU - Andrulis, Irene

AU - Hopper, John L

AU - John, Esther M

AU - Malone, Kathi

AU - Ursin, Giske

AU - Gammon, Marilie D

AU - Thomas, Duncan C

AU - Seminara, Daniela

AU - Casey, Graham

AU - Knight, Julia A

AU - Southey, Melissa C

AU - Giles, Graham G

AU - Santella, Regina M

AU - Lee, Eunjung

AU - Conti, David

AU - Duggan, David

AU - Gallinger, Steve

AU - Haile, Robert

AU - Jenkins, Mark

AU - Lindor, Noralane M

AU - Newcomb, Polly

AU - Michailidou, Kyriaki

AU - Apicella, Carmel

AU - Park, Daniel J

AU - Peto, Julian

AU - Fletcher, Olivia

AU - dos Santos Silva, Isabel

AU - Lathrop, Mark

AU - Hunter, David J

AU - Chanock, Stephen J

AU - Meindl, Alfons

AU - Schmutzler, Rita K

AU - Müller-Myhsok, Bertram

AU - Lochmann, Magdalena

AU - Beckmann, Lars

AU - Hein, Rebecca

AU - Makalic, Enes

AU - Schmidt, Daniel F

AU - Bui, Quang Minh

AU - Stone, Jennifer

AU - Flesch-Janys, Dieter

AU - Dahmen, Norbert

AU - Nevanlinna, Heli

AU - Aittomäki, Kristiina

AU - Blomqvist, Carl

AU - Hall, Per

AU - Czene, Kamila

AU - Irwanto, Astrid

AU - Liu, Jianjun

AU - Rahman, Nazneen

AU - Turnbull, Clare

AU - Dunning, Alison M

AU - Pharoah, Paul

AU - Waisfisz, Quinten

AU - Meijers-Heijboer, Hanne

AU - Uitterlinden, Andre G

AU - Rivadeneira, Fernando

AU - Nicolae, Dan

AU - Easton, Douglas F

AU - Cox, Nancy J

AU - Whittemore, Alice S

AU - Familial Breast Cancer Study

PY - 2014/4/1

Y1 - 2014/4/1

N2 - 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.

AB - 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.

KW - Breast Neoplasms

KW - Case-Control Studies

KW - Female

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Middle Aged

KW - Phosphofructokinase-1, Muscle Type

KW - Polymorphism, Single Nucleotide

KW - Tumor Markers, Biological

U2 - 10.1158/1055-9965.EPI-13-0340

DO - 10.1158/1055-9965.EPI-13-0340

M3 - SCORING: Journal article

C2 - 24493630

VL - 23

SP - 658

EP - 669

JO - CANCER EPIDEM BIOMAR

JF - CANCER EPIDEM BIOMAR

SN - 1055-9965

IS - 4

ER -