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 Andrulis, John L. Hopper, Esther M. John, Kathi 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 Conti, David Duggan, Steve Gallinger, Robert Haile, Mark Jenkins, Noralane Morey Lindor, Polly Newcomb, Kyriaki Michailidou, Carmel Apicella, Daniel J. Park, Julian Peto, Olivia Fletcher, Isabel Dos Santos Silva, Mark 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 Stone, Dieter Flesch-Janys, Norbert Dahmen, Heli Nevanlinna, Kristiina Aittomäki, Carl Blomqvist, Per Hall, Kamila Czene, Astrid Irwanto, Jianjun Liu, Nazneen Rahman, Clare Turnbull, Alison M. Dunning, Paul Pharoah, Quinten Waisfisz, Hanne Meijers-Heijboer, Andre G. Uitterlinden, Fernando Rivadeneira, Dan Nicolae, Douglas F. Easton, Nancy J. Cox, Alice S. Whittemore

Research output: Contribution to journalArticle

44 Citations (Scopus)

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 (US)
Pages (from-to)658-669
Number of pages12
JournalCancer Epidemiology Biomarkers and Prevention
Volume23
Issue number4
DOIs
StatePublished - 2014

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Phosphofructokinases
Neoplasm Genes
Genome-Wide Association Study
Breast Neoplasms
Muscles
Single Nucleotide Polymorphism
Genes
Muscle Neoplasms
Chromosomes
Population Control

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

Cite this

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. / 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 Morey; Newcomb, Polly; Michailidou, Kyriaki; Apicella, Carmel; Park, Daniel J.; Peto, Julian; Fletcher, Olivia; Silva, Isabel Dos Santos; 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; 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.

In: Cancer Epidemiology Biomarkers and Prevention, Vol. 23, No. 4, 2014, p. 658-669.

Research output: Contribution to journalArticle

Ahsan, H, Halpern, J, Kibriya, MG, Pierce, BL, 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, Hopper, JL, John, EM, Malone, K, Ursin, G, Gammon, MD, Thomas, DC, Seminara, D, Casey, G, Knight, JA, Southey, MC, Giles, GG, Santella, RM, Lee, E, Conti, D, Duggan, D, Gallinger, S, Haile, R, Jenkins, M, Lindor, NM, Newcomb, P, Michailidou, K, Apicella, C, Park, DJ, Peto, J, Fletcher, O, Silva, IDS, Lathrop, M, Hunter, DJ, Chanock, SJ, Meindl, A, Schmutzler, RK, Müller-Myhsok, B, Lochmann, M, Beckmann, L, Hein, R, Makalic, E, Schmidt, DF, Bui, QM, Stone, J, Flesch-Janys, D, Dahmen, N, Nevanlinna, H, Aittomäki, K, Blomqvist, C, Hall, P, Czene, K, Irwanto, A, Liu, J, Rahman, N, Turnbull, C, Dunning, AM, Pharoah, P, Waisfisz, Q, Meijers-Heijboer, H, Uitterlinden, AG, Rivadeneira, F, Nicolae, D, Easton, DF, Cox, NJ & Whittemore, AS 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 and Prevention, vol. 23, no. 4, pp. 658-669. https://doi.org/10.1158/1055-9965.EPI-13-0340
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 Morey ; Newcomb, Polly ; Michailidou, Kyriaki ; Apicella, Carmel ; Park, Daniel J. ; Peto, Julian ; Fletcher, Olivia ; Silva, Isabel Dos Santos ; 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 ; 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. / 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. In: Cancer Epidemiology Biomarkers and Prevention. 2014 ; Vol. 23, No. 4. pp. 658-669.
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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",
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.",
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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 Morey

AU - Newcomb, Polly

AU - Michailidou, Kyriaki

AU - Apicella, Carmel

AU - Park, Daniel J.

AU - Peto, Julian

AU - Fletcher, Olivia

AU - Silva, Isabel Dos Santos

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.

PY - 2014

Y1 - 2014

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 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.

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 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.

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