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 Ursin; Marilie 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 M. 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

doi:10.1158/1055-9965.EPI-13-0340

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 M. 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 journal › Article › peer-review

56 Scopus citations

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 language	English (US)
Pages (from-to)	658-669
Number of pages	12
Journal	Cancer Epidemiology Biomarkers and Prevention
Volume	23
Issue number	4
DOIs	https://doi.org/10.1158/1055-9965.EPI-13-0340
State	Published - Apr 2014

ASJC Scopus subject areas

General Medicine

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10.1158/1055-9965.EPI-13-0340

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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., Hopper, J. L., John, E. M., Malone, K., ... 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 and Prevention, 23(4), 658-669. https://doi.org/10.1158/1055-9965.EPI-13-0340

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. et al.
In: Cancer Epidemiology Biomarkers and Prevention, Vol. 23, No. 4, 04.2014, p. 658-669.

Research output: Contribution to journal › Article › peer-review

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

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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.",

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

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doi = "10.1158/1055-9965.EPI-13-0340",

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AU - Ahsan, Habibul

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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

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AU - Southey, Melissa C.

AU - Giles, Graham G.

AU - Santella, Regina M.

AU - Lee, Eunjung

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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

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AU - Makalic, Enes

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AU - Dahmen, Norbert

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AU - Aittomäki, Kristiina

AU - Blomqvist, Carl

AU - Hall, Per

AU - Czene, Kamila

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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.

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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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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

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