Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170

Alison M. Dunning; Kyriaki Michailidou; Karoline B. Kuchenbaecker; Deborah Thompson; Juliet D. French; Jonathan Beesley; Catherine S. Healey; Siddhartha Kar; Karen A. Pooley; Elena Lopez-Knowles; Ed Dicks; Daniel Barrowdale; Nicholas A. Sinnott-Armstrong; Richard C. Sallari; Kristine M. Hillman; Susanne Kaufmann; Haran Sivakumaran; Mahdi Moradi Marjaneh; Jason S. Lee; Margaret Hills; Monika Jarosz; Suzie Drury; Sander Canisius; Manjeet K. Bolla; Joe Dennis; Qin Wang; John L. Hopper; Melissa C. Southey; Annegien Broeks; Marjanka K. Schmidt; Artitaya Lophatananon; Kenneth Muir; Matthias W. Beckmann; Peter A. Fasching; Isabel dos-Santos-Silva; Julian Peto; Elinor J. Sawyer; Ian Tomlinson; Barbara Burwinkel; Frederik Marme; Pascal Guenel; Therese Truong; Stig E. Bojesen; Henrik Flyger; Anna Gonzalez-Neira; Jose I. A. Perez; Arjen R. Mensenkamp; EMBRACE; GEMO Study Collaborators; HEBON; kConFab Investigators

doi:10.1038/ng.3521

Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170

Alison M. Dunning, Kyriaki Michailidou, Karoline B. Kuchenbaecker, Deborah Thompson, Juliet D. French, Jonathan Beesley, Catherine S. Healey, Siddhartha Kar, Karen A. Pooley, Elena Lopez-Knowles, Ed Dicks, Daniel Barrowdale, Nicholas A. Sinnott-Armstrong, Richard C. Sallari, Kristine M. Hillman, Susanne Kaufmann, Haran Sivakumaran, Mahdi Moradi Marjaneh, Jason S. Lee, Margaret HillsMonika Jarosz, Suzie Drury, Sander Canisius, Manjeet K. Bolla, Joe Dennis, Qin Wang, John L. Hopper, Melissa C. Southey, Annegien Broeks, Marjanka K. Schmidt, Artitaya Lophatananon, Kenneth Muir, Matthias W. Beckmann, Peter A. Fasching, Isabel dos-Santos-Silva, Julian Peto, Elinor J. Sawyer, Ian Tomlinson, Barbara Burwinkel, Frederik Marme, Pascal Guenel, Therese Truong, Stig E. Bojesen, Henrik Flyger, Anna Gonzalez-Neira, Jose I. A. Perez, Arjen R. Mensenkamp, EMBRACE, GEMO Study Collaborators, HEBON, kConFab Investigators

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

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Abstract

We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor a) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER+ or ER-) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER-tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.

Original language	English
Pages (from-to)	374-+
Number of pages	16
Journal	Nature Genetics
Volume	48
Issue number	4
DOIs	https://doi.org/10.1038/ng.3521
Publication status	Published - Apr-2016

Keywords

GENOME-WIDE ASSOCIATION
BRCA2 MUTATION CARRIERS
BONE-MINERAL DENSITY
MAMMOGRAPHIC DENSITY
SUSCEPTIBILITY LOCUS
METAANALYSIS
EXPRESSION
MODIFIERS
REVEALS
DISEASE

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Breast cancer risk variants at 6q25 display different phenotype
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Dunning, A. M., Michailidou, K., Kuchenbaecker, K. B., Thompson, D., French, J. D., Beesley, J., Healey, C. S., Kar, S., Pooley, K. A., Lopez-Knowles, E., Dicks, E., Barrowdale, D., Sinnott-Armstrong, N. A., Sallari, R. C., Hillman, K. M., Kaufmann, S., Sivakumaran, H., Marjaneh, M. M., Lee, J. S., ... kConFab Investigators (2016). Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170. Nature Genetics, 48(4), 374-+. https://doi.org/10.1038/ng.3521

@article{1cee39d66d304f3abfd77152fe0443c1,

title = "Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170",

abstract = "We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor a) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER+ or ER-) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER-tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.",

keywords = "GENOME-WIDE ASSOCIATION, BRCA2 MUTATION CARRIERS, BONE-MINERAL DENSITY, MAMMOGRAPHIC DENSITY, SUSCEPTIBILITY LOCUS, METAANALYSIS, EXPRESSION, MODIFIERS, REVEALS, DISEASE",

author = "Dunning, {Alison M.} and Kyriaki Michailidou and Kuchenbaecker, {Karoline B.} and Deborah Thompson and French, {Juliet D.} and Jonathan Beesley and Healey, {Catherine S.} and Siddhartha Kar and Pooley, {Karen A.} and Elena Lopez-Knowles and Ed Dicks and Daniel Barrowdale and Sinnott-Armstrong, {Nicholas A.} and Sallari, {Richard C.} and Hillman, {Kristine M.} and Susanne Kaufmann and Haran Sivakumaran and Marjaneh, {Mahdi Moradi} and Lee, {Jason S.} and Margaret Hills and Monika Jarosz and Suzie Drury and Sander Canisius and Bolla, {Manjeet K.} and Joe Dennis and Qin Wang and Hopper, {John L.} and Southey, {Melissa C.} and Annegien Broeks and Schmidt, {Marjanka K.} and Artitaya Lophatananon and Kenneth Muir and Beckmann, {Matthias W.} and Fasching, {Peter A.} and Isabel dos-Santos-Silva and Julian Peto and Sawyer, {Elinor J.} and Ian Tomlinson and Barbara Burwinkel and Frederik Marme and Pascal Guenel and Therese Truong and Bojesen, {Stig E.} and Henrik Flyger and Anna Gonzalez-Neira and Perez, {Jose I. A.} and Mensenkamp, {Arjen R.} and EMBRACE and {GEMO Study Collaborators} and HEBON and {kConFab Investigators} and Ligtenberg, {J. J. M.} and Oosterwijk, {J. C.} and {van der Hout}, {A. H.}",

year = "2016",

month = apr,

doi = "10.1038/ng.3521",

language = "English",

volume = "48",

pages = "374--+",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "4",

}

Dunning, AM, Michailidou, K, Kuchenbaecker, KB, Thompson, D, French, JD, Beesley, J, Healey, CS, Kar, S, Pooley, KA, Lopez-Knowles, E, Dicks, E, Barrowdale, D, Sinnott-Armstrong, NA, Sallari, RC, Hillman, KM, Kaufmann, S, Sivakumaran, H, Marjaneh, MM, Lee, JS, Hills, M, Jarosz, M, Drury, S, Canisius, S, Bolla, MK, Dennis, J, Wang, Q, Hopper, JL, Southey, MC, Broeks, A, Schmidt, MK, Lophatananon, A, Muir, K, Beckmann, MW, Fasching, PA, dos-Santos-Silva, I, Peto, J, Sawyer, EJ, Tomlinson, I, Burwinkel, B, Marme, F, Guenel, P, Truong, T, Bojesen, SE, Flyger, H, Gonzalez-Neira, A, Perez, JIA, Mensenkamp, AR, EMBRACE, GEMO Study Collaborators, HEBON & kConFab Investigators 2016, 'Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170', Nature Genetics, vol. 48, no. 4, pp. 374-+. https://doi.org/10.1038/ng.3521

TY - JOUR

T1 - Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170

AU - Dunning, Alison M.

AU - Michailidou, Kyriaki

AU - Kuchenbaecker, Karoline B.

AU - Thompson, Deborah

AU - French, Juliet D.

AU - Beesley, Jonathan

AU - Healey, Catherine S.

AU - Kar, Siddhartha

AU - Pooley, Karen A.

AU - Lopez-Knowles, Elena

AU - Dicks, Ed

AU - Barrowdale, Daniel

AU - Sinnott-Armstrong, Nicholas A.

AU - Sallari, Richard C.

AU - Hillman, Kristine M.

AU - Kaufmann, Susanne

AU - Sivakumaran, Haran

AU - Marjaneh, Mahdi Moradi

AU - Lee, Jason S.

AU - Hills, Margaret

AU - Jarosz, Monika

AU - Drury, Suzie

AU - Canisius, Sander

AU - Bolla, Manjeet K.

AU - Dennis, Joe

AU - Wang, Qin

AU - Hopper, John L.

AU - Southey, Melissa C.

AU - Broeks, Annegien

AU - Schmidt, Marjanka K.

AU - Lophatananon, Artitaya

AU - Muir, Kenneth

AU - Beckmann, Matthias W.

AU - Fasching, Peter A.

AU - dos-Santos-Silva, Isabel

AU - Peto, Julian

AU - Sawyer, Elinor J.

AU - Tomlinson, Ian

AU - Burwinkel, Barbara

AU - Marme, Frederik

AU - Guenel, Pascal

AU - Truong, Therese

AU - Bojesen, Stig E.

AU - Flyger, Henrik

AU - Gonzalez-Neira, Anna

AU - Perez, Jose I. A.

AU - Mensenkamp, Arjen R.

AU - EMBRACE

AU - GEMO Study Collaborators

AU - HEBON

AU - kConFab Investigators

AU - Ligtenberg, J. J. M.

AU - Oosterwijk, J. C.

AU - van der Hout, A. H.

PY - 2016/4

Y1 - 2016/4

N2 - We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor a) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER+ or ER-) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER-tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.

AB - We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor a) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER+ or ER-) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER-tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.

KW - GENOME-WIDE ASSOCIATION

KW - BRCA2 MUTATION CARRIERS

KW - BONE-MINERAL DENSITY

KW - MAMMOGRAPHIC DENSITY

KW - SUSCEPTIBILITY LOCUS

KW - METAANALYSIS

KW - EXPRESSION

KW - MODIFIERS

KW - REVEALS

KW - DISEASE

U2 - 10.1038/ng.3521

DO - 10.1038/ng.3521

M3 - Article

VL - 48

SP - 374-+

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 4

ER -