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 Guénel; Thérèse Truong; Stig E Bojesen; Henrik Lavlund Flyger; Anna González-Neira; Jose I A Perez; Hoda Anton-Culver; Lee Eunjung; Volker Arndt; Hermann Brenner; EMBRACE

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 Guénel, Thérèse Truong, Stig E Bojesen, Henrik Lavlund Flyger, Anna González-Neira, Jose I A Perez, Hoda Anton-Culver, Lee Eunjung, Volker Arndt, Hermann Brenner, EMBRACE

Institut for Klinisk Medicin

70 Citationer (Scopus)

Abstract

We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) 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.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	48
Udgave nummer	4
Sider (fra-til)	374-86
Antal sider	13
ISSN	1061-4036
DOI	https://doi.org/10.1038/ng.3521
Status	Udgivet - 29 mar. 2016

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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., Moradi Marjaneh, M., Lee, J. S., ... EMBRACE (2016). Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170. Nature Genetics, 48(4), 374-86. https://doi.org/10.1038/ng.3521

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, Moradi Marjaneh, M, 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, Guénel, P, Truong, T, Bojesen, SE, Flyger, HL, González-Neira, A, Perez, JIA, Anton-Culver, H, Eunjung, L, Arndt, V, Brenner, H & EMBRACE 2016, 'Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170', Nature Genetics, bind 48, nr. 4, s. 374-86. https://doi.org/10.1038/ng.3521

@article{6ed245345197454c986b9a1d617fe62d,

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 α) 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 = "Base Sequence, Breast Neoplasms, Carrier Proteins, Cell Cycle Proteins, Chromosomes, Human, Pair 6, Estrogen Receptor alpha, Female, Gene Expression, Gene Expression Regulation, Neoplastic, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Phenotype, Polymorphism, Single Nucleotide, Protein Binding, Risk Factors, Journal Article, Meta-Analysis, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.",

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 {Moradi Marjaneh}, Mahdi 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 Gu{\'e}nel and Th{\'e}r{\`e}se Truong and Bojesen, {Stig E} and Flyger, {Henrik Lavlund} and Anna Gonz{\'a}lez-Neira and Perez, {Jose I A} and Hoda Anton-Culver and Lee Eunjung and Volker Arndt and Hermann Brenner and EMBRACE",

year = "2016",

month = mar,

day = "29",

doi = "10.1038/ng.3521",

language = "English",

volume = "48",

pages = "374--86",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "nature publishing group",

number = "4",

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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 - Moradi Marjaneh, Mahdi

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 - Guénel, Pascal

AU - Truong, Thérèse

AU - Bojesen, Stig E

AU - Flyger, Henrik Lavlund

AU - González-Neira, Anna

AU - Perez, Jose I A

AU - Anton-Culver, Hoda

AU - Eunjung, Lee

AU - Arndt, Volker

AU - Brenner, Hermann

AU - EMBRACE

PY - 2016/3/29

Y1 - 2016/3/29

N2 - We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) 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 α) 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 - Base Sequence

KW - Breast Neoplasms

KW - Carrier Proteins

KW - Cell Cycle Proteins

KW - Chromosomes, Human, Pair 6

KW - Estrogen Receptor alpha

KW - Female

KW - Gene Expression

KW - Gene Expression Regulation, Neoplastic

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Humans

KW - Phenotype

KW - Polymorphism, Single Nucleotide

KW - Protein Binding

KW - Risk Factors

KW - Journal Article

KW - Meta-Analysis

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

KW - Research Support, U.S. Gov't, Non-P.H.S.

U2 - 10.1038/ng.3521

DO - 10.1038/ng.3521

M3 - Journal article

C2 - 26928228

SN - 1061-4036

VL - 48

SP - 374

EP - 386

JO - Nature Genetics

JF - Nature Genetics

IS - 4

ER -

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

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