Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1

Dylan M Glubb; Mel J Maranian; Kyriaki Michailidou; Karen A Pooley; Kerstin B Meyer; Siddhartha Kar; Saskia Carlebur; Martin O'Reilly; Joshua A Betts; Kristine M Hillman; Susanne Kaufmann; Jonathan Beesley; Sander Canisius; John L Hopper; Melissa C Southey; Helen Tsimiklis; Carmel Apicella; Marjanka K Schmidt; Annegien Broeks; Frans B Hogervorst; C Ellen van der Schoot; Kenneth Muir; Artitaya Lophatananon; Sarah Stewart-Brown; Pornthep Siriwanarangsan; Peter A Fasching; Matthias Ruebner; Arif B Ekici; Matthias W Beckmann; Julian Peto; Isabel dos-Santos-Silva; Olivia Fletcher; Nichola Johnson; Paul D P Pharoah; Manjeet K Bolla; Qin Wang; Joe Dennis; Elinor J Sawyer; Ian Tomlinson; Michael J Kerin; Nicola Miller; Barbara Burwinkel; Frederik Marme; Rongxi Yang; Harald Surowy; Pascal Guénel; Thérèse Truong; Stig E Bojesen; Børge G Nordestgaard; Sune Fallgaard Nielsen; GENICA Network

doi:10.1016/j.ajhg.2014.11.009

Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1

Dylan M Glubb, Mel J Maranian, Kyriaki Michailidou, Karen A Pooley, Kerstin B Meyer, Siddhartha Kar, Saskia Carlebur, Martin O'Reilly, Joshua A Betts, Kristine M Hillman, Susanne Kaufmann, Jonathan Beesley, Sander Canisius, John L Hopper, Melissa C Southey, Helen Tsimiklis, Carmel Apicella, Marjanka K Schmidt, Annegien Broeks, Frans B HogervorstC Ellen van der Schoot, Kenneth Muir, Artitaya Lophatananon, Sarah Stewart-Brown, Pornthep Siriwanarangsan, Peter A Fasching, Matthias Ruebner, Arif B Ekici, Matthias W Beckmann, Julian Peto, Isabel dos-Santos-Silva, Olivia Fletcher, Nichola Johnson, Paul D P Pharoah, Manjeet K Bolla, Qin Wang, Joe Dennis, Elinor J Sawyer, Ian Tomlinson, Michael J Kerin, Nicola Miller, Barbara Burwinkel, Frederik Marme, Rongxi Yang, Harald Surowy, Pascal Guénel, Thérèse Truong, Stig E Bojesen, Børge G Nordestgaard, Sune Fallgaard Nielsen, GENICA Network

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Abstract

Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER(+): odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, ptrend = 5.7 × 10(-44)) and estrogen-receptor-negative (ER(-): OR = 1.10, 95% CI = 1.05-1.15, ptrend = 3.0 × 10(-4)) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [pcond = 1.61 × 10(-5)]) and five variants composing iCHAV3 (lead rs11949391; ER(+): OR = 0.90, 95% CI = 0.87-0.93, pcond = 1.4 × 10(-4)). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival.

Originalsprog	Engelsk
Tidsskrift	American Journal of Human Genetics
Vol/bind	96
Udgave nummer	1
Sider (fra-til)	5-20
Antal sider	16
ISSN	0002-9297
DOI	https://doi.org/10.1016/j.ajhg.2014.11.009
Status	Udgivet - 8 jan. 2015

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10.1016/j.ajhg.2014.11.009Licens: CC BY-NC-ND

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Glubb, D. M., Maranian, M. J., Michailidou, K., Pooley, K. A., Meyer, K. B., Kar, S., Carlebur, S., O'Reilly, M., Betts, J. A., Hillman, K. M., Kaufmann, S., Beesley, J., Canisius, S., Hopper, J. L., Southey, M. C., Tsimiklis, H., Apicella, C., Schmidt, M. K., Broeks, A., ... GENICA Network (2015). Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1. American Journal of Human Genetics, 96(1), 5-20. https://doi.org/10.1016/j.ajhg.2014.11.009

Glubb, DM, Maranian, MJ, Michailidou, K, Pooley, KA, Meyer, KB, Kar, S, Carlebur, S, O'Reilly, M, Betts, JA, Hillman, KM, Kaufmann, S, Beesley, J, Canisius, S, Hopper, JL, Southey, MC, Tsimiklis, H, Apicella, C, Schmidt, MK, Broeks, A, Hogervorst, FB, van der Schoot, CE, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Fasching, PA, Ruebner, M, Ekici, AB, Beckmann, MW, Peto, J, dos-Santos-Silva, I, Fletcher, O, Johnson, N, Pharoah, PDP, Bolla, MK, Wang, Q, Dennis, J, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Burwinkel, B, Marme, F, Yang, R, Surowy, H, Guénel, P, Truong, T, Bojesen, SE , Nordestgaard, BG, Nielsen, SF & GENICA Network 2015, 'Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1', American Journal of Human Genetics, bind 96, nr. 1, s. 5-20. https://doi.org/10.1016/j.ajhg.2014.11.009

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title = "Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1",

abstract = "Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER(+): odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, ptrend = 5.7 × 10(-44)) and estrogen-receptor-negative (ER(-): OR = 1.10, 95% CI = 1.05-1.15, ptrend = 3.0 × 10(-4)) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [pcond = 1.61 × 10(-5)]) and five variants composing iCHAV3 (lead rs11949391; ER(+): OR = 0.90, 95% CI = 0.87-0.93, pcond = 1.4 × 10(-4)). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival.",

keywords = "Alleles, Breast Neoplasms, Case-Control Studies, Cell Line, Tumor, Chromosome Mapping, Chromosomes, Human, Pair 5, Continental Population Groups, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotyping Techniques, Humans, MAP Kinase Kinase Kinase 1, MCF-7 Cells, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Quantitative Trait Loci, Risk Factors",

author = "Glubb, {Dylan M} and Maranian, {Mel J} and Kyriaki Michailidou and Pooley, {Karen A} and Meyer, {Kerstin B} and Siddhartha Kar and Saskia Carlebur and Martin O'Reilly and Betts, {Joshua A} and Hillman, {Kristine M} and Susanne Kaufmann and Jonathan Beesley and Sander Canisius and Hopper, {John L} and Southey, {Melissa C} and Helen Tsimiklis and Carmel Apicella and Schmidt, {Marjanka K} and Annegien Broeks and Hogervorst, {Frans B} and {van der Schoot}, {C Ellen} and Kenneth Muir and Artitaya Lophatananon and Sarah Stewart-Brown and Pornthep Siriwanarangsan and Fasching, {Peter A} and Matthias Ruebner and Ekici, {Arif B} and Beckmann, {Matthias W} and Julian Peto and Isabel dos-Santos-Silva and Olivia Fletcher and Nichola Johnson and Pharoah, {Paul D P} and Bolla, {Manjeet K} and Qin Wang and Joe Dennis and Sawyer, {Elinor J} and Ian Tomlinson and Kerin, {Michael J} and Nicola Miller and Barbara Burwinkel and Frederik Marme and Rongxi Yang and Harald Surowy and Pascal Gu{\'e}nel and Th{\'e}r{\`e}se Truong and Bojesen, {Stig E} and Nordestgaard, {B{\o}rge G} and Nielsen, {Sune Fallgaard} and {GENICA Network}",

year = "2015",

month = jan,

day = "8",

doi = "10.1016/j.ajhg.2014.11.009",

language = "English",

volume = "96",

pages = "5--20",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "1",

}

TY - JOUR

T1 - Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1

AU - Glubb, Dylan M

AU - Maranian, Mel J

AU - Michailidou, Kyriaki

AU - Pooley, Karen A

AU - Meyer, Kerstin B

AU - Kar, Siddhartha

AU - Carlebur, Saskia

AU - O'Reilly, Martin

AU - Betts, Joshua A

AU - Hillman, Kristine M

AU - Kaufmann, Susanne

AU - Beesley, Jonathan

AU - Canisius, Sander

AU - Hopper, John L

AU - Southey, Melissa C

AU - Tsimiklis, Helen

AU - Apicella, Carmel

AU - Schmidt, Marjanka K

AU - Broeks, Annegien

AU - Hogervorst, Frans B

AU - van der Schoot, C Ellen

AU - Muir, Kenneth

AU - Lophatananon, Artitaya

AU - Stewart-Brown, Sarah

AU - Siriwanarangsan, Pornthep

AU - Fasching, Peter A

AU - Ruebner, Matthias

AU - Ekici, Arif B

AU - Beckmann, Matthias W

AU - Peto, Julian

AU - dos-Santos-Silva, Isabel

AU - Fletcher, Olivia

AU - Johnson, Nichola

AU - Pharoah, Paul D P

AU - Bolla, Manjeet K

AU - Wang, Qin

AU - Dennis, Joe

AU - Sawyer, Elinor J

AU - Tomlinson, Ian

AU - Kerin, Michael J

AU - Miller, Nicola

AU - Burwinkel, Barbara

AU - Marme, Frederik

AU - Yang, Rongxi

AU - Surowy, Harald

AU - Guénel, Pascal

AU - Truong, Thérèse

AU - Bojesen, Stig E

AU - Nordestgaard, Børge G

AU - Nielsen, Sune Fallgaard

AU - GENICA Network

PY - 2015/1/8

Y1 - 2015/1/8

N2 - Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER(+): odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, ptrend = 5.7 × 10(-44)) and estrogen-receptor-negative (ER(-): OR = 1.10, 95% CI = 1.05-1.15, ptrend = 3.0 × 10(-4)) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [pcond = 1.61 × 10(-5)]) and five variants composing iCHAV3 (lead rs11949391; ER(+): OR = 0.90, 95% CI = 0.87-0.93, pcond = 1.4 × 10(-4)). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival.

AB - Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER(+): odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, ptrend = 5.7 × 10(-44)) and estrogen-receptor-negative (ER(-): OR = 1.10, 95% CI = 1.05-1.15, ptrend = 3.0 × 10(-4)) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [pcond = 1.61 × 10(-5)]) and five variants composing iCHAV3 (lead rs11949391; ER(+): OR = 0.90, 95% CI = 0.87-0.93, pcond = 1.4 × 10(-4)). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival.

KW - Alleles

KW - Breast Neoplasms

KW - Case-Control Studies

KW - Cell Line, Tumor

KW - Chromosome Mapping

KW - Chromosomes, Human, Pair 5

KW - Continental Population Groups

KW - Female

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Genotyping Techniques

KW - Humans

KW - MAP Kinase Kinase Kinase 1

KW - MCF-7 Cells

KW - Polymorphism, Single Nucleotide

KW - Promoter Regions, Genetic

KW - Quantitative Trait Loci

KW - Risk Factors

U2 - 10.1016/j.ajhg.2014.11.009

DO - 10.1016/j.ajhg.2014.11.009

M3 - Journal article

C2 - 25529635

SN - 0002-9297

VL - 96

SP - 5

EP - 20

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 1

ER -

Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1

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