Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation

Maya Ghoussaini; Juliet D French; Kyriaki Michailidou; Silje Nord; Jonathan Beesley; Sander Canisus; Kristine M Hillman; Susanne Kaufmann; Haran Sivakumaran; Mahdi Moradi Marjaneh; Jason S Lee; Joe Dennis; Manjeet K Bolla; Qin Wang; Ed Dicks; Roger L Milne; John L Hopper; Melissa C Southey; Marjanka K Schmidt; Annegien Broeks; Kenneth Muir; Artitaya Lophatananon; Peter A Fasching; Matthias W Beckmann; Olivia Fletcher; Nichola Johnson; Elinor J Sawyer; Ian Tomlinson; Barbara Burwinkel; Frederik Marme; Pascal Guénel; Thérèse Truong; Stig E Bojesen; Henrik Flyger; Javier Benitez; Anna González-Neira; M Rosario Alonso; Guillermo Pita; Susan L Neuhausen; Hoda Anton-Culver; Hermann Brenner; Volker Arndt; Alfons Meindl; Rita K Schmutzler; Hiltrud Brauch; Ute Hamann; Daniel C Tessier; Soo H Teo; Judith S Brand; Paul Brennan; kConFab/AOCS Investigators

doi:10.1016/j.ajhg.2016.07.017

Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation

Maya Ghoussaini, Juliet D French, Kyriaki Michailidou, Silje Nord, Jonathan Beesley, Sander Canisus, Kristine M Hillman, Susanne Kaufmann, Haran Sivakumaran, Mahdi Moradi Marjaneh, Jason S Lee, Joe Dennis, Manjeet K Bolla, Qin Wang, Ed Dicks, Roger L Milne, John L Hopper, Melissa C Southey, Marjanka K Schmidt, Annegien BroeksKenneth Muir, Artitaya Lophatananon, Peter A Fasching, Matthias W Beckmann, Olivia Fletcher, Nichola Johnson, Elinor J Sawyer, Ian Tomlinson, Barbara Burwinkel, Frederik Marme, Pascal Guénel, Thérèse Truong, Stig E Bojesen, Henrik Flyger, Javier Benitez, Anna González-Neira, M Rosario Alonso, Guillermo Pita, Susan L Neuhausen, Hoda Anton-Culver, Hermann Brenner, Volker Arndt, Alfons Meindl, Rita K Schmutzler, Hiltrud Brauch, Ute Hamann, Daniel C Tessier, Soo H Teo, Judith S Brand, Paul Brennan, kConFab/AOCS Investigators

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Abstract

Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495-45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER+) breast cancer (per-g allele OR ER+ = 1.15; 95% CI 1.13-1.18; p = 8.35 × 10-30). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER-) breast cancer (lead SNP rs6864776: per-a allele OR ER- = 1.10; 95% CI 1.05-1.14; p conditional = 1.44 × 10-12), and a single signal 3 SNP (rs200229088: per-t allele OR ER+ = 1.12; 95% CI 1.09-1.15; p conditional = 1.12 × 10-05). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis.

Original language	English
Pages (from-to)	903-911
Number of pages	9
Journal	American Journal of Human Genetics
Volume	99
Issue number	4
Early online date	15 Sept 2016
DOIs	https://doi.org/10.1016/j.ajhg.2016.07.017
Publication status	Published - 6 Oct 2016

Keywords

Alleles
Breast Neoplasms
Case-Control Studies
Cell Line, Tumor
Chromosomes, Human, Pair 5
Enhancer Elements, Genetic
Fibroblast Growth Factor 10
Genetic Predisposition to Disease
Haplotypes
Humans
Polymorphism, Single Nucleotide
Promoter Regions, Genetic
Quantitative Trait Loci
Receptor, Fibroblast Growth Factor, Type 2
Receptors, Estrogen
Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Ghoussaini, M., French, J. D., Michailidou, K., Nord, S., Beesley, J., Canisus, S., Hillman, K. M., Kaufmann, S., Sivakumaran, H., Moradi Marjaneh, M., Lee, J. S., Dennis, J., Bolla, M. K., Wang, Q., Dicks, E., Milne, R. L., Hopper, J. L., Southey, M. C., Schmidt, M. K., ... kConFab/AOCS Investigators (2016). Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation. American Journal of Human Genetics, 99(4), 903-911. https://doi.org/10.1016/j.ajhg.2016.07.017

@article{1aa274fd926742ba99716fcd0fc4de15,

title = "Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation",

abstract = "Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495-45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER+) breast cancer (per-g allele OR ER+ = 1.15; 95% CI 1.13-1.18; p = 8.35 × 10-30). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER-) breast cancer (lead SNP rs6864776: per-a allele OR ER- = 1.10; 95% CI 1.05-1.14; p conditional = 1.44 × 10-12), and a single signal 3 SNP (rs200229088: per-t allele OR ER+ = 1.12; 95% CI 1.09-1.15; p conditional = 1.12 × 10-05). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis.",

keywords = "Alleles, Breast Neoplasms, Case-Control Studies, Cell Line, Tumor, Chromosomes, Human, Pair 5, Enhancer Elements, Genetic, Fibroblast Growth Factor 10, Genetic Predisposition to Disease, Haplotypes, Humans, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Quantitative Trait Loci, Receptor, Fibroblast Growth Factor, Type 2, Receptors, Estrogen, Journal Article",

author = "Maya Ghoussaini and French, {Juliet D} and Kyriaki Michailidou and Silje Nord and Jonathan Beesley and Sander Canisus and Hillman, {Kristine M} and Susanne Kaufmann and Haran Sivakumaran and {Moradi Marjaneh}, Mahdi and Lee, {Jason S} and Joe Dennis and Bolla, {Manjeet K} and Qin Wang and Ed Dicks and Milne, {Roger L} and Hopper, {John L} and Southey, {Melissa C} and Schmidt, {Marjanka K} and Annegien Broeks and Kenneth Muir and Artitaya Lophatananon and Fasching, {Peter A} and Beckmann, {Matthias W} and Olivia Fletcher and Nichola Johnson 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 Henrik Flyger and Javier Benitez and Anna Gonz{\'a}lez-Neira and Alonso, {M Rosario} and Guillermo Pita and Neuhausen, {Susan L} and Hoda Anton-Culver and Hermann Brenner and Volker Arndt and Alfons Meindl and Schmutzler, {Rita K} and Hiltrud Brauch and Ute Hamann and Tessier, {Daniel C} and Teo, {Soo H} and Brand, {Judith S} and Paul Brennan and {kConFab/AOCS Investigators}",

year = "2016",

month = oct,

day = "6",

doi = "10.1016/j.ajhg.2016.07.017",

language = "English",

volume = "99",

pages = "903--911",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

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number = "4",

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Ghoussaini, M, French, JD, Michailidou, K, Nord, S, Beesley, J, Canisus, S, Hillman, KM, Kaufmann, S, Sivakumaran, H, Moradi Marjaneh, M, Lee, JS, Dennis, J, Bolla, MK, Wang, Q, Dicks, E, Milne, RL, Hopper, JL, Southey, MC, Schmidt, MK, Broeks, A, Muir, K, Lophatananon, A, Fasching, PA, Beckmann, MW, Fletcher, O, Johnson, N, Sawyer, EJ, Tomlinson, I, Burwinkel, B, Marme, F, Guénel, P, Truong, T, Bojesen, SE, Flyger, H, Benitez, J, González-Neira, A, Alonso, MR, Pita, G, Neuhausen, SL, Anton-Culver, H, Brenner, H, Arndt, V, Meindl, A, Schmutzler, RK, Brauch, H, Hamann, U, Tessier, DC, Teo, SH, Brand, JS, Brennan, P & kConFab/AOCS Investigators 2016, 'Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation', American Journal of Human Genetics, vol. 99, no. 4, pp. 903-911. https://doi.org/10.1016/j.ajhg.2016.07.017

Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation. / Ghoussaini, Maya; French, Juliet D; Michailidou, Kyriaki et al.
In: American Journal of Human Genetics, Vol. 99, No. 4, 06.10.2016, p. 903-911.

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

TY - JOUR

T1 - Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation

AU - Ghoussaini, Maya

AU - French, Juliet D

AU - Michailidou, Kyriaki

AU - Nord, Silje

AU - Beesley, Jonathan

AU - Canisus, Sander

AU - Hillman, Kristine M

AU - Kaufmann, Susanne

AU - Sivakumaran, Haran

AU - Moradi Marjaneh, Mahdi

AU - Lee, Jason S

AU - Dennis, Joe

AU - Bolla, Manjeet K

AU - Wang, Qin

AU - Dicks, Ed

AU - Milne, Roger L

AU - Hopper, John L

AU - Southey, Melissa C

AU - Schmidt, Marjanka K

AU - Broeks, Annegien

AU - Muir, Kenneth

AU - Lophatananon, Artitaya

AU - Fasching, Peter A

AU - Beckmann, Matthias W

AU - Fletcher, Olivia

AU - Johnson, Nichola

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

AU - Benitez, Javier

AU - González-Neira, Anna

AU - Alonso, M Rosario

AU - Pita, Guillermo

AU - Neuhausen, Susan L

AU - Anton-Culver, Hoda

AU - Brenner, Hermann

AU - Arndt, Volker

AU - Meindl, Alfons

AU - Schmutzler, Rita K

AU - Brauch, Hiltrud

AU - Hamann, Ute

AU - Tessier, Daniel C

AU - Teo, Soo H

AU - Brand, Judith S

AU - Brennan, Paul

AU - kConFab/AOCS Investigators

PY - 2016/10/6

Y1 - 2016/10/6

N2 - Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495-45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER+) breast cancer (per-g allele OR ER+ = 1.15; 95% CI 1.13-1.18; p = 8.35 × 10-30). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER-) breast cancer (lead SNP rs6864776: per-a allele OR ER- = 1.10; 95% CI 1.05-1.14; p conditional = 1.44 × 10-12), and a single signal 3 SNP (rs200229088: per-t allele OR ER+ = 1.12; 95% CI 1.09-1.15; p conditional = 1.12 × 10-05). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis.

AB - Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495-45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER+) breast cancer (per-g allele OR ER+ = 1.15; 95% CI 1.13-1.18; p = 8.35 × 10-30). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER-) breast cancer (lead SNP rs6864776: per-a allele OR ER- = 1.10; 95% CI 1.05-1.14; p conditional = 1.44 × 10-12), and a single signal 3 SNP (rs200229088: per-t allele OR ER+ = 1.12; 95% CI 1.09-1.15; p conditional = 1.12 × 10-05). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis.

KW - Alleles

KW - Breast Neoplasms

KW - Case-Control Studies

KW - Cell Line, Tumor

KW - Chromosomes, Human, Pair 5

KW - Enhancer Elements, Genetic

KW - Fibroblast Growth Factor 10

KW - Genetic Predisposition to Disease

KW - Haplotypes

KW - Humans

KW - Polymorphism, Single Nucleotide

KW - Promoter Regions, Genetic

KW - Quantitative Trait Loci

KW - Receptor, Fibroblast Growth Factor, Type 2

KW - Receptors, Estrogen

KW - Journal Article

U2 - 10.1016/j.ajhg.2016.07.017

DO - 10.1016/j.ajhg.2016.07.017

M3 - Article (Academic Journal)

C2 - 27640304

SN - 0002-9297

VL - 99

SP - 903

EP - 911

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 4

ER -

Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation

Abstract

Keywords

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