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, Daniel Vincent, Heli Nevanlinna, Sofia Khan, Keitaro Matsuo, Hidemi Ito, Thilo Dörk, Natalia V. Bogdanova, Annika Lindblom, Sara Margolin, Arto Mannermaa, Veli Matti Kosma, Anna H. Wu, David Van Den Berg, Diether Lambrechts, Giuseppe Floris, Jenny Chang-Claude, Anja Rudolph, Paolo Radice, Monica Barile, Fergus J Couch, Emily Hallberg, Graham G. Giles, Christopher A. Haiman, Loic Le Marchand, Mark S. Goldberg, Soo H. Teo, Cheng Har Yip, Anne Lise Borresen-Dale, Wei Zheng, Qiuyin Cai, Robert Winqvist, Katri Pylkäs, Irene L. Andrulis, Peter Devilee, Rob A E M Tollenaar, Montserrat García-Closas, Jonine Figueroa, Per Hall, Kamila Czene, Judith S. Brand, Hatef Darabi, Mikael Eriksson, Maartje J. Hooning, Linetta B. Koppert, Jingmei Li, Xiao Ou Shu, Ying Zheng, Angela Cox, Simon S. Cross, Mitul Shah, Valerie Rhenius, Ji Yeob Choi, Daehee Kang, Mikael Hartman, Kee Seng Chia, Maria Kabisch, Diana Torres, Craig Luccarini, Don M. Conroy, Anna Jakubowska, Jan Lubinski, Suleeporn Sangrajrang, Paul Brennan, Curtis Olswold, Susan L Slager, Chen Yang Shen, Ming Feng Hou, Anthony Swerdlow, Minouk J. Schoemaker, Jacques Simard, Paul D P Pharoah, Vessela Kristensen, Georgia Chenevix-Trench, Douglas F. Easton, Alison M. Dunning, Stacey L. Edwards

Research output: Contribution to journalArticle

21 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)903-911
Number of pages9
JournalAmerican Journal of Human Genetics
Volume99
Issue number4
DOIs
StatePublished - Oct 6 2016

Fingerprint

Estrogen Receptors
Breast Neoplasms
Single Nucleotide Polymorphism
Alleles
Quantitative Trait Loci
Genome-Wide Association Study
Oncogenes
Genetic Promoter Regions
Case-Control Studies
Breast
Apoptosis
Cell Line
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

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; Nord, Silje; Beesley, Jonathan; Canisus, Sander; Hillman, Kristine M.; Kaufmann, Susanne; Sivakumaran, Haran; Moradi Marjaneh, Mahdi; Lee, Jason S.; Dennis, Joe; Bolla, Manjeet K.; Wang, Qin; Dicks, Ed; Milne, Roger L.; Hopper, John L.; Southey, Melissa C.; Schmidt, Marjanka K.; Broeks, Annegien; Muir, Kenneth; Lophatananon, Artitaya; Fasching, Peter A.; Beckmann, Matthias W.; Fletcher, Olivia; Johnson, Nichola; Sawyer, Elinor J.; Tomlinson, Ian; Burwinkel, Barbara; Marme, Frederik; Guénel, Pascal; Truong, Thérèse; Bojesen, Stig E.; Flyger, Henrik; Benitez, Javier; González-Neira, Anna; Alonso, M. Rosario; Pita, Guillermo; Neuhausen, Susan L.; Anton-Culver, Hoda; Brenner, Hermann; Arndt, Volker; Meindl, Alfons; Schmutzler, Rita K.; Brauch, Hiltrud; Hamann, Ute; Tessier, Daniel C.; Vincent, Daniel; Nevanlinna, Heli; Khan, Sofia; Matsuo, Keitaro; Ito, Hidemi; Dörk, Thilo; Bogdanova, Natalia V.; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli Matti; Wu, Anna H.; Van Den Berg, David; Lambrechts, Diether; Floris, Giuseppe; Chang-Claude, Jenny; Rudolph, Anja; Radice, Paolo; Barile, Monica; Couch, Fergus J; Hallberg, Emily; Giles, Graham G.; Haiman, Christopher A.; Le Marchand, Loic; Goldberg, Mark S.; Teo, Soo H.; Yip, Cheng Har; Borresen-Dale, Anne Lise; Zheng, Wei; Cai, Qiuyin; Winqvist, Robert; Pylkäs, Katri; Andrulis, Irene L.; Devilee, Peter; Tollenaar, Rob A E M; García-Closas, Montserrat; Figueroa, Jonine; Hall, Per; Czene, Kamila; Brand, Judith S.; Darabi, Hatef; Eriksson, Mikael; Hooning, Maartje J.; Koppert, Linetta B.; Li, Jingmei; Shu, Xiao Ou; Zheng, Ying; Cox, Angela; Cross, Simon S.; Shah, Mitul; Rhenius, Valerie; Choi, Ji Yeob; Kang, Daehee; Hartman, Mikael; Chia, Kee Seng; Kabisch, Maria; Torres, Diana; Luccarini, Craig; Conroy, Don M.; Jakubowska, Anna; Lubinski, Jan; Sangrajrang, Suleeporn; Brennan, Paul; Olswold, Curtis; Slager, Susan L; Shen, Chen Yang; Hou, Ming Feng; Swerdlow, Anthony; Schoemaker, Minouk J.; Simard, Jacques; Pharoah, Paul D P; Kristensen, Vessela; Chenevix-Trench, Georgia; Easton, Douglas F.; Dunning, Alison M.; Edwards, Stacey L.

In: American Journal of Human Genetics, Vol. 99, No. 4, 06.10.2016, p. 903-911.

Research output: Contribution to journalArticle

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, Vincent, D, Nevanlinna, H, Khan, S, Matsuo, K, Ito, H, Dörk, T, Bogdanova, NV, Lindblom, A, Margolin, S, Mannermaa, A, Kosma, VM, Wu, AH, Van Den Berg, D, Lambrechts, D, Floris, G, Chang-Claude, J, Rudolph, A, Radice, P, Barile, M, Couch, FJ, Hallberg, E, Giles, GG, Haiman, CA, Le Marchand, L, Goldberg, MS, Teo, SH, Yip, CH, Borresen-Dale, AL, Zheng, W, Cai, Q, Winqvist, R, Pylkäs, K, Andrulis, IL, Devilee, P, Tollenaar, RAEM, García-Closas, M, Figueroa, J, Hall, P, Czene, K, Brand, JS, Darabi, H, Eriksson, M, Hooning, MJ, Koppert, LB, Li, J, Shu, XO, Zheng, Y, Cox, A, Cross, SS, Shah, M, Rhenius, V, Choi, JY, Kang, D, Hartman, M, Chia, KS, Kabisch, M, Torres, D, Luccarini, C, Conroy, DM, Jakubowska, A, Lubinski, J, Sangrajrang, S, Brennan, P, Olswold, C, Slager, SL, Shen, CY, Hou, MF, Swerdlow, A, Schoemaker, MJ, Simard, J, Pharoah, PDP, Kristensen, V, Chenevix-Trench, G, Easton, DF, Dunning, AM & Edwards, SL 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
Ghoussaini, Maya ; French, Juliet D. ; Michailidou, Kyriaki ; Nord, Silje ; Beesley, Jonathan ; Canisus, Sander ; Hillman, Kristine M. ; Kaufmann, Susanne ; Sivakumaran, Haran ; Moradi Marjaneh, Mahdi ; Lee, Jason S. ; Dennis, Joe ; Bolla, Manjeet K. ; Wang, Qin ; Dicks, Ed ; Milne, Roger L. ; Hopper, John L. ; Southey, Melissa C. ; Schmidt, Marjanka K. ; Broeks, Annegien ; Muir, Kenneth ; Lophatananon, Artitaya ; Fasching, Peter A. ; Beckmann, Matthias W. ; Fletcher, Olivia ; Johnson, Nichola ; Sawyer, Elinor J. ; Tomlinson, Ian ; Burwinkel, Barbara ; Marme, Frederik ; Guénel, Pascal ; Truong, Thérèse ; Bojesen, Stig E. ; Flyger, Henrik ; Benitez, Javier ; González-Neira, Anna ; Alonso, M. Rosario ; Pita, Guillermo ; Neuhausen, Susan L. ; Anton-Culver, Hoda ; Brenner, Hermann ; Arndt, Volker ; Meindl, Alfons ; Schmutzler, Rita K. ; Brauch, Hiltrud ; Hamann, Ute ; Tessier, Daniel C. ; Vincent, Daniel ; Nevanlinna, Heli ; Khan, Sofia ; Matsuo, Keitaro ; Ito, Hidemi ; Dörk, Thilo ; Bogdanova, Natalia V. ; Lindblom, Annika ; Margolin, Sara ; Mannermaa, Arto ; Kosma, Veli Matti ; Wu, Anna H. ; Van Den Berg, David ; Lambrechts, Diether ; Floris, Giuseppe ; Chang-Claude, Jenny ; Rudolph, Anja ; Radice, Paolo ; Barile, Monica ; Couch, Fergus J ; Hallberg, Emily ; Giles, Graham G. ; Haiman, Christopher A. ; Le Marchand, Loic ; Goldberg, Mark S. ; Teo, Soo H. ; Yip, Cheng Har ; Borresen-Dale, Anne Lise ; Zheng, Wei ; Cai, Qiuyin ; Winqvist, Robert ; Pylkäs, Katri ; Andrulis, Irene L. ; Devilee, Peter ; Tollenaar, Rob A E M ; García-Closas, Montserrat ; Figueroa, Jonine ; Hall, Per ; Czene, Kamila ; Brand, Judith S. ; Darabi, Hatef ; Eriksson, Mikael ; Hooning, Maartje J. ; Koppert, Linetta B. ; Li, Jingmei ; Shu, Xiao Ou ; Zheng, Ying ; Cox, Angela ; Cross, Simon S. ; Shah, Mitul ; Rhenius, Valerie ; Choi, Ji Yeob ; Kang, Daehee ; Hartman, Mikael ; Chia, Kee Seng ; Kabisch, Maria ; Torres, Diana ; Luccarini, Craig ; Conroy, Don M. ; Jakubowska, Anna ; Lubinski, Jan ; Sangrajrang, Suleeporn ; Brennan, Paul ; Olswold, Curtis ; Slager, Susan L ; Shen, Chen Yang ; Hou, Ming Feng ; Swerdlow, Anthony ; Schoemaker, Minouk J. ; Simard, Jacques ; Pharoah, Paul D P ; Kristensen, Vessela ; Chenevix-Trench, Georgia ; Easton, Douglas F. ; Dunning, Alison M. ; Edwards, Stacey L. / Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation. In: American Journal of Human Genetics. 2016 ; Vol. 99, No. 4. pp. 903-911.
@article{d2f27986564f4bed8587e253a14316df,
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.",
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 Daniel Vincent and Heli Nevanlinna and Sofia Khan and Keitaro Matsuo and Hidemi Ito and Thilo D{\"o}rk and Bogdanova, {Natalia V.} and Annika Lindblom and Sara Margolin and Arto Mannermaa and Kosma, {Veli Matti} and Wu, {Anna H.} and {Van Den Berg}, David and Diether Lambrechts and Giuseppe Floris and Jenny Chang-Claude and Anja Rudolph and Paolo Radice and Monica Barile and Couch, {Fergus J} and Emily Hallberg and Giles, {Graham G.} and Haiman, {Christopher A.} and {Le Marchand}, Loic and Goldberg, {Mark S.} and Teo, {Soo H.} and Yip, {Cheng Har} and Borresen-Dale, {Anne Lise} and Wei Zheng and Qiuyin Cai and Robert Winqvist and Katri Pylk{\"a}s and Andrulis, {Irene L.} and Peter Devilee and Tollenaar, {Rob A E M} and Montserrat Garc{\'i}a-Closas and Jonine Figueroa and Per Hall and Kamila Czene and Brand, {Judith S.} and Hatef Darabi and Mikael Eriksson and Hooning, {Maartje J.} and Koppert, {Linetta B.} and Jingmei Li and Shu, {Xiao Ou} and Ying Zheng and Angela Cox and Cross, {Simon S.} and Mitul Shah and Valerie Rhenius and Choi, {Ji Yeob} and Daehee Kang and Mikael Hartman and Chia, {Kee Seng} and Maria Kabisch and Diana Torres and Craig Luccarini and Conroy, {Don M.} and Anna Jakubowska and Jan Lubinski and Suleeporn Sangrajrang and Paul Brennan and Curtis Olswold and Slager, {Susan L} and Shen, {Chen Yang} and Hou, {Ming Feng} and Anthony Swerdlow and Schoemaker, {Minouk J.} and Jacques Simard and Pharoah, {Paul D P} and Vessela Kristensen and Georgia Chenevix-Trench and Easton, {Douglas F.} and Dunning, {Alison M.} and Edwards, {Stacey L.}",
year = "2016",
month = "10",
day = "6",
doi = "10.1016/j.ajhg.2016.07.017",
language = "English (US)",
volume = "99",
pages = "903--911",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "4",

}

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 - Vincent, Daniel

AU - Nevanlinna, Heli

AU - Khan, Sofia

AU - Matsuo, Keitaro

AU - Ito, Hidemi

AU - Dörk, Thilo

AU - Bogdanova, Natalia V.

AU - Lindblom, Annika

AU - Margolin, Sara

AU - Mannermaa, Arto

AU - Kosma, Veli Matti

AU - Wu, Anna H.

AU - Van Den Berg, David

AU - Lambrechts, Diether

AU - Floris, Giuseppe

AU - Chang-Claude, Jenny

AU - Rudolph, Anja

AU - Radice, Paolo

AU - Barile, Monica

AU - Couch, Fergus J

AU - Hallberg, Emily

AU - Giles, Graham G.

AU - Haiman, Christopher A.

AU - Le Marchand, Loic

AU - Goldberg, Mark S.

AU - Teo, Soo H.

AU - Yip, Cheng Har

AU - Borresen-Dale, Anne Lise

AU - Zheng, Wei

AU - Cai, Qiuyin

AU - Winqvist, Robert

AU - Pylkäs, Katri

AU - Andrulis, Irene L.

AU - Devilee, Peter

AU - Tollenaar, Rob A E M

AU - García-Closas, Montserrat

AU - Figueroa, Jonine

AU - Hall, Per

AU - Czene, Kamila

AU - Brand, Judith S.

AU - Darabi, Hatef

AU - Eriksson, Mikael

AU - Hooning, Maartje J.

AU - Koppert, Linetta B.

AU - Li, Jingmei

AU - Shu, Xiao Ou

AU - Zheng, Ying

AU - Cox, Angela

AU - Cross, Simon S.

AU - Shah, Mitul

AU - Rhenius, Valerie

AU - Choi, Ji Yeob

AU - Kang, Daehee

AU - Hartman, Mikael

AU - Chia, Kee Seng

AU - Kabisch, Maria

AU - Torres, Diana

AU - Luccarini, Craig

AU - Conroy, Don M.

AU - Jakubowska, Anna

AU - Lubinski, Jan

AU - Sangrajrang, Suleeporn

AU - Brennan, Paul

AU - Olswold, Curtis

AU - Slager, Susan L

AU - Shen, Chen Yang

AU - Hou, Ming Feng

AU - Swerdlow, Anthony

AU - Schoemaker, Minouk J.

AU - Simard, Jacques

AU - Pharoah, Paul D P

AU - Kristensen, Vessela

AU - Chenevix-Trench, Georgia

AU - Easton, Douglas F.

AU - Dunning, Alison M.

AU - Edwards, Stacey L.

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.

UR - http://www.scopus.com/inward/record.url?scp=84991598798&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84991598798&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2016.07.017

DO - 10.1016/j.ajhg.2016.07.017

M3 - Article

C2 - 27640304

AN - SCOPUS:84991598798

VL - 99

SP - 903

EP - 911

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 4

ER -