Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation
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...
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| Veröffentlicht in: | American journal of human genetics 2016-10, Vol.99 (4), p.903-911 |
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| creator | French, Juliet D. Michailidou, Kyriaki Nord, Silje Beesley, Jonathan Canisus, Sander Kaufmann, Susanne Moradi Marjaneh, Mahdi Lee, Jason S. Dennis, Joe Bolla, Manjeet K. Wang, Qin Milne, Roger L. Hopper, John L. Southey, Melissa C. Schmidt, Marjanka K. 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 Flyger, Henrik Benitez, Javier González-Neira, Anna Alonso, M. Rosario Pita, Guillermo Neuhausen, Susan L. Anton-Culver, Hoda Brenner, Hermann Arndt, Volker 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 Wu, Anna H. Van Den Berg, David Lambrechts, Diether Floris, Giuseppe Chang-Claude, Jenny Rudolph, Anja Barile, Monica Couch, Fergus J. Hallberg, Emily Giles, Graham G. Le Marchand, Loic Goldberg, Mark S. Yip, Cheng Har Zheng, Wei Winqvist, Robert Pylkäs, Katri Andrulis, Irene L. Devilee, Peter Tollenaar, Rob A.E.M. García-Closas, Montserrat Figueroa, Jonine Hall, Per Czene, Kamila Darabi, Hatef Eriksson, Mikael Hooning, Maartje J. Koppert, Linetta B. Li, Jingmei Shu, Xiao-Ou Cox, Angela Cross, Simon S. Kang, Daehee Hartman, Mikael Chia, Kee Seng Kabisch, Maria Torres, Diana Luccarini, Craig Conroy, Don M. Jakubowska, Anna Sangrajrang, Suleeporn Brennan, Paul Olswold, Curtis Slager, Susan Shen, Chen-Yang Hou, Ming-Feng Swerdlow, Anthony Schoemaker, Minouk J. Pharoah, Paul D.P. Kristensen, Vessela Dunning, Alison M. Edwards, Stacey L. |
| description | 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. |
| doi_str_mv | 10.1016/j.ajhg.2016.07.017 |
| format | Article |
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Rosario ; Pita, Guillermo ; Neuhausen, Susan L. ; Anton-Culver, Hoda ; Brenner, Hermann ; Arndt, Volker ; 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 ; Wu, Anna H. ; Van Den Berg, David ; Lambrechts, Diether ; Floris, Giuseppe ; Chang-Claude, Jenny ; Rudolph, Anja ; Barile, Monica ; Couch, Fergus J. ; Hallberg, Emily ; Giles, Graham G. ; Le Marchand, Loic ; Goldberg, Mark S. ; Yip, Cheng Har ; Zheng, Wei ; Winqvist, Robert ; Pylkäs, Katri ; Andrulis, Irene L. ; Devilee, Peter ; Tollenaar, Rob A.E.M. ; García-Closas, Montserrat ; Figueroa, Jonine ; Hall, Per ; Czene, Kamila ; Darabi, Hatef ; Eriksson, Mikael ; Hooning, Maartje J. ; Koppert, Linetta B. ; Li, Jingmei ; Shu, Xiao-Ou ; Cox, Angela ; Cross, Simon S. ; Kang, Daehee ; Hartman, Mikael ; Chia, Kee Seng ; Kabisch, Maria ; Torres, Diana ; Luccarini, Craig ; Conroy, Don M. ; Jakubowska, Anna ; Sangrajrang, Suleeporn ; Brennan, Paul ; Olswold, Curtis ; Slager, Susan ; Shen, Chen-Yang ; Hou, Ming-Feng ; Swerdlow, Anthony ; Schoemaker, Minouk J. ; Pharoah, Paul D.P. ; Kristensen, Vessela ; Dunning, Alison M. ; Edwards, Stacey L.</creator><creatorcontrib>French, Juliet D. ; Michailidou, Kyriaki ; Nord, Silje ; Beesley, Jonathan ; Canisus, Sander ; Kaufmann, Susanne ; Moradi Marjaneh, Mahdi ; Lee, Jason S. ; Dennis, Joe ; Bolla, Manjeet K. ; Wang, Qin ; Milne, Roger L. ; Hopper, John L. ; Southey, Melissa C. ; Schmidt, Marjanka K. ; 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 ; Flyger, Henrik ; Benitez, Javier ; González-Neira, Anna ; Alonso, M. Rosario ; Pita, Guillermo ; Neuhausen, Susan L. ; Anton-Culver, Hoda ; Brenner, Hermann ; Arndt, Volker ; 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 ; Wu, Anna H. ; Van Den Berg, David ; Lambrechts, Diether ; Floris, Giuseppe ; Chang-Claude, Jenny ; Rudolph, Anja ; Barile, Monica ; Couch, Fergus J. ; Hallberg, Emily ; Giles, Graham G. ; Le Marchand, Loic ; Goldberg, Mark S. ; Yip, Cheng Har ; Zheng, Wei ; Winqvist, Robert ; Pylkäs, Katri ; Andrulis, Irene L. ; Devilee, Peter ; Tollenaar, Rob A.E.M. ; García-Closas, Montserrat ; Figueroa, Jonine ; Hall, Per ; Czene, Kamila ; Darabi, Hatef ; Eriksson, Mikael ; Hooning, Maartje J. ; Koppert, Linetta B. ; Li, Jingmei ; Shu, Xiao-Ou ; Cox, Angela ; Cross, Simon S. ; Kang, Daehee ; Hartman, Mikael ; Chia, Kee Seng ; Kabisch, Maria ; Torres, Diana ; Luccarini, Craig ; Conroy, Don M. ; Jakubowska, Anna ; Sangrajrang, Suleeporn ; Brennan, Paul ; Olswold, Curtis ; Slager, Susan ; Shen, Chen-Yang ; Hou, Ming-Feng ; Swerdlow, Anthony ; Schoemaker, Minouk J. ; Pharoah, Paul D.P. ; Kristensen, Vessela ; Dunning, Alison M. ; Edwards, Stacey L. ; kConFab/AOCS Investigators ; NBCS Collaborators</creatorcontrib><description>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.</description><identifier>ISSN: 0002-9297</identifier><identifier>EISSN: 1537-6605</identifier><identifier>DOI: 10.1016/j.ajhg.2016.07.017</identifier><identifier>PMID: 27640304</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Alleles ; Breast cancer ; Breast Neoplasms - genetics ; Breast Neoplasms - metabolism ; Case-Control Studies ; Cell Line, Tumor ; Chromosomes, Human, Pair 5 - genetics ; Enhancer Elements, Genetic - genetics ; Fibroblast Growth Factor 10 - genetics ; Fibroblast Growth Factor 10 - metabolism ; Gene expression ; Genetic Predisposition to Disease - genetics ; Genetics ; Genomes ; Haplotypes - genetics ; Humans ; Life Sciences ; Polymorphism, Single Nucleotide - genetics ; Promoter Regions, Genetic - genetics ; Proteins ; Quantitative Trait Loci - genetics ; Receptor, Fibroblast Growth Factor, Type 2 - metabolism ; Receptors, Estrogen - metabolism</subject><ispartof>American journal of human genetics, 2016-10, Vol.99 (4), p.903-911</ispartof><rights>2016 The Author(s)</rights><rights>Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.</rights><rights>Copyright Cell Press Oct 6, 2016</rights><rights>Attribution</rights><rights>2016 The Author(s) 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c555t-b93a78dedd8faf2d72dddd8ffdcc8aed9682dc45e59efabe3d7f2c093ab511633</citedby><cites>FETCH-LOGICAL-c555t-b93a78dedd8faf2d72dddd8ffdcc8aed9682dc45e59efabe3d7f2c093ab511633</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5065698/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0002929716302919$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,550,723,776,780,881,3537,27901,27902,53766,53768,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27640304$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-04687065$$DView record in HAL$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:134384426$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>French, Juliet D.</creatorcontrib><creatorcontrib>Michailidou, Kyriaki</creatorcontrib><creatorcontrib>Nord, Silje</creatorcontrib><creatorcontrib>Beesley, Jonathan</creatorcontrib><creatorcontrib>Canisus, Sander</creatorcontrib><creatorcontrib>Kaufmann, Susanne</creatorcontrib><creatorcontrib>Moradi Marjaneh, Mahdi</creatorcontrib><creatorcontrib>Lee, Jason S.</creatorcontrib><creatorcontrib>Dennis, Joe</creatorcontrib><creatorcontrib>Bolla, Manjeet K.</creatorcontrib><creatorcontrib>Wang, Qin</creatorcontrib><creatorcontrib>Milne, Roger L.</creatorcontrib><creatorcontrib>Hopper, John L.</creatorcontrib><creatorcontrib>Southey, Melissa C.</creatorcontrib><creatorcontrib>Schmidt, Marjanka K.</creatorcontrib><creatorcontrib>Lophatananon, Artitaya</creatorcontrib><creatorcontrib>Fasching, Peter A.</creatorcontrib><creatorcontrib>Beckmann, Matthias W.</creatorcontrib><creatorcontrib>Fletcher, Olivia</creatorcontrib><creatorcontrib>Johnson, Nichola</creatorcontrib><creatorcontrib>Sawyer, Elinor J.</creatorcontrib><creatorcontrib>Tomlinson, Ian</creatorcontrib><creatorcontrib>Burwinkel, Barbara</creatorcontrib><creatorcontrib>Marme, Frederik</creatorcontrib><creatorcontrib>Guénel, Pascal</creatorcontrib><creatorcontrib>Truong, Thérèse</creatorcontrib><creatorcontrib>Flyger, Henrik</creatorcontrib><creatorcontrib>Benitez, Javier</creatorcontrib><creatorcontrib>González-Neira, Anna</creatorcontrib><creatorcontrib>Alonso, M. 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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.</description><subject>Alleles</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - metabolism</subject><subject>Case-Control Studies</subject><subject>Cell Line, Tumor</subject><subject>Chromosomes, Human, Pair 5 - genetics</subject><subject>Enhancer Elements, Genetic - genetics</subject><subject>Fibroblast Growth Factor 10 - genetics</subject><subject>Fibroblast Growth Factor 10 - metabolism</subject><subject>Gene expression</subject><subject>Genetic Predisposition to Disease - genetics</subject><subject>Genetics</subject><subject>Genomes</subject><subject>Haplotypes - genetics</subject><subject>Humans</subject><subject>Life Sciences</subject><subject>Polymorphism, Single Nucleotide - genetics</subject><subject>Promoter Regions, Genetic - genetics</subject><subject>Proteins</subject><subject>Quantitative Trait Loci - genetics</subject><subject>Receptor, Fibroblast Growth Factor, Type 2 - metabolism</subject><subject>Receptors, Estrogen - metabolism</subject><issn>0002-9297</issn><issn>1537-6605</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>D8T</sourceid><recordid>eNp9ks1uEzEUhUcIREvhBVggS2xgMeHaE49nJFSpREmLFESVAlvLse8kDpNxsD1BfQseGQ8JFe2CjX3l-53jv5NlLymMKNDy3WakNuvViKV6BGIEVDzKTikvRF6WwB9npwDA8prV4iR7FsIGgNIKiqfZCRPlGAoYn2a_pntrsNNI4lrFNCDhO8rIN-Wt6iLxgUI9pqWoycR1DfpAbvqgcRft0rY23pLoyDRE71bY5QscOs7n1y7YaPdIPnhUIZKJSlv4ZO9dv1qT2eWMAlGdIZ8W1zcFkAWu-lZF67rn2ZNGtQFfHOez7Ots-mVylc8_X36cXMxzzTmP-bIulKgMGlM1qmFGMGOGujFaVwpNXVbM6DFHXmOjllgY0TANSbXklJZFcZblB9_wE3f9Uu683Sp_K52y8rj0PVUoObCCD_z5gU-dLRqNXfSqvSe73-nsWq7cPulLXtZVMnh7MFg_kF1dzOWwBuOyEgne08S-OW7m3Y8eQ5Rbmx69bVWHrg-SVulItaDAE_r6Abpxve_S0_2hyqoGColiB0p7F4LH5u4EFOQQJrmRQ5jkECYJQqYwJdGrf698J_mbngS8PwCYPmpv0cug7RAmYz3qKI2z__P_DeI13CU</recordid><startdate>20161006</startdate><enddate>20161006</enddate><creator>French, Juliet D.</creator><creator>Michailidou, Kyriaki</creator><creator>Nord, Silje</creator><creator>Beesley, Jonathan</creator><creator>Canisus, Sander</creator><creator>Kaufmann, Susanne</creator><creator>Moradi Marjaneh, Mahdi</creator><creator>Lee, Jason S.</creator><creator>Dennis, Joe</creator><creator>Bolla, Manjeet K.</creator><creator>Wang, Qin</creator><creator>Milne, Roger L.</creator><creator>Hopper, John L.</creator><creator>Southey, Melissa C.</creator><creator>Schmidt, Marjanka K.</creator><creator>Lophatananon, Artitaya</creator><creator>Fasching, Peter A.</creator><creator>Beckmann, Matthias W.</creator><creator>Fletcher, Olivia</creator><creator>Johnson, Nichola</creator><creator>Sawyer, Elinor J.</creator><creator>Tomlinson, Ian</creator><creator>Burwinkel, Barbara</creator><creator>Marme, Frederik</creator><creator>Guénel, Pascal</creator><creator>Truong, Thérèse</creator><creator>Flyger, Henrik</creator><creator>Benitez, Javier</creator><creator>González-Neira, Anna</creator><creator>Alonso, M. Rosario</creator><creator>Pita, Guillermo</creator><creator>Neuhausen, Susan L.</creator><creator>Anton-Culver, Hoda</creator><creator>Brenner, Hermann</creator><creator>Arndt, Volker</creator><creator>Schmutzler, Rita K.</creator><creator>Brauch, Hiltrud</creator><creator>Hamann, Ute</creator><creator>Tessier, Daniel C.</creator><creator>Vincent, Daniel</creator><creator>Nevanlinna, Heli</creator><creator>Khan, Sofia</creator><creator>Matsuo, Keitaro</creator><creator>Ito, Hidemi</creator><creator>Dörk, Thilo</creator><creator>Bogdanova, Natalia V.</creator><creator>Lindblom, Annika</creator><creator>Margolin, Sara</creator><creator>Mannermaa, Arto</creator><creator>Wu, Anna H.</creator><creator>Van Den Berg, David</creator><creator>Lambrechts, Diether</creator><creator>Floris, Giuseppe</creator><creator>Chang-Claude, Jenny</creator><creator>Rudolph, Anja</creator><creator>Barile, Monica</creator><creator>Couch, Fergus J.</creator><creator>Hallberg, Emily</creator><creator>Giles, Graham G.</creator><creator>Le Marchand, Loic</creator><creator>Goldberg, Mark S.</creator><creator>Yip, Cheng Har</creator><creator>Zheng, Wei</creator><creator>Winqvist, Robert</creator><creator>Pylkäs, Katri</creator><creator>Andrulis, Irene L.</creator><creator>Devilee, Peter</creator><creator>Tollenaar, Rob A.E.M.</creator><creator>García-Closas, Montserrat</creator><creator>Figueroa, Jonine</creator><creator>Hall, Per</creator><creator>Czene, Kamila</creator><creator>Darabi, Hatef</creator><creator>Eriksson, Mikael</creator><creator>Hooning, Maartje J.</creator><creator>Koppert, Linetta B.</creator><creator>Li, Jingmei</creator><creator>Shu, Xiao-Ou</creator><creator>Cox, Angela</creator><creator>Cross, Simon S.</creator><creator>Kang, Daehee</creator><creator>Hartman, Mikael</creator><creator>Chia, Kee Seng</creator><creator>Kabisch, Maria</creator><creator>Torres, Diana</creator><creator>Luccarini, Craig</creator><creator>Conroy, Don M.</creator><creator>Jakubowska, Anna</creator><creator>Sangrajrang, Suleeporn</creator><creator>Brennan, Paul</creator><creator>Olswold, Curtis</creator><creator>Slager, Susan</creator><creator>Shen, Chen-Yang</creator><creator>Hou, Ming-Feng</creator><creator>Swerdlow, Anthony</creator><creator>Schoemaker, Minouk J.</creator><creator>Pharoah, Paul D.P.</creator><creator>Kristensen, Vessela</creator><creator>Dunning, Alison M.</creator><creator>Edwards, Stacey L.</creator><general>Elsevier Inc</general><general>Cell Press</general><general>Elsevier (Cell Press)</general><general>Elsevier</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7TK</scope><scope>7TM</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>1XC</scope><scope>VOOES</scope><scope>5PM</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>D8T</scope><scope>ZZAVC</scope></search><sort><creationdate>20161006</creationdate><title>Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation</title><author>French, Juliet D. ; Michailidou, Kyriaki ; Nord, Silje ; Beesley, Jonathan ; Canisus, Sander ; Kaufmann, Susanne ; Moradi Marjaneh, Mahdi ; Lee, Jason S. ; Dennis, Joe ; Bolla, Manjeet K. ; Wang, Qin ; Milne, Roger L. ; Hopper, John L. ; Southey, Melissa C. ; Schmidt, Marjanka K. ; 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 ; Flyger, Henrik ; Benitez, Javier ; González-Neira, Anna ; Alonso, M. Rosario ; Pita, Guillermo ; Neuhausen, Susan L. ; Anton-Culver, Hoda ; Brenner, Hermann ; Arndt, Volker ; 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 ; Wu, Anna H. ; Van Den Berg, David ; Lambrechts, Diether ; Floris, Giuseppe ; Chang-Claude, Jenny ; Rudolph, Anja ; Barile, Monica ; Couch, Fergus J. ; Hallberg, Emily ; Giles, Graham G. ; Le Marchand, Loic ; Goldberg, Mark S. ; Yip, Cheng Har ; Zheng, Wei ; Winqvist, Robert ; Pylkäs, Katri ; Andrulis, Irene L. ; Devilee, Peter ; Tollenaar, Rob A.E.M. ; García-Closas, Montserrat ; Figueroa, Jonine ; Hall, Per ; Czene, Kamila ; Darabi, Hatef ; Eriksson, Mikael ; Hooning, Maartje J. ; Koppert, Linetta B. ; Li, Jingmei ; Shu, Xiao-Ou ; Cox, Angela ; Cross, Simon S. ; Kang, Daehee ; Hartman, Mikael ; Chia, Kee Seng ; Kabisch, Maria ; Torres, Diana ; Luccarini, Craig ; Conroy, Don M. ; Jakubowska, Anna ; Sangrajrang, Suleeporn ; Brennan, Paul ; Olswold, Curtis ; Slager, Susan ; Shen, Chen-Yang ; Hou, Ming-Feng ; Swerdlow, Anthony ; Schoemaker, Minouk J. ; Pharoah, Paul D.P. ; Kristensen, Vessela ; Dunning, Alison M. ; Edwards, Stacey L.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c555t-b93a78dedd8faf2d72dddd8ffdcc8aed9682dc45e59efabe3d7f2c093ab511633</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Alleles</topic><topic>Breast cancer</topic><topic>Breast Neoplasms - genetics</topic><topic>Breast Neoplasms - metabolism</topic><topic>Case-Control Studies</topic><topic>Cell Line, Tumor</topic><topic>Chromosomes, Human, Pair 5 - genetics</topic><topic>Enhancer Elements, Genetic - genetics</topic><topic>Fibroblast Growth Factor 10 - genetics</topic><topic>Fibroblast Growth Factor 10 - metabolism</topic><topic>Gene expression</topic><topic>Genetic Predisposition to Disease - genetics</topic><topic>Genetics</topic><topic>Genomes</topic><topic>Haplotypes - genetics</topic><topic>Humans</topic><topic>Life Sciences</topic><topic>Polymorphism, Single Nucleotide - genetics</topic><topic>Promoter Regions, Genetic - genetics</topic><topic>Proteins</topic><topic>Quantitative Trait Loci - genetics</topic><topic>Receptor, Fibroblast Growth Factor, Type 2 - metabolism</topic><topic>Receptors, Estrogen - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>French, Juliet D.</creatorcontrib><creatorcontrib>Michailidou, Kyriaki</creatorcontrib><creatorcontrib>Nord, Silje</creatorcontrib><creatorcontrib>Beesley, Jonathan</creatorcontrib><creatorcontrib>Canisus, Sander</creatorcontrib><creatorcontrib>Kaufmann, Susanne</creatorcontrib><creatorcontrib>Moradi Marjaneh, Mahdi</creatorcontrib><creatorcontrib>Lee, Jason S.</creatorcontrib><creatorcontrib>Dennis, Joe</creatorcontrib><creatorcontrib>Bolla, Manjeet K.</creatorcontrib><creatorcontrib>Wang, Qin</creatorcontrib><creatorcontrib>Milne, Roger L.</creatorcontrib><creatorcontrib>Hopper, John L.</creatorcontrib><creatorcontrib>Southey, Melissa C.</creatorcontrib><creatorcontrib>Schmidt, Marjanka K.</creatorcontrib><creatorcontrib>Lophatananon, Artitaya</creatorcontrib><creatorcontrib>Fasching, Peter A.</creatorcontrib><creatorcontrib>Beckmann, Matthias W.</creatorcontrib><creatorcontrib>Fletcher, Olivia</creatorcontrib><creatorcontrib>Johnson, Nichola</creatorcontrib><creatorcontrib>Sawyer, Elinor J.</creatorcontrib><creatorcontrib>Tomlinson, Ian</creatorcontrib><creatorcontrib>Burwinkel, Barbara</creatorcontrib><creatorcontrib>Marme, Frederik</creatorcontrib><creatorcontrib>Guénel, Pascal</creatorcontrib><creatorcontrib>Truong, Thérèse</creatorcontrib><creatorcontrib>Flyger, Henrik</creatorcontrib><creatorcontrib>Benitez, Javier</creatorcontrib><creatorcontrib>González-Neira, Anna</creatorcontrib><creatorcontrib>Alonso, M. 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Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SwePub Articles full text</collection><jtitle>American journal of human genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>French, Juliet D.</au><au>Michailidou, Kyriaki</au><au>Nord, Silje</au><au>Beesley, Jonathan</au><au>Canisus, Sander</au><au>Kaufmann, Susanne</au><au>Moradi Marjaneh, Mahdi</au><au>Lee, Jason S.</au><au>Dennis, Joe</au><au>Bolla, Manjeet K.</au><au>Wang, Qin</au><au>Milne, Roger L.</au><au>Hopper, John L.</au><au>Southey, Melissa C.</au><au>Schmidt, Marjanka K.</au><au>Lophatananon, Artitaya</au><au>Fasching, Peter A.</au><au>Beckmann, Matthias W.</au><au>Fletcher, Olivia</au><au>Johnson, Nichola</au><au>Sawyer, Elinor J.</au><au>Tomlinson, Ian</au><au>Burwinkel, Barbara</au><au>Marme, Frederik</au><au>Guénel, Pascal</au><au>Truong, Thérèse</au><au>Flyger, Henrik</au><au>Benitez, Javier</au><au>González-Neira, Anna</au><au>Alonso, M. Rosario</au><au>Pita, Guillermo</au><au>Neuhausen, Susan L.</au><au>Anton-Culver, Hoda</au><au>Brenner, Hermann</au><au>Arndt, Volker</au><au>Schmutzler, Rita K.</au><au>Brauch, Hiltrud</au><au>Hamann, Ute</au><au>Tessier, Daniel C.</au><au>Vincent, Daniel</au><au>Nevanlinna, Heli</au><au>Khan, Sofia</au><au>Matsuo, Keitaro</au><au>Ito, Hidemi</au><au>Dörk, Thilo</au><au>Bogdanova, Natalia V.</au><au>Lindblom, Annika</au><au>Margolin, Sara</au><au>Mannermaa, Arto</au><au>Wu, Anna H.</au><au>Van Den Berg, David</au><au>Lambrechts, Diether</au><au>Floris, Giuseppe</au><au>Chang-Claude, Jenny</au><au>Rudolph, Anja</au><au>Barile, Monica</au><au>Couch, Fergus J.</au><au>Hallberg, Emily</au><au>Giles, Graham G.</au><au>Le Marchand, Loic</au><au>Goldberg, Mark S.</au><au>Yip, Cheng Har</au><au>Zheng, Wei</au><au>Winqvist, Robert</au><au>Pylkäs, Katri</au><au>Andrulis, Irene L.</au><au>Devilee, Peter</au><au>Tollenaar, Rob A.E.M.</au><au>García-Closas, Montserrat</au><au>Figueroa, Jonine</au><au>Hall, Per</au><au>Czene, Kamila</au><au>Darabi, Hatef</au><au>Eriksson, Mikael</au><au>Hooning, Maartje J.</au><au>Koppert, Linetta B.</au><au>Li, Jingmei</au><au>Shu, Xiao-Ou</au><au>Cox, Angela</au><au>Cross, Simon S.</au><au>Kang, Daehee</au><au>Hartman, Mikael</au><au>Chia, Kee Seng</au><au>Kabisch, Maria</au><au>Torres, Diana</au><au>Luccarini, Craig</au><au>Conroy, Don M.</au><au>Jakubowska, Anna</au><au>Sangrajrang, Suleeporn</au><au>Brennan, Paul</au><au>Olswold, Curtis</au><au>Slager, Susan</au><au>Shen, Chen-Yang</au><au>Hou, Ming-Feng</au><au>Swerdlow, Anthony</au><au>Schoemaker, Minouk J.</au><au>Pharoah, Paul D.P.</au><au>Kristensen, Vessela</au><au>Dunning, Alison M.</au><au>Edwards, Stacey L.</au><aucorp>kConFab/AOCS Investigators</aucorp><aucorp>NBCS Collaborators</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation</atitle><jtitle>American journal of human genetics</jtitle><addtitle>Am J Hum Genet</addtitle><date>2016-10-06</date><risdate>2016</risdate><volume>99</volume><issue>4</issue><spage>903</spage><epage>911</epage><pages>903-911</pages><issn>0002-9297</issn><eissn>1537-6605</eissn><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.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>27640304</pmid><doi>10.1016/j.ajhg.2016.07.017</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0002-9297 |
| ispartof | American journal of human genetics, 2016-10, Vol.99 (4), p.903-911 |
| issn | 0002-9297 1537-6605 |
| language | eng |
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| source | MEDLINE; Cell Press Free Archives; Elsevier ScienceDirect Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; SWEPUB Freely available online |
| subjects | Alleles Breast cancer Breast Neoplasms - genetics Breast Neoplasms - metabolism Case-Control Studies Cell Line, Tumor Chromosomes, Human, Pair 5 - genetics Enhancer Elements, Genetic - genetics Fibroblast Growth Factor 10 - genetics Fibroblast Growth Factor 10 - metabolism Gene expression Genetic Predisposition to Disease - genetics Genetics Genomes Haplotypes - genetics Humans Life Sciences Polymorphism, Single Nucleotide - genetics Promoter Regions, Genetic - genetics Proteins Quantitative Trait Loci - genetics Receptor, Fibroblast Growth Factor, Type 2 - metabolism Receptors, Estrogen - metabolism |
| title | Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-05T11%3A06%3A15IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_swepu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Evidence%20that%20the%205p12%20Variant%20rs10941679%20Confers%20Susceptibility%20to%20Estrogen-Receptor-Positive%20Breast%20Cancer%20through%20FGF10%20and%20MRPS30%20Regulation&rft.jtitle=American%20journal%20of%20human%20genetics&rft.au=French,%20Juliet%20D.&rft.aucorp=kConFab/AOCS%20Investigators&rft.date=2016-10-06&rft.volume=99&rft.issue=4&rft.spage=903&rft.epage=911&rft.pages=903-911&rft.issn=0002-9297&rft.eissn=1537-6605&rft_id=info:doi/10.1016/j.ajhg.2016.07.017&rft_dat=%3Cproquest_swepu%3E4237331291%3C/proquest_swepu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1835689010&rft_id=info:pmid/27640304&rft_els_id=S0002929716302919&rfr_iscdi=true |