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Fine-scale mapping of the FGFR2 breast cancer risk locus: putative functional variants differentially bind FOXA1 and E2F1.

ABSTRACT: The 10q26 locus in the second intron of FGFR2 is the locus most strongly associated with estrogen-receptor-positive breast cancer in genome-wide association studies. We conducted fine-scale mapping in case-control studies genotyped with a custom chip (iCOGS), comprising 41 studies (n = 89,050) of European ancestry, 9 Asian ancestry studies (n = 13,983), and 2 African ancestry studies (n = 2,028) from the Breast Cancer Association Consortium. We identified three statistically independent risk signals within the locus. Within risk signals 1 and 3, genetic analysis identified five and two variants, respectively, highly correlated with the most strongly associated SNPs. By using a combination of genetic fine mapping, data on DNase hypersensitivity, and electrophoretic mobility shift assays to study protein-DNA binding, we identified rs35054928, rs2981578, and rs45631563 as putative functional SNPs. Chromatin immunoprecipitation showed that FOXA1 preferentially bound to the risk-associated allele (C) of rs2981578 and was able to recruit ER? to this site in an allele-specific manner, whereas E2F1 preferentially bound the risk variant of rs35054928. The risk alleles were preferentially found in open chromatin and bound by Ser5 phosphorylated RNA polymerase II, suggesting that the risk alleles are associated with changes in transcription. Chromatin conformation capture demonstrated that the risk region was able to interact with the promoter of FGFR2, the likely target gene of this risk region. A role for FOXA1 in mediating breast cancer susceptibility at this locus is consistent with the finding that the FGFR2 risk locus primarily predisposes to estrogen-receptor-positive disease.

SUBMITTER: Meyer KB

PROVIDER: S-EPMC3852923 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Fine-scale mapping of the FGFR2 breast cancer risk locus: putative functional variants differentially bind FOXA1 and E2F1.

Meyer Kerstin B KB O'Reilly Martin M Michailidou Kyriaki K Carlebur Saskia S Edwards Stacey L SL French Juliet D JD Prathalingham Radhika R Dennis Joe J Bolla Manjeet K MK Wang Qin Q de Santiago Ines I Hopper John L JL Tsimiklis Helen H Apicella Carmel C Southey Melissa C MC Schmidt Marjanka K MK Broeks Annegien A Van 't Veer Laura J LJ Hogervorst Frans B FB Muir Kenneth K Lophatananon Artitaya A Stewart-Brown Sarah S Siriwanarangsan Pornthep P Fasching Peter A PA Lux Michael P MP Ekici Arif B AB Beckmann Matthias W MW Peto Julian J Dos Santos Silva Isabel I Fletcher Olivia O Johnson Nichola N Sawyer Elinor J EJ Tomlinson Ian I Kerin Michael J MJ Miller Nicola N Marme Federick F Schneeweiss Andreas A Sohn Christof C Burwinkel Barbara B Guénel Pascal P Truong Thérèse T Laurent-Puig Pierre P Menegaux Florence F Bojesen Stig E SE Nordestgaard Børge G BG Nielsen Sune F SF Flyger Henrik H Milne Roger L RL Zamora M Pilar MP Arias Jose I JI Benitez Javier J Neuhausen Susan S Anton-Culver Hoda H Ziogas Argyrios A Dur Christina C CC Brenner Hermann H Müller Heiko H Arndt Volker V Stegmaier Christa C Meindl Alfons A Schmutzler Rita K RK Engel Christoph C Ditsch Nina N Brauch Hiltrud H Brüning Thomas T Ko Yon-Dschun YD Nevanlinna Heli H Muranen Taru A TA Aittomäki Kristiina K Blomqvist Carl C Matsuo Keitaro K Ito Hidemi H Iwata Hiroji H Yatabe Yasushi Y Dörk Thilo T Helbig Sonja S Bogdanova Natalia V NV Lindblom Annika A Margolin Sara S Mannermaa Arto A Kataja Vesa V Kosma Veli-Matti VM Hartikainen Jaana M JM Chenevix-Trench Georgia G Wu Anna H AH Tseng Chiu-Chen CC Van Den Berg David D Stram Daniel O DO Lambrechts Diether D Thienpont Bernard B Christiaens Marie-Rose MR Smeets Ann A Chang-Claude Jenny J Rudolph Anja A Seibold Petra P Flesch-Janys Dieter D Radice Paolo P Peterlongo Paolo P Bonanni Bernardo B Bernard Loris L Couch Fergus J FJ Olson Janet E JE Wang Xianshu X Purrington Kristen K Giles Graham G GG Severi Gianluca G Baglietto Laura L McLean Catriona C Haiman Christopher A CA Henderson Brian E BE Schumacher Fredrick F Le Marchand Loic L Simard Jacques J Goldberg Mark S MS Labrèche France F Dumont Martine M Teo Soo-Hwang SH Yip Cheng-Har CH Phuah Sze-Yee SY Kristensen Vessela V Grenaker Alnæs Grethe G Børresen-Dale Anne-Lise AL Zheng Wei W Deming-Halverson Sandra S Shrubsole Martha M Long Jirong J Winqvist Robert R Pylkäs Katri K Jukkola-Vuorinen Arja A Kauppila Saila S Andrulis Irene L IL Knight Julia A JA Glendon Gord G Tchatchou Sandrine S Devilee Peter P Tollenaar Robert A E M RA Seynaeve Caroline M CM García-Closas Montserrat M Figueroa Jonine J Chanock Stephen J SJ Lissowska Jolanta J Czene Kamila K Darabi Hartef H Eriksson Kimael K Hooning Maartje J MJ Martens John W M JW van den Ouweland Ans M W AM van Deurzen Carolien H M CH Hall Per P Li Jingmei J Liu Jianjun J Humphreys Keith K Shu Xiao-Ou XO Lu Wei W Gao Yu-Tang YT Cai Hui H Cox Angela A Reed Malcolm W R MW Blot William W Signorello Lisa B LB Cai Qiuyin Q Pharoah Paul D P PD Ghoussaini Maya M Harrington Patricia P Tyrer Jonathan J Kang Daehee D Choi Ji-Yeob JY Park Sue K SK Noh Dong-Young DY Hartman Mikael M Hui Miao M Lim Wei-Yen WY Buhari Shaik A SA Hamann Ute U Försti Asta A Rüdiger Thomas T Ulmer Hans-Ulrich HU Jakubowska Anna A Lubinski Jan J Jaworska Katarzyna K Durda Katarzyna K Sangrajrang Suleeporn S Gaborieau Valerie V Brennan Paul P McKay James J Vachon Celine C Slager Susan S Fostira Florentia F Pilarski Robert R Shen Chen-Yang CY Hsiung Chia-Ni CN Wu Pei-Ei PE Hou Ming-Feng MF Swerdlow Anthony A Ashworth Alan A Orr Nick N Schoemaker Minouk J MJ Ponder Bruce A J BA Dunning Alison M AM Easton Douglas F DF

American journal of human genetics 20131127 6

The 10q26 locus in the second intron of FGFR2 is the locus most strongly associated with estrogen-receptor-positive breast cancer in genome-wide association studies. We conducted fine-scale mapping in case-control studies genotyped with a custom chip (iCOGS), comprising 41 studies (n = 89,050) of European ancestry, 9 Asian ancestry studies (n = 13,983), and 2 African ancestry studies (n = 2,028) from the Breast Cancer Association Consortium. We identified three statistically independent risk sig ...[more]

PMID: 24290378

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Project description:BackgroundMultiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk.MethodWe performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation.ResultsAnalysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05.ConclusionThis study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.

Dataset Information

Fine-scale mapping of the FGFR2 breast cancer risk locus: putative functional variants differentially bind FOXA1 and E2F1.

Publications

Fine-scale mapping of the FGFR2 breast cancer risk locus: putative functional variants differentially bind FOXA1 and E2F1.

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