Dataset Information

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.

SUBMITTER: Glubb DM

PROVIDER: S-EPMC4289692 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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

Glubb Dylan M DM Maranian Mel J MJ Michailidou Kyriaki K Pooley Karen A KA Meyer Kerstin B KB Kar Siddhartha S Carlebur Saskia S O'Reilly Martin M Betts Joshua A JA Hillman Kristine M KM Kaufmann Susanne S Beesley Jonathan J Canisius Sander S Hopper John L JL Southey Melissa C MC Tsimiklis Helen H Apicella Carmel C Schmidt Marjanka K MK Broeks Annegien A Hogervorst Frans B FB van der Schoot C Ellen CE Muir Kenneth K Lophatananon Artitaya A Stewart-Brown Sarah S Siriwanarangsan Pornthep P Fasching Peter A PA Ruebner Matthias M Ekici Arif B AB Beckmann Matthias W MW Peto Julian J dos-Santos-Silva Isabel I Fletcher Olivia O Johnson Nichola N Pharoah Paul D P PD Bolla Manjeet K MK Wang Qin Q Dennis Joe J Sawyer Elinor J EJ Tomlinson Ian I Kerin Michael J MJ Miller Nicola N Burwinkel Barbara B Marme Frederik F Yang Rongxi R Surowy Harald H Guénel Pascal P Truong Thérèse T Menegaux Florence F Sanchez Marie M Bojesen Stig E SE Nordestgaard Børge G BG Nielsen Sune F SF Flyger Henrik H González-Neira Anna A Benitez Javier J Zamora M Pilar MP Arias Perez Jose Ignacio JI Anton-Culver Hoda H Neuhausen Susan L SL Brenner Hermann H Dieffenbach Aida Karina AK Arndt Volker V Stegmaier Christa C Meindl Alfons A Schmutzler Rita K RK Brauch Hiltrud H Ko Yon-Dschun YD Brüning Thomas T Nevanlinna Heli H Muranen Taru A TA Aittomäki Kristiina K Blomqvist Carl C Matsuo Keitaro K Ito Hidemi H Iwata Hiroji H Tanaka Hideo H Dörk Thilo T Bogdanova Natalia V NV Helbig Sonja S Lindblom Annika A Margolin Sara S Mannermaa Arto A Kataja Vesa V Kosma Veli-Matti VM Hartikainen Jaana M JM Wu Anna H AH Tseng Chiu-chen CC Van Den Berg David D Stram Daniel O DO Lambrechts Diether D Zhao Hui H Weltens Caroline C van Limbergen Erik E Chang-Claude Jenny J Flesch-Janys Dieter D Rudolph Anja A Seibold Petra P Radice Paolo P Peterlongo Paolo P Barile Monica M Capra Fabio F Couch Fergus J FJ Olson Janet E JE Hallberg Emily E Vachon Celine C Giles Graham G GG Milne Roger L RL 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 See Mee-Hoong MH Cornes Belinda B Cheng Ching-Yu CY Ikram M Kamran MK Kristensen Vessela V Zheng Wei W Halverson Sandra L SL 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 C Van Asperen Christi J CJ García-Closas Montserrat M Figueroa Jonine J Chanock Stephen J SJ Lissowska Jolanta J Czene Kamila K Klevebring Daniel D Darabi Hatef H Eriksson Mikael M Hooning Maartje J MJ Hollestelle Antoinette A Martens John W M JW Collée J Margriet JM Hall Per P Li Jingmei J Humphreys Keith K Shu Xiao-Ou XO Lu Wei W Gao Yu-Tang YT Cai Hui H Cox Angela A Cross Simon S SS Reed Malcolm W R MW Blot William W Signorello Lisa B LB Cai Qiuyin Q Shah Mitul M Ghoussaini Maya M Kang Daehee D Choi Ji-Yeob JY Park Sue K SK Noh Dong-Young DY Hartman Mikael M Miao Hui H Lim Wei Yen WY Tang Anthony A Hamann Ute U Torres Diana D Jakubowska Anna A Lubinski Jan J Jaworska Katarzyna K Durda Katarzyna K Sangrajrang Suleeporn S Gaborieau Valerie V Brennan Paul P McKay James J Olswold Curtis C Slager Susan S Toland Amanda E AE Yannoukakos Drakoulis D Shen Chen-Yang CY Wu Pei-Ei PE Yu Jyh-Cherng JC Hou Ming-Feng MF Swerdlow Anthony A Ashworth Alan A Orr Nick N Jones Michael M Pita Guillermo G Alonso M Rosario MR Álvarez Nuria N Herrero Daniel D Tessier Daniel C DC Vincent Daniel D Bacot Francois F Luccarini Craig C Baynes Caroline C Ahmed Shahana S Healey Catherine S CS Brown Melissa A MA Ponder Bruce A J BA Chenevix-Trench Georgia G Thompson Deborah J DJ Edwards Stacey L SL Easton Douglas F DF Dunning Alison M AM French Juliet D JD

American journal of human genetics 20141218 1

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 ...[more]

PMID: 25529635

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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 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1.

Publications

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

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