Dataset Information

Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.

ABSTRACT: We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor ?) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.

SUBMITTER: Dunning AM

PROVIDER: S-EPMC4938803 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.

Dunning Alison M AM Michailidou Kyriaki K Kuchenbaecker Karoline B KB Thompson Deborah D French Juliet D JD Beesley Jonathan J Healey Catherine S CS Kar Siddhartha S Pooley Karen A KA Lopez-Knowles Elena E Dicks Ed E Barrowdale Daniel D Sinnott-Armstrong Nicholas A NA Sallari Richard C RC Hillman Kristine M KM Kaufmann Susanne S Sivakumaran Haran H Moradi Marjaneh Mahdi M Lee Jason S JS Hills Margaret M Jarosz Monika M Drury Suzie S Canisius Sander S Bolla Manjeet K MK Dennis Joe J Wang Qin Q Hopper John L JL Southey Melissa C MC Broeks Annegien A Schmidt Marjanka K MK Lophatananon Artitaya A Muir Kenneth K Beckmann Matthias W MW Fasching Peter A PA Dos-Santos-Silva Isabel I Peto Julian J Sawyer Elinor J EJ Tomlinson Ian I Burwinkel Barbara B Marme Frederik F Guénel Pascal P Truong Thérèse T Bojesen Stig E SE Flyger Henrik H González-Neira Anna A Perez Jose I A JI Anton-Culver Hoda H Eunjung Lee L Arndt Volker V Brenner Hermann H Meindl Alfons A Schmutzler Rita K RK Brauch Hiltrud H Hamann Ute U Aittomäki Kristiina K Blomqvist Carl C Ito Hidemi H Matsuo Keitaro K Bogdanova Natasha N Dörk Thilo T Lindblom Annika A Margolin Sara S Kosma Veli-Matti VM Mannermaa Arto A Tseng Chiu-Chen CC Wu Anna H AH Lambrechts Diether D Wildiers Hans H Chang-Claude Jenny J Rudolph Anja A Peterlongo Paolo P Radice Paolo P Olson Janet E JE Giles Graham G GG Milne Roger L RL Haiman Christopher A CA Henderson Brian E BE Goldberg Mark S MS Teo Soo H SH Yip Cheng Har CH Nord Silje S Borresen-Dale Anne-Lise AL Kristensen Vessela V Long Jirong J Zheng Wei W Pylkäs Katri K Winqvist Robert R Andrulis Irene L IL Knight Julia A JA Devilee Peter P Seynaeve Caroline C Figueroa Jonine J Sherman Mark E ME Czene Kamila K Darabi Hatef H Hollestelle Antoinette A van den Ouweland Ans M W AM Humphreys Keith K Gao Yu-Tang YT Shu Xiao-Ou XO Cox Angela A Cross Simon S SS Blot William W Cai Qiuyin Q Ghoussaini Maya M Perkins Barbara J BJ Shah Mitul M Choi Ji-Yeob JY Kang Daehee D Lee Soo Chin SC Hartman Mikael M Kabisch Maria M Torres Diana D Jakubowska Anna A Lubinski Jan J Brennan Paul P Sangrajrang Suleeporn S Ambrosone Christine B CB Toland Amanda E AE Shen Chen-Yang CY Wu Pei-Ei PE Orr Nick N Swerdlow Anthony A McGuffog Lesley L Healey Sue S Lee Andrew A Kapuscinski Miroslav M John Esther M EM Terry Mary Beth MB Daly Mary B MB Goldgar David E DE Buys Saundra S SS Janavicius Ramunas R Tihomirova Laima L Tung Nadine N Dorfling Cecilia M CM van Rensburg Elizabeth J EJ Neuhausen Susan L SL Ejlertsen Bent B Hansen Thomas V O TV Osorio Ana A Benitez Javier J Rando Rachel R Weitzel Jeffrey N JN Bonanni Bernardo B Peissel Bernard B Manoukian Siranoush S Papi Laura L Ottini Laura L Konstantopoulou Irene I Apostolou Paraskevi P Garber Judy J Rashid Muhammad Usman MU Frost Debra D Izatt Louise L Ellis Steve S Godwin Andrew K AK Arnold Norbert N Niederacher Dieter D Rhiem Kerstin K Bogdanova-Markov Nadja N Sagne Charlotte C Stoppa-Lyonnet Dominique D Damiola Francesca F Sinilnikova Olga M OM Mazoyer Sylvie S Isaacs Claudine C Claes Kathleen B M KB De Leeneer Kim K de la Hoya Miguel M Caldes Trinidad T Nevanlinna Heli H Khan Sofia S Mensenkamp Arjen R AR Hooning Maartje J MJ Rookus Matti A MA Kwong Ava A Olah Edith E Diez Orland O Brunet Joan J Pujana Miquel Angel MA Gronwald Jacek J Huzarski Tomasz T Barkardottir Rosa B RB Laframboise Rachel R Soucy Penny P Montagna Marco M Agata Simona S Teixeira Manuel R MR Park Sue Kyung SK Lindor Noralane N Couch Fergus J FJ Tischkowitz Marc M Foretova Lenka L Vijai Joseph J Offit Kenneth K Singer Christian F CF Rappaport Christine C Phelan Catherine M CM Greene Mark H MH Mai Phuong L PL Rennert Gad G Imyanitov Evgeny N EN Hulick Peter J PJ Phillips Kelly-Anne KA Piedmonte Marion M Mulligan Anna Marie AM Glendon Gord G Bojesen Anders A Thomassen Mads M Caligo Maria A MA Yoon Sook-Yee SY Friedman Eitan E Laitman Yael Y Borg Ake A von Wachenfeldt Anna A Ehrencrona Hans H Rantala Johanna J Olopade Olufunmilayo I OI Ganz Patricia A PA Nussbaum Robert L RL Gayther Simon A SA Nathanson Katherine L KL Domchek Susan M SM Arun Banu K BK Mitchell Gillian G Karlan Beth Y BY Lester Jenny J Maskarinec Gertraud G Woolcott Christy C Scott Christopher C Stone Jennifer J Apicella Carmel C Tamimi Rulla R Luben Robert R Khaw Kay-Tee KT Helland Åslaug Å Haakensen Vilde V Dowsett Mitch M Pharoah Paul D P PD Simard Jacques J Hall Per P García-Closas Montserrat M Vachon Celine C Chenevix-Trench Georgia G Antoniou Antonis C AC Easton Douglas F DF Edwards Stacey L SL

Nature genetics 20160229 4

We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their ...[more]

PMID: 26928228

Similar Datasets

Project description:BACKGROUND:Endocrine therapy is the most common treatment for estrogen receptor (ER)-positive breast cancer, but its effectiveness is limited by high rates of primary and acquired resistance. There are likely many genetic causes, and recent studies suggest the important role of ESR1 mutations and fusions in endocrine resistance. Previously, we reported a recurrent ESR1 fusion called ESR1-CCDC170 in 6-8% of the luminal B breast cancers that has a worse clinical outcome after endocrine therapy. Despite being the most frequent ESR1 fusion, its functional role in endocrine resistance has not been studied in vivo, and the engaged mechanism and therapeutic relevance remain uncharacterized. METHODS:The endocrine sensitivities of HCC1428 or T47D breast cancer cells following genetic perturbations of ESR1-CCDC170 were assessed using clonogenic assays and/or xenograft mouse models. The underlying mechanisms were investigated by reverse phase protein array, western blotting, immunoprecipitation, and bimolecular fluorescence complementation assays. The sensitivity of ESR1-CCDC170 expressing breast cancer cells to concomitant treatments of tamoxifen and HER/SRC inhibitors was assessed by clonogenic assays. RESULTS:Our results suggested that different ESR1-CCDC170 fusions endow different levels of reduced endocrine sensitivity in vivo, resulting in significant survival disadvantages. Further investigation revealed a novel mechanism that ESR1-CCDC170 binds to HER2/HER3/SRC and activates SRC/PI3K/AKT signaling. Silencing of ESR1-CCDC170 in the fusion-positive cell line, HCC1428, downregulates HER2/HER3, represses pSRC/pAKT, and improves endocrine sensitivity. More important, breast cancer cells expressing ectopic or endogenous ESR1-CCDC170 are highly sensitive to treatment regimens combining endocrine agents with the HER2 inhibitor lapatinib and/or the SRC inhibitor dasatinib. CONCLUSION:ESR1-CCDC170 may endow breast cancer cell survival under endocrine therapy via maintaining/activating HER2/HER3/SRC/AKT signaling which implies a potential therapeutic strategy for managing these fusion positive tumors.

Project description:Osteoporosis is a common and debilitating bone disease that is characterised by a low bone mineral density (BMD), a highly heritable trait. Genome-wide association studies (GWAS) have proven to be very successful in identifying common genetic variants associated with BMD adjusted for age, gender and weight, however a large portion of the genetic variance for this trait remains unexplained. There is evidence to suggest significant genetic correlation between body size traits and BMD. It has also recently been suggested that unintended bias can be introduced as a result of adjusting a phenotype for a correlated trait. We performed a GWAS meta-analysis in two populations (total n = 6,696) using BMD data adjusted for only age and gender, in an attempt to identify genetic variants associated with BMD including those that may have potential pleiotropic effects on BMD and body size traits.We observed a single variant, rs2566752, associated with spine BMD at the genome-wide significance level in the meta-analysis (P = 3.36 × 10(-09)). Logistic regression analysis also revealed an association between rs2566752 and fracture rate in one of our study cohorts (P = 0.017, n = 5,654). This is an intronic variant located in the wntless Wnt ligand secretion mediator (WLS) gene (1p31.3), a known BMD locus which encodes an integral component of the Wnt ligand secretion pathway. Bioinformatics analyses of variants in moderate LD with rs2566752 produced strong evidence for a regulatory role for the variants rs72670452, rs17130567 and rs1430738. Expression quantitative trait locus (eQTL) analysis suggested that the variants rs12568456 and rs17130567 are associated with expression of the WLS gene in whole blood, cerebellum and temporal cortex brain tissue (P = 0.034-1.19 × 10(-23)). Gene-wide association testing using the VErsatile Gene-based Association Study 2 (VEGAS2) software revealed associations between the coiled-coil domain containing 170 (CCDC170) gene, located adjacent to the oestrogen receptor 1 (ESR1) gene, and BMD at the spine, femoral neck and total hip sites (P = 1.0 × 10(-06), 2.0 × 10(-06) and 2.0 × 10(-06) respectively).Genetic variation at the WLS and CCDC170/ESR1 loci were found to be significantly associated with BMD adjusted for only age and gender at the genome-wide level in this meta-analysis.

Project description:BackgroundBreast cancer is a partially heritable trait and genome-wide association studies (GWAS) have identified over 180 common genetic variants associated with breast cancer. We have previously performed breast cancer GWAS in Latinas and identified a strongly protective single nucleotide polymorphism (SNP) at 6q25, with the protective minor allele originating from indigenous American ancestry. Here we report on fine mapping of the 6q25 locus in an expanded sample of Latinas.MethodsWe performed GWAS in 2385 cases and 6416 controls who were either US Latinas or Mexican women. We replicated the top SNPs in 2412 cases and 1620 controls of US Latina, Mexican, and Colombian women. In addition, we validated the top novel variants in studies of African, Asian and European ancestry. In each dataset we used logistic regression models to test the association between SNPs and breast cancer risk and corrected for genetic ancestry using either principal components or genetic ancestry inferred from ancestry informative markers using a model-based approach.ResultsWe identified a novel set of SNPs at the 6q25 locus associated with genome-wide levels of significance (p = 3.3 × 10- 8 - 6.0 × 10- 9) not in linkage disequilibrium (LD) with variants previously reported at this locus. These SNPs were in high LD (r2 > 0.9) with each other, with the top SNP, rs3778609, associated with breast cancer with an odds ratio (OR) and 95% confidence interval (95% CI) of 0.76 (0.70-0.84). In a replication in women of Latin American origin, we also observed a consistent effect (OR 0.88; 95% CI 0.78-0.99; p = 0.037). We also performed a meta-analysis of these SNPs in East Asians, African ancestry and European ancestry populations and also observed a consistent effect (rs3778609, OR 0.95; 95% CI 0.91-0.97; p = 0.0017).ConclusionOur study adds to evidence about the importance of the 6q25 locus for breast cancer susceptibility. Our finding also highlights the utility of performing additional searches for genetic variants for breast cancer in non-European populations.

Dataset Information

Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.

Publications

Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets