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

• Authors: DUNNING Alison M.; MICHAILIDOU Kyriaki; KUCHENBAECKER Karoline B.; THOMPSON Deborah; FRENCH Juliet D.; BEESLEY Jonathan; HEALEY Catherine S.; KAR Siddhartha; POOLEY Karen A.; LOPEZ-KNOWLES Elena; DICKS Ed; BARROWDALE Daniel; SINNOTT-ARMSTRONG Nicholas A.; SALLARI Richard C.; HILLMAN Kristine M.; KAUFMANN Susanne; SIVAKUMARAN Haran; MARJANEH Mahdi Moradi; LEE Jason S.; HILLS Margaret; JAROSZ Monika; DRURY Suzie; CANISIUS Sander; BOLLA Manjeet K.; DENNIS Joe; WANG Qin; HOPPER John L.; SOUTHEY Melissa C.; BROEKS Annegien; SCHMIDT Marjanka K.; LOPHATANANON Artitaya; MUIR Kenneth; BECKMANN Matthias W.; FASCHING Peter A.; DOS-SANTOS-SILVA Isabel; PETO Julian; SAWYER Elinor J.; TOMLINSON Ian; BURWINKEL Barbara; MARME Frederik; GUÉNEL Pascal; TRUONG Thérese; BOJESEN Stig E.; FLYGER Henrik; GONZÁLEZ-NEIRA Anna; PEREZ Jose I. A.; ANTON-CULVER Hoda; EUNJUNG Lee; ARNDT Volker; BRENNER Hermann; MEINDL Alfons; SCHMUTZLER Rita K.; BRAUCH Hiltrud; HAMANN Ute; AITTOMÄKI Kristiina; BLOMQVIST Carl; ITO Hidemi; MATSUO Keitaro; BOGDANOVA Natasha; DÖRK Thilo; LINDBLOM Annika; MARGOLIN Sara; KOSMA Veli-Matti; MANNERMAA Arto; TSENG Chiu-chen; WU Anna H.; LAMBRECHTS Diether; WILDIERS Hans; CHANG-CLAUDE Jenny; RUDOLPH Anja; PETERLONGO Paolo; RADICE Paolo; OLSON Janet E.; GILES Graham G.; MILNE Roger L.; HAIMAN Christopher A.; HENDERSON Brian E.; GOLDBERG Mark S.; TEO Soo H.; YIP Cheng Har; NORD Silje; BORRESEN-DALE Anne-Lise; KRISTENSEN Vessela; LONG Jirong; ZHENG Wei; PYLKÄS Katri; WINQVIST Robert; ANDRULIS Irene L.; KNIGHT Julia A.; DEVILEE Peter; SEYNAEVE Caroline; FIGUEROA Jonine; SHERMAN Mark E.; CZENE Kamila; DARABI Hatef; HOLLESTELLE Antoinette; OUWELAND Ans M. W. den; HUMPHREYS Keith; GAO Yu-Tang; SHU Xiao-Ou; COX Angela; CROSS Simon S.; BLOT William; CAI Qiuyin; GHOUSSAINI Maya; PERKINS Barbara J.; SHAH Mitul; CHOI Ji-Yeob; KANG Daehee; LEE Soo Chin; HARTMAN Mikael; KABISCH Maria; TORRES Diana; JAKUBOWSKA Anna; LUBINSKI Jan; BRENNAN Paul; SANGRAJRANG Suleeporn; AMBROSONE Christine B.; TOLAND Amanda E.; SHEN Chen-Yang; WU Pei-Ei; ORR Nick; SWERDLOW Anthony; MCGUFFOG Lesley; HEALEY Sue; LEE Andrew; KAPUSCINSKI Miroslav; JOHN Esther M.; TERRY Mary Beth; DALY Mary B.; GOLDGAR David E.; BUYS Saundra S.; JANAVICIUS Ramunas; TIHOMIROVA Laima; TUNG Nadine; DORFLING Cecilia M.; RENSBURG Elizabeth J. van; NEUHAUSEN Susan L.; EJLERTSEN Bent; HANSEN Thomas V. O.; OSORIO Ana; BENITEZ Javier; RANDO Rachel; WEITZEL Jeffrey N.; BONANNI Bernardo; PEISSEL Bernard; MANOUKIAN Siranoush; PAPI Laura; OTTINI Laura; KONSTANTOPOULOU Irene; APOSTOLOU Paraskevi; GARBER Judy; RASHID Muhammad Usman; FROST Debra; IZATT Louise; ELLIS Steve; GODWIN Andrew K.; ARNOLD Norbert; NIEDERACHER Dieter; RHIEM Kerstin; BOGDANOVA-MARKOV Nadja; SAGNE Charlotte; STOPPA-LYONNET Dominique; DAMIOLA Francesca; SINILNIKOVA Olga M.; MAZOYER Sylvie; ISAACS Claudine; CLAES Kathleen B. M.; LEENEER Kim de; HOYA Miguel de la; CALDES Trinidad; NEVANLINNA Heli; KHAN Sofia; MENSENKAMP Arjen R.; HOONING Maartje J.; ROOKUS Matti A.; KWONG Ava; OLAH Edith; DIEZ Orland; BRUNET Joan; PUJANA Miquel Angel; GRONWALD Jacek; HUZARSKI Tomasz; BARKARDOTTIR Rosa B.; LAFRAMBOISE Rachel; SOUCY Penny; MONTAGNA Marco; AGATA Simona; TEIXEIRA Manuel R.; PARK Sue Kyung; LINDOR Noralane; COUCH Fergus J.; TISCHKOWITZ Marc; FORETOVÁ Lenka; VIJAI Joseph; OFFIT Kenneth; SINGER Christian F.; RAPPAPORT Christine; PHELAN Catherine M.; GREENE Mark H.; MAI Phuong L.; RENNERT Gad; IMYANITOV Evgeny N.; HULICK Peter J.; PHILLIPS Kelly-Anne; PIEDMONTE Marion; MULLIGAN Anna Marie; GLENDON Gord; BOJESEN Anders; THOMASSEN Mads; CALIGO Maria A.; YOON Sook-Yee; FRIEDMAN Eitan; LAITMAN Yael; BORG Ake; WACHENFELDT Anna von; EHRENCRONA Hans; RANTALA Johanna; OLOPADE Olufunmilayo I.; GANZ Patricia A.; NUSSBAUM Robert L.; GAYTHER Simon A.; NATHANSON Katherine L.; DOMCHEK Susan M.; ARUN Banu K.; MITCHELL Gillian; KARLAN Beth Y.; LESTER Jenny; MASKARINEC Gertraud; WOOLCOTT Christy; SCOTT Christopher; STONE Jennifer; APICELLA Carmel; TAMIMI Rulla; LUBEN Robert; KHAW Kay-Tee; HELLAND Aslaug; HAAKENSEN Vilde; DOWSETT Mitch; PHAROAH Paul D. P.; SIMARD Jacques; HALL Per; GARCÍA-CLOSAS Montserrat; VACHON Celine; CHENEVIX-TRENCH Georgia; ANTONIOU Antonis C.; EASTON Douglas F.; EDWARDS Stacey L.
• Year of publication: 2016
• Type: Article in Periodical
• Magazine / Source: Nature genetics
• MU Faculty or unit: Faculty of Medicine
• Doi: http://dx.doi.org/10.1038/ng.3521
• Field: Oncology and hematology
• Keywords: GENOME-WIDE ASSOCIATION; BRCA2 MUTATION CARRIERS; BONE-MINERAL DENSITY; MAMMOGRAPHIC DENSITY; SUSCEPTIBILITY LOCUS; METAANALYSIS; EXPRESSION; MODIFIERS; REVEALS; DISEASE
• Description: We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor a) 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.