Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.
Dunning AM., Michailidou K., Kuchenbaecker KB., Thompson D., French JD., Beesley J., Healey CS., Kar S., Pooley KA., Lopez-Knowles E., Dicks E., Barrowdale D., Sinnott-Armstrong NA., Sallari RC., Hillman KM., Kaufmann S., Sivakumaran H., Moradi Marjaneh M., Lee JS., Hills M., Jarosz M., Drury S., Canisius S., Bolla MK., Dennis J., Wang Q., Hopper JL., Southey MC., Broeks A., Schmidt MK., Lophatananon A., Muir K., Beckmann MW., Fasching PA., Dos-Santos-Silva I., Peto J., Sawyer EJ., Tomlinson I., Burwinkel B., Marme F., Guénel P., Truong T., Bojesen SE., Flyger H., González-Neira A., Perez JIA., Anton-Culver H., Eunjung L., Arndt V., Brenner H., Meindl A., Schmutzler RK., Brauch H., Hamann U., Aittomäki K., Blomqvist C., Ito H., Matsuo K., Bogdanova N., Dörk T., Lindblom A., Margolin S., Kosma V-M., Mannermaa A., Tseng C-C., Wu AH., Lambrechts D., Wildiers H., Chang-Claude J., Rudolph A., Peterlongo P., Radice P., Olson JE., Giles GG., Milne RL., Haiman CA., Henderson BE., Goldberg MS., Teo SH., Yip CH., Nord S., Borresen-Dale A-L., Kristensen V., Long J., Zheng W., Pylkäs K., Winqvist R., Andrulis IL., Knight JA., Devilee P., Seynaeve C., Figueroa J., Sherman ME., Czene K., Darabi H., Hollestelle A., van den Ouweland AMW., Humphreys K., Gao Y-T., Shu X-O., Cox A., Cross SS., Blot W., Cai Q., Ghoussaini M., Perkins BJ., Shah M., Choi J-Y., Kang D., Lee SC., Hartman M., Kabisch M., Torres D., Jakubowska A., Lubinski J., Brennan P., Sangrajrang S., Ambrosone CB., Toland AE., Shen C-Y., Wu P-E., Orr N., Swerdlow A., McGuffog L., Healey S., Lee A., Kapuscinski M., John EM., Terry MB., Daly MB., Goldgar DE., Buys SS., Janavicius R., Tihomirova L., Tung N., Dorfling CM., van Rensburg EJ., Neuhausen SL., Ejlertsen B., Hansen TVO., Osorio A., Benitez J., Rando R., Weitzel JN., Bonanni B., Peissel B., Manoukian S., Papi L., Ottini L., Konstantopoulou I., Apostolou P., Garber J., Rashid MU., Frost D., EMBRACE None., Izatt L., Ellis S., Godwin AK., Arnold N., Niederacher D., Rhiem K., Bogdanova-Markov N., Sagne C., Stoppa-Lyonnet D., Damiola F., GEMO Study Collaborators None., Sinilnikova OM., Mazoyer S., Isaacs C., Claes KBM., De Leeneer K., de la Hoya M., Caldes T., Nevanlinna H., Khan S., Mensenkamp AR., HEBON None., Hooning MJ., Rookus MA., Kwong A., Olah E., Diez O., Brunet J., Pujana MA., Gronwald J., Huzarski T., Barkardottir RB., Laframboise R., Soucy P., Montagna M., Agata S., Teixeira MR., kConFab Investigators None., Park SK., Lindor N., Couch FJ., Tischkowitz M., Foretova L., Vijai J., Offit K., Singer CF., Rappaport C., Phelan CM., Greene MH., Mai PL., Rennert G., Imyanitov EN., Hulick PJ., Phillips K-A., Piedmonte M., Mulligan AM., Glendon G., Bojesen A., Thomassen M., Caligo MA., Yoon S-Y., Friedman E., Laitman Y., Borg A., von Wachenfeldt A., Ehrencrona H., Rantala J., Olopade OI., Ganz PA., Nussbaum RL., Gayther SA., Nathanson KL., Domchek SM., Arun BK., Mitchell G., Karlan BY., Lester J., Maskarinec G., Woolcott C., Scott C., Stone J., Apicella C., Tamimi R., Luben R., Khaw K-T., Helland Å., Haakensen V., Dowsett M., Pharoah PDP., Simard J., Hall P., García-Closas M., Vachon C., Chenevix-Trench G., Antoniou AC., Easton DF., Edwards SL.
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 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.