Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast - Ovarian cancer susceptibility locus Journal Article


Authors: Lawrenson, K.; Kar, S.; McCue, K.; Kuchenbaeker, K.; Michailidou, K.; Tyrer, J.; Beesley, J.; Ramus, S. J.; Li, Q.; Delgado, M. K.; Lee, J. M.; Aittomäki, K.; Andrulis, I. L.; Anton-Culver, H.; Arndt, V.; Arun, B. K.; Arver, B.; Bandera, E. V.; Barile, M.; Barkardottir, R. B.; Barrowdale, D.; Beckmann, M. W.; Benitez, J.; Berchuck, A.; Bisogna, M.; Bjorge, L.; Blomqvist, C.; Blot, W.; Bogdanova, N.; Bojesen, A.; Bojesen, S. E.; Bolla, M. K.; Bonanni, B.; Børresen-Dale, A. L.; Brauch, H.; Brennan, P.; Brenner, H.; Bruinsma, F.; Brunet, J.; Buhari, S. A.; Burwinkel, B.; Butzow, R.; Buys, S. S.; Cai, Q.; Caldes, T.; Campbell, I.; Canniotto, R.; Chang-Claude, J.; Chiquette, J.; Choi, J. Y.; Claes, K. B. M.; GEMO Study Collaborators; Cook, L. S.; Cox, A.; Cramer, D. W.; Cross, S. S.; Cybulski, C.; Czene, K.; Daly, M. B.; Damiola, F.; Dansonka-Mieszkowska, A.; Darabi, H.; Dennis, J.; Devilee, P.; Diez, O.; Doherty, J. A.; Domchek, S. M.; Dorfling, C. M.; Dörk, T.; Dumont, M.; Ehrencrona, H.; Ejlertsen, B.; Ellis, S.; EMBRACE; Engel, C.; Lee, E.; Evans, D. G.; Fasching, P. A.; Feliubadalo, L.; Figueroa, J.; Flesch-Janys, D.; Fletcher, O.; Flyger, H.; Foretova, L.; Fostira, F.; Foulkes, W. D.; Fridley, B. L.; Friedman, E.; Frost, D.; Gambino, G.; Ganz, P. A.; Garber, J.; García-Closas, M.; Gentry-Maharaj, A.; Ghoussaini, M.; Giles, G. G.; Glasspool, R.; Godwin, A. K.; Goldberg, M. S.; Goldgar, D. E.; González-Neira, A.; Goode, E. L.; Goodman, M. T.; Greene, M. H.; Gronwald, J.; Guénel, P.; Haiman, C. A.; Hall, P.; Hallberg, E.; Hamann, U.; Hansen, T. V. O.; Harrington, P. A.; Hartman, M.; Hassan, N.; Healey, S.; The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON); Heitz, F.; Herzog, J.; Høgdall, E.; Høgdall, C. K.; Hogervorst, F. B. L.; Hollestelle, A.; Hopper, J. L.; Hulick, P. J.; Huzarski, T.; Imyanitov, E. N.; KConFab Investigators; Australian Ovarian Cancer Study Group; Isaacs, C.; Ito, H.; Jakubowska, A.; Janavicius, R.; Jensen, A.; John, E. M.; Johnson, N.; Kabisch, M.; Kang, D.; Kapuscinski, M.; Karlan, B. Y.; Khan, S.; Kiemeney, L. A.; Kjaer, S. K.; Knight, J. A.; Konstantopoulou, I.; Kosma, V. M.; Kristensen, V.; Kupryjanczyk, J.; Kwong, A.; De La Hoya, M.; Laitman, Y.; Lambrechts, D.; Le, N.; De Leeneer, K.; Lester, J.; Levine, D. A.; Li, J.; Lindblom, A.; Long, J.; Lophatananon, A.; Loud, J. T.; Lu, K.; Lubinski, J.; Mannermaa, A.; Manoukian, S.; Le Marchand, L.; Margolin, S.; Marme, F.; Massuger, L. F. A. G.; Matsuo, K.; Mazoyer, S.; McGuffog, L.; McLean, C.; McNeish, I.; Meindl, A.; Menon, U.; Mensenkamp, A. R.; Milne, R. L.; Montagna, M.; Moysich, K. B.; Muir, K.; Mulligan, A. M.; Nathanson, K. L.; Ness, R. B.; Neuhausen, S. L.; Nevanlinna, H.; Nord, S.; Nussbaum, R. L.; Odunsi, K.; Offit, K.; Olah, E.; Olopade, O. I.; Olson, J. E.; Olswold, C.; O'Malley, D.; Orlow, I.; Orr, N.; Osorio, A.; Park, S. K.; Pearce, C. L.; Pejovic, T.; Peterlongo, P.; Pfeiler, G.; Phelan, C. M.; Poole, E. M.; Pylkäs, K.; Radice, P.; Rantala, J.; Rashid, M. U.; Rennert, G.; Rhenius, V.; Rhiem, K.; Risch, H. A.; Rodriguez, G.; Rossing, M. A.; Rudolph, A.; Salvesen, H. B.; Sangrajrang, S.; Sawyer, E. J.; Schildkraut, J. M.; Schmidt, M. K.; Schmutzler, R. K.; Sellers, T. A.; Seynaeve, C.; Shah, M.; Shen, C. Y.; Shu, X. O.; Sieh, W.; Singer, C. F.; Sinilnikova, O. M.; Slager, S.; Song, H.; Soucy, P.; Southey, M. C.; Stenmark-Askmalm, M.; Stoppa-Lyonnet, D.; Sutter, C.; Swerdlow, A.; Tchatchou, S.; Teixeira, M. R.; Teo, S. H.; Terry, K. L.; Terry, M. B.; Thomassen, M.; Tibiletti, M. G.; Tihomirova, L.; Tognazzo, S.; Toland, A. E.; Tomlinson, I.; Torres, D.; Truong, T.; Tseng, C. C.; Tung, N.; Tworoger, S. S.; Vachon, C.; Van Den Ouweland, A. M. W.; Van Doorn, H. C.; Van Rensburg, E. J.; Van't Veer, L. J.; Vanderstichele, A.; Vergote, I.; Vijai, J.; Wang, Q.; Wang-Gohrke, S.; Weitzel, J. N.; Wentzensen, N.; Whittemore, A. S.; Wildiers, H.; Winqvist, R.; Wu, A. H.; Yannoukakos, D.; Yoon, S. Y.; Yu, J. C.; Zheng, W.; Zheng, Y.; Khanna, K. K.; Simard, J.; Monteiro, A. N.; French, J. D.; Couch, F. J.; Freedman, M. L.; Easton, D. F.; Dunning, A. M.; Pharoah, P. D.; Edwards, S. L.; Chenevix-Trench, G.; Antoniou, A. C.; Gayther, S. A.
Article Title: Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast - Ovarian cancer susceptibility locus
Abstract: A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk. © 2016 The Author(s).
Journal Title: Nature Communications
Volume: 7
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2016-09-07
Start Page: 12675
Language: English
DOI: 10.1038/ncomms12675
PROVIDER: scopus
PMCID: PMC5023955
PUBMED: 27601076
DOI/URL:
Notes: Article -- Export Date: 3 October 2016 -- Source: Scopus
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  1. Kenneth Offit
    765 Offit
  2. Douglas A Levine
    379 Levine
  3. Irene Orlow
    239 Orlow
  4. Vijai Joseph
    204 Joseph