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

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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 x 10(-20)), ER-negative BC (P = 1.1 x 10(-13)), BRCA1-associated BC (P = 7.7 x 10(-16)) and triple negative BC (P-diff = 2 x 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P = 2 x 10(-3)) and ABHD8 (P<2 x 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 30-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.
Keywords
BRCA2 MUTATION CARRIERS, GENOME-WIDE ASSOCIATION, EPITHELIAL-CELLS, COMMON VARIANTS, IDENTIFIES 3, MODIFIERS, REVEALS, GWAS, GENE, INVESTIGATORS

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Chicago
Lawrenson, K, S Kar, K McCue, K Kuchenbaeker, K Michailidou, J Tyrer, J Beesley, et al. 2016. “Functional Mechanisms Underlying Pleiotropic Risk Alleles at the 19p13.1 Breast-ovarian Cancer Susceptibility Locus.” Nature Communications 7.
APA
Lawrenson, K., Kar, S., McCue, K., Kuchenbaeker, K., Michailidou, K., Tyrer, J., Beesley, J., et al. (2016). Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus. NATURE COMMUNICATIONS, 7.
Vancouver
1.
Lawrenson K, Kar S, McCue K, Kuchenbaeker K, Michailidou K, Tyrer J, et al. Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus. NATURE COMMUNICATIONS. 2016;7.
MLA
Lawrenson, K, S Kar, K McCue, et al. “Functional Mechanisms Underlying Pleiotropic Risk Alleles at the 19p13.1 Breast-ovarian Cancer Susceptibility Locus.” NATURE COMMUNICATIONS 7 (2016): n. pag. Print.
@article{8152866,
  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 x 10(-20)), ER-negative BC (P = 1.1 x 10(-13)), BRCA1-associated BC (P = 7.7 x 10(-16)) and triple negative BC (P-diff = 2 x 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P = 2 x 10(-3)) and ABHD8 (P{\textlangle}2 x 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 30-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.},
  articleno    = {12675},
  author       = {Lawrenson, K and Kar, S and McCue, K and Kuchenbaeker, K and Michailidou, K and Tyrer, J and Beesley, J and Ramus, SJ and Li, QY and Delgado, MK and Lee, JM and Aittomaki, K and Andrulis, IL and Anton-Culver, H and Arndt, V and Arun, BK and Arver, B and Bandera, EV and Barile, M and Barkardottir, RB and Barrowdale, D and Beckmann, MW and Benitez, J and Berchuck, A and Bisogna, M and Bjorge, L and Blomqvist, C and Blot, W and Bogdanova, N and Bojesen, A and Bojesen, SE and Bolla, MK and Bonanni, B and Borresen-Dale, AL and Brauch, H and Brennan, P and Brenner, H and Bruinsma, F and Brunet, J and Buhari, SA and Burwinkel, B and Butzow, R and Buys, SS and Cai, QY and Caldes, T and Campbell, I and Canniotto, R and Chang-Claude, J and Chiquette, J and Choi, JY and Claes, Kathleen and Cook, LS and Cox, A and Cramer, DW and Cross, SS and Cybulski, C and Czene, K and Daly, MB and Damiola, F and Dansonka-Mieszkowska, A and Darabi, H and Dennis, J and Devilee, P and Diez, O and Doherty, JA and Domchek, SM and Dorfling, CM and Dork, T and Dumont, M and Ehrencrona, H and Ejlertsen, B and Ellis, S and Engel, C and Lee, E and Evans, DG and Fasching, PA and Feliubadalo, L and Figueroa, J and Flesch-Janys, D and Fletcher, O and Flyger, H and Foretova, L and Fostira, F and Foulkes, WD and Fridley, BL and Friedman, E and Frost, D and Gambino, G and Ganz, PA and Garber, J and Garcia-Closas, M and Gentry-Maharaj, A and Ghoussaini, M and Giles, GG and Glasspool, R and Godwin, AK and Goldberg, MS and Goldgar, DE and Gonzalez-Neira, A and Goode, EL and Goodman, MT and Greene, MH and Gronwald, J and Guenel, P and Haiman, CA and Hall, P and Hallberg, E and Hamann, U and Hansen, TVO and Harrington, PA and Hartman, M and Hassan, N and Healey, S and Heitz, F and Herzog, J and Hogdall, E and Hogdall, CK and Hogervorst, FBL and Hollestelle, A and Hopper, JL and Hulick, PJ and Huzarski, T and Imyanitov, EN and Isaacs, C and Ito, H and Jakubowska, A and Janavicius, R and Jensen, A and John, EM and Johnson, N and Kabisch, M and Kang, D and Kapuscinski, M and Karlan, BY and Khan, S and Kiemeney, LA and Kjaer, SK and Knight, JA and Konstantopoulou, I and Kosma, VM and Kristensen, V and Kupryjanczyk, J and Kwong, A and de la Hoya, M and Laitman, Y and Lambrechts, D and Le, N and De Leeneer, Kim and Lester, J and Levine, DA and Li, JM and Lindblom, A and Long, J and Lophatananon, A and Loud, JT and Lu, KR and Lubinski, J and Mannermaa, A and Manoukian, S and Le Marchand, L and Margolin, S and Marme, F and Massuger, LFAG and Matsuo, K and Mazoyer, S and McGuffog, L and McLean, C and McNeish, I and Meindl, A and Menon, U and Mensenkamp, AR and Milne, RL and Montagna, M and Moysich, KB and Muir, K and Mulligan, AM and Nathanson, KL and Ness, RB and Neuhausen, SL and Nevanlinna, H and Nord, S and Nussbaum, RL and Odunsi, K and Offit, K and Olah, E and Olopade, OI and Olson, JE and Olswold, C and O'Malley, D and Orlow, I and Orr, N and Osorio, A and Park, SK and Pearce, CL and Pejovic, T and Peterlongo, P and Pfeiler, G and Phelan, CM and Poole, EM and Pylkas, K and Radice, P and Rantala, J and Rashid, MU and Rennert, G and Rhenius, V and Rhiem, K and Risch, HA and Rodriguez, G and Rossing, MA and Rudolph, A and Salvesen, HB and Sangrajrang, S and Sawyer, EJ and Schildkraut, JM and Schmidt, MK and Schmutzler, RK and Sellers, TA and Seynaeve, C and Shah, M and Shen, CY and Shu, XO and Sieh, W and Singer, CF and Sinilnikova, OM and Slager, S and Song, HL and Soucy, P and Southey, MC and Stenmark-Askmalm, M and Stoppa-Lyonnet, D and Sutter, C and Swerdlow, A and Tchatchou, S and Teixeira, MR and Teo, SH and Terry, KL and Terry, MB and Thomassen, M and Tibiletti, MG and Tihomirova, L and Tognazzo, S and Toland, AE and Tomlinson, I and Torres, D and Truong, T and Tseng, CC and Tung, N and Tworoger, SS and Vachon, C and van den Ouweland, AMW and van Doorn, HC and van Rensburg, EJ and Van't Veer, LJ and Vanderstichele, A and Vergote, I and Vijai, J and Wang, Q and Wang-Gohrke, S and Weitzel, JN and Wentzensen, N and Whittemore, AS and Wildiers, H and Winqvist, R and Wu, AH and Yannoukakos, D and Yoon, SY and Yu, JC and Zheng, W and Zheng, Y and Khanna, KK and Simard, J and Monteiro, AN and French, JD and Couch, FJ and Freedman, ML and Easton, DF and Dunning, AM and Pharoah, PD and Edwards, SL and Chenevix-Trench, G and Antoniou, AC and Gayther, SA},
  issn         = {2041-1723},
  journal      = {NATURE COMMUNICATIONS},
  keyword      = {BRCA2 MUTATION CARRIERS,GENOME-WIDE ASSOCIATION,EPITHELIAL-CELLS,COMMON VARIANTS,IDENTIFIES 3,MODIFIERS,REVEALS,GWAS,GENE,INVESTIGATORS},
  language     = {eng},
  pages        = {22},
  title        = {Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus},
  url          = {http://dx.doi.org/10.1038/ncomms12675},
  volume       = {7},
  year         = {2016},
}

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