Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus.
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-nega...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Nature Publishing Group
2016
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| _version_ | 1797076907685052416 |
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| author | Lawrenson, K Kar, S McCue, K Kuchenbaeker, K Michailidou, K Tyrer, J Beesley, J Ramus, SJ Li, Q Delgado, MK Lee, JM Aittomäki, K Andrulis, IL Anton-Culver, H Arndt, V Arun, BK Arver, B Bandera, EV Barile, M Barkardottir, RB Barrowdale, D Beckmann, MW Benitez, J Berchuck, A Bisogna, M Bjorge, L Blomqvist, C Blot, W Bogdanova, N Bojesen, A Bojesen, SE Bolla, MK Bonanni, B Børresen-Dale, AL Brauch, H Brennan, P Brenner, H Bruinsma, F Brunet, J Buhari, SA Burwinkel, B Butzow, R Buys, SS Cai, Q Caldes, T Campbell, I Canniotto, R Chang-Claude, J Chiquette, J Choi, JY Claes, KB Cook, LS Cox, A Cramer, DW Cross, SS Cybulski, C Czene, K Daly, MB Damiola, F Dansonka-Mieszkowska, A Darabi, H Dennis, J Devilee, P Diez, O Doherty, JA Domchek, SM Dorfling, CM Dörk, T Dumont, M Ehrencrona, H Ejlertsen, B Ellis, S Engel, C Lee, E Evans, DG Fasching, PA Feliubadalo, L Figueroa, J Flesch-Janys, D Fletcher, O Flyger, H Foretova, L Fostira, F Foulkes, WD Fridley, BL Friedman, E Frost, D Gambino, G Ganz, PA Garber, J García-Closas, M Gentry-Maharaj, A Ghoussaini, M Giles, GG Glasspool, R Godwin, AK Goldberg, MS Goldgar, DE González-Neira, A Goode, EL Goodman, MT Greene, MH Gronwald, J Guénel, P Haiman, CA Hall, P Hallberg, E Hamann, U Hansen, TV Harrington, PA Hartman, M Hassan, N Healey, S Heitz, F Herzog, J Høgdall, E Høgdall, CK Hogervorst, FB Hollestelle, A Hopper, JL Hulick, PJ Huzarski, T Imyanitov, EN Isaacs, C Ito, H Jakubowska, A Janavicius, R Jensen, A John, EM Johnson, N Kabisch, M Kang, D Kapuscinski, M Karlan, BY Khan, S Kiemeney, LA Kjaer, SK Knight, JA Konstantopoulou, I Kosma, VM Kristensen, V Kupryjanczyk, J Kwong, A de la Hoya, M Laitman, Y Lambrechts, D Le, N De Leeneer, K Lester, J Levine, DA Li, J Lindblom, A Long, J Lophatananon, A Loud, JT Lu, K Lubinski, J Mannermaa, A Manoukian, S Le Marchand, L Margolin, S Marme, F Massuger, LF Matsuo, K Mazoyer, S McGuffog, L McLean, C McNeish, I Meindl, A Menon, U Mensenkamp, AR Milne, RL Montagna, M Moysich, KB Muir, K Mulligan, AM Nathanson, KL Ness, RB Neuhausen, SL Nevanlinna, H Nord, S Nussbaum, RL Odunsi, K Offit, K Olah, E Olopade, OI Olson, JE Olswold, C O'Malley, D Orlow, I Orr, N Osorio, A Park, SK Pearce, CL Pejovic, T Peterlongo, P Pfeiler, G Phelan, CM Poole, EM Pylkäs, K Radice, P Rantala, J Rashid, MU Rennert, G Rhenius, V Rhiem, K Risch, HA Rodriguez, G Rossing, MA Rudolph, A Salvesen, HB Sangrajrang, S Sawyer, EJ Schildkraut, JM Schmidt, MK Schmutzler, RK Sellers, TA Seynaeve, C Shah, M Shen, CY Shu, XO Sieh, W Singer, CF Sinilnikova, OM Slager, S Song, H Soucy, P Southey, MC Stenmark-Askmalm, M Stoppa-Lyonnet, D Sutter, C Swerdlow, A Tchatchou, S Teixeira, MR Teo, SH Terry, KL Terry, MB Thomassen, M Tibiletti, MG Tihomirova, L Tognazzo, S Toland, AE Tomlinson, I Torres, D Truong, T Tseng, CC Tung, N Tworoger, SS Vachon, C van den Ouweland, AM van Doorn, HC van Rensburg, EJ Veer, LJ Vanderstichele, A Vergote, I Vijai, J Wang, Q Wang-Gohrke, S Weitzel, JN Wentzensen, N Whittemore, AS Wildiers, H Winqvist, R Wu, AH Yannoukakos, D Yoon, SY Yu, JC Zheng, W Zheng, Y Khanna, KK Simard, J Monteiro, AN French, JD Couch, FJ Freedman, ML Easton, DF Dunning, AM Pharoah, PD Edwards, SL Chenevix-Trench, G Antoniou, AC Gayther, SA |
| author_facet | Lawrenson, K Kar, S McCue, K Kuchenbaeker, K Michailidou, K Tyrer, J Beesley, J Ramus, SJ Li, Q Delgado, MK Lee, JM Aittomäki, K Andrulis, IL Anton-Culver, H Arndt, V Arun, BK Arver, B Bandera, EV Barile, M Barkardottir, RB Barrowdale, D Beckmann, MW Benitez, J Berchuck, A Bisogna, M Bjorge, L Blomqvist, C Blot, W Bogdanova, N Bojesen, A Bojesen, SE Bolla, MK Bonanni, B Børresen-Dale, AL Brauch, H Brennan, P Brenner, H Bruinsma, F Brunet, J Buhari, SA Burwinkel, B Butzow, R Buys, SS Cai, Q Caldes, T Campbell, I Canniotto, R Chang-Claude, J Chiquette, J Choi, JY Claes, KB Cook, LS Cox, A Cramer, DW Cross, SS Cybulski, C Czene, K Daly, MB Damiola, F Dansonka-Mieszkowska, A Darabi, H Dennis, J Devilee, P Diez, O Doherty, JA Domchek, SM Dorfling, CM Dörk, T Dumont, M Ehrencrona, H Ejlertsen, B Ellis, S Engel, C Lee, E Evans, DG Fasching, PA Feliubadalo, L Figueroa, J Flesch-Janys, D Fletcher, O Flyger, H Foretova, L Fostira, F Foulkes, WD Fridley, BL Friedman, E Frost, D Gambino, G Ganz, PA Garber, J García-Closas, M Gentry-Maharaj, A Ghoussaini, M Giles, GG Glasspool, R Godwin, AK Goldberg, MS Goldgar, DE González-Neira, A Goode, EL Goodman, MT Greene, MH Gronwald, J Guénel, P Haiman, CA Hall, P Hallberg, E Hamann, U Hansen, TV Harrington, PA Hartman, M Hassan, N Healey, S Heitz, F Herzog, J Høgdall, E Høgdall, CK Hogervorst, FB Hollestelle, A Hopper, JL Hulick, PJ Huzarski, T Imyanitov, EN Isaacs, C Ito, H Jakubowska, A Janavicius, R Jensen, A John, EM Johnson, N Kabisch, M Kang, D Kapuscinski, M Karlan, BY Khan, S Kiemeney, LA Kjaer, SK Knight, JA Konstantopoulou, I Kosma, VM Kristensen, V Kupryjanczyk, J Kwong, A de la Hoya, M Laitman, Y Lambrechts, D Le, N De Leeneer, K Lester, J Levine, DA Li, J Lindblom, A Long, J Lophatananon, A Loud, JT Lu, K Lubinski, J Mannermaa, A Manoukian, S Le Marchand, L Margolin, S Marme, F Massuger, LF Matsuo, K Mazoyer, S McGuffog, L McLean, C McNeish, I Meindl, A Menon, U Mensenkamp, AR Milne, RL Montagna, M Moysich, KB Muir, K Mulligan, AM Nathanson, KL Ness, RB Neuhausen, SL Nevanlinna, H Nord, S Nussbaum, RL Odunsi, K Offit, K Olah, E Olopade, OI Olson, JE Olswold, C O'Malley, D Orlow, I Orr, N Osorio, A Park, SK Pearce, CL Pejovic, T Peterlongo, P Pfeiler, G Phelan, CM Poole, EM Pylkäs, K Radice, P Rantala, J Rashid, MU Rennert, G Rhenius, V Rhiem, K Risch, HA Rodriguez, G Rossing, MA Rudolph, A Salvesen, HB Sangrajrang, S Sawyer, EJ Schildkraut, JM Schmidt, MK Schmutzler, RK Sellers, TA Seynaeve, C Shah, M Shen, CY Shu, XO Sieh, W Singer, CF Sinilnikova, OM Slager, S Song, H Soucy, P Southey, MC Stenmark-Askmalm, M Stoppa-Lyonnet, D Sutter, C Swerdlow, A Tchatchou, S Teixeira, MR Teo, SH Terry, KL Terry, MB Thomassen, M Tibiletti, MG Tihomirova, L Tognazzo, S Toland, AE Tomlinson, I Torres, D Truong, T Tseng, CC Tung, N Tworoger, SS Vachon, C van den Ouweland, AM van Doorn, HC van Rensburg, EJ Veer, LJ Vanderstichele, A Vergote, I Vijai, J Wang, Q Wang-Gohrke, S Weitzel, JN Wentzensen, N Whittemore, AS Wildiers, H Winqvist, R Wu, AH Yannoukakos, D Yoon, SY Yu, JC Zheng, W Zheng, Y Khanna, KK Simard, J Monteiro, AN French, JD Couch, FJ Freedman, ML Easton, DF Dunning, AM Pharoah, PD Edwards, SL Chenevix-Trench, G Antoniou, AC Gayther, SA |
| author_sort | Lawrenson, K |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T00:10:16Z |
| format | Journal article |
| id | oxford-uuid:78fda653-a6ba-4d12-bbc7-c528a492090c |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T00:10:16Z |
| publishDate | 2016 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | oxford-uuid:78fda653-a6ba-4d12-bbc7-c528a492090c2022-03-26T20:35:08ZFunctional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:78fda653-a6ba-4d12-bbc7-c528a492090cEnglishSymplectic Elements at OxfordNature Publishing Group2016Lawrenson, KKar, SMcCue, KKuchenbaeker, KMichailidou, KTyrer, JBeesley, JRamus, SJLi, QDelgado, MKLee, JMAittomäki, KAndrulis, ILAnton-Culver, HArndt, VArun, BKArver, BBandera, EVBarile, MBarkardottir, RBBarrowdale, DBeckmann, MWBenitez, JBerchuck, ABisogna, MBjorge, LBlomqvist, CBlot, WBogdanova, NBojesen, ABojesen, SEBolla, MKBonanni, BBørresen-Dale, ALBrauch, HBrennan, PBrenner, HBruinsma, FBrunet, JBuhari, SABurwinkel, BButzow, RBuys, SSCai, QCaldes, TCampbell, ICanniotto, RChang-Claude, JChiquette, JChoi, JYClaes, KBCook, LSCox, ACramer, DWCross, SSCybulski, CCzene, KDaly, MBDamiola, FDansonka-Mieszkowska, ADarabi, HDennis, JDevilee, PDiez, ODoherty, JADomchek, SMDorfling, CMDörk, TDumont, MEhrencrona, HEjlertsen, BEllis, SEngel, CLee, EEvans, DGFasching, PAFeliubadalo, LFigueroa, JFlesch-Janys, DFletcher, OFlyger, HForetova, LFostira, FFoulkes, WDFridley, BLFriedman, EFrost, DGambino, GGanz, PAGarber, JGarcía-Closas, MGentry-Maharaj, AGhoussaini, MGiles, GGGlasspool, RGodwin, AKGoldberg, MSGoldgar, DEGonzález-Neira, AGoode, ELGoodman, MTGreene, MHGronwald, JGuénel, PHaiman, CAHall, PHallberg, EHamann, UHansen, TVHarrington, PAHartman, MHassan, NHealey, SHeitz, FHerzog, JHøgdall, EHøgdall, CKHogervorst, FBHollestelle, AHopper, JLHulick, PJHuzarski, TImyanitov, ENIsaacs, CIto, HJakubowska, AJanavicius, RJensen, AJohn, EMJohnson, NKabisch, MKang, DKapuscinski, MKarlan, BYKhan, SKiemeney, LAKjaer, SKKnight, JAKonstantopoulou, IKosma, VMKristensen, VKupryjanczyk, JKwong, Ade la Hoya, MLaitman, YLambrechts, DLe, NDe Leeneer, KLester, JLevine, DALi, JLindblom, ALong, JLophatananon, ALoud, JTLu, KLubinski, JMannermaa, AManoukian, SLe Marchand, LMargolin, SMarme, FMassuger, LFMatsuo, KMazoyer, SMcGuffog, LMcLean, CMcNeish, IMeindl, AMenon, UMensenkamp, ARMilne, RLMontagna, MMoysich, KBMuir, KMulligan, AMNathanson, KLNess, RBNeuhausen, SLNevanlinna, HNord, SNussbaum, RLOdunsi, KOffit, KOlah, EOlopade, OIOlson, JEOlswold, CO'Malley, DOrlow, IOrr, NOsorio, APark, SKPearce, CLPejovic, TPeterlongo, PPfeiler, GPhelan, CMPoole, EMPylkäs, KRadice, PRantala, JRashid, MURennert, GRhenius, VRhiem, KRisch, HARodriguez, GRossing, MARudolph, ASalvesen, HBSangrajrang, SSawyer, EJSchildkraut, JMSchmidt, MKSchmutzler, RKSellers, TASeynaeve, CShah, MShen, CYShu, XOSieh, WSinger, CFSinilnikova, OMSlager, SSong, HSoucy, PSouthey, MCStenmark-Askmalm, MStoppa-Lyonnet, DSutter, CSwerdlow, ATchatchou, STeixeira, MRTeo, SHTerry, KLTerry, MBThomassen, MTibiletti, MGTihomirova, LTognazzo, SToland, AETomlinson, ITorres, DTruong, TTseng, CCTung, NTworoger, SSVachon, Cvan den Ouweland, AMvan Doorn, HCvan Rensburg, EJVeer, LJVanderstichele, AVergote, IVijai, JWang, QWang-Gohrke, SWeitzel, JNWentzensen, NWhittemore, ASWildiers, HWinqvist, RWu, AHYannoukakos, DYoon, SYYu, JCZheng, WZheng, YKhanna, KKSimard, JMonteiro, ANFrench, JDCouch, FJFreedman, MLEaston, DFDunning, AMPharoah, PDEdwards, SLChenevix-Trench, GAntoniou, ACGayther, SAA 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. |
| spellingShingle | Lawrenson, K Kar, S McCue, K Kuchenbaeker, K Michailidou, K Tyrer, J Beesley, J Ramus, SJ Li, Q Delgado, MK Lee, JM Aittomäki, K Andrulis, IL Anton-Culver, H Arndt, V Arun, BK Arver, B Bandera, EV Barile, M Barkardottir, RB Barrowdale, D Beckmann, MW Benitez, J Berchuck, A Bisogna, M Bjorge, L Blomqvist, C Blot, W Bogdanova, N Bojesen, A Bojesen, SE Bolla, MK Bonanni, B Børresen-Dale, AL Brauch, H Brennan, P Brenner, H Bruinsma, F Brunet, J Buhari, SA Burwinkel, B Butzow, R Buys, SS Cai, Q Caldes, T Campbell, I Canniotto, R Chang-Claude, J Chiquette, J Choi, JY Claes, KB Cook, LS Cox, A Cramer, DW Cross, SS Cybulski, C Czene, K Daly, MB Damiola, F Dansonka-Mieszkowska, A Darabi, H Dennis, J Devilee, P Diez, O Doherty, JA Domchek, SM Dorfling, CM Dörk, T Dumont, M Ehrencrona, H Ejlertsen, B Ellis, S Engel, C Lee, E Evans, DG Fasching, PA Feliubadalo, L Figueroa, J Flesch-Janys, D Fletcher, O Flyger, H Foretova, L Fostira, F Foulkes, WD Fridley, BL Friedman, E Frost, D Gambino, G Ganz, PA Garber, J García-Closas, M Gentry-Maharaj, A Ghoussaini, M Giles, GG Glasspool, R Godwin, AK Goldberg, MS Goldgar, DE González-Neira, A Goode, EL Goodman, MT Greene, MH Gronwald, J Guénel, P Haiman, CA Hall, P Hallberg, E Hamann, U Hansen, TV Harrington, PA Hartman, M Hassan, N Healey, S Heitz, F Herzog, J Høgdall, E Høgdall, CK Hogervorst, FB Hollestelle, A Hopper, JL Hulick, PJ Huzarski, T Imyanitov, EN Isaacs, C Ito, H Jakubowska, A Janavicius, R Jensen, A John, EM Johnson, N Kabisch, M Kang, D Kapuscinski, M Karlan, BY Khan, S Kiemeney, LA Kjaer, SK Knight, JA Konstantopoulou, I Kosma, VM Kristensen, V Kupryjanczyk, J Kwong, A de la Hoya, M Laitman, Y Lambrechts, D Le, N De Leeneer, K Lester, J Levine, DA Li, J Lindblom, A Long, J Lophatananon, A Loud, JT Lu, K Lubinski, J Mannermaa, A Manoukian, S Le Marchand, L Margolin, S Marme, F Massuger, LF Matsuo, K Mazoyer, S McGuffog, L McLean, C McNeish, I Meindl, A Menon, U Mensenkamp, AR Milne, RL Montagna, M Moysich, KB Muir, K Mulligan, AM Nathanson, KL Ness, RB Neuhausen, SL Nevanlinna, H Nord, S Nussbaum, RL Odunsi, K Offit, K Olah, E Olopade, OI Olson, JE Olswold, C O'Malley, D Orlow, I Orr, N Osorio, A Park, SK Pearce, CL Pejovic, T Peterlongo, P Pfeiler, G Phelan, CM Poole, EM Pylkäs, K Radice, P Rantala, J Rashid, MU Rennert, G Rhenius, V Rhiem, K Risch, HA Rodriguez, G Rossing, MA Rudolph, A Salvesen, HB Sangrajrang, S Sawyer, EJ Schildkraut, JM Schmidt, MK Schmutzler, RK Sellers, TA Seynaeve, C Shah, M Shen, CY Shu, XO Sieh, W Singer, CF Sinilnikova, OM Slager, S Song, H Soucy, P Southey, MC Stenmark-Askmalm, M Stoppa-Lyonnet, D Sutter, C Swerdlow, A Tchatchou, S Teixeira, MR Teo, SH Terry, KL Terry, MB Thomassen, M Tibiletti, MG Tihomirova, L Tognazzo, S Toland, AE Tomlinson, I Torres, D Truong, T Tseng, CC Tung, N Tworoger, SS Vachon, C van den Ouweland, AM van Doorn, HC van Rensburg, EJ Veer, LJ Vanderstichele, A Vergote, I Vijai, J Wang, Q Wang-Gohrke, S Weitzel, JN Wentzensen, N Whittemore, AS Wildiers, H Winqvist, R Wu, AH Yannoukakos, D Yoon, SY Yu, JC Zheng, W Zheng, Y Khanna, KK Simard, J Monteiro, AN French, JD Couch, FJ Freedman, ML Easton, DF Dunning, AM Pharoah, PD Edwards, SL Chenevix-Trench, G Antoniou, AC Gayther, SA Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus. |
| title | Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus. |
| title_full | Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus. |
| title_fullStr | Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus. |
| title_full_unstemmed | Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus. |
| title_short | Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus. |
| title_sort | functional mechanisms underlying pleiotropic risk alleles at the 19p13 1 breast ovarian cancer susceptibility locus |
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