Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element.
Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element.
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DOI：
10.1016/j.ajhg.2021.05.013
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发表时间：
2021-07-01
影响因子：
9.8
通讯作者：
Fletcher O
中科院分区：
文献类型：
--
作者：
Baxter JS;Johnson N;Tomczyk K;Gillespie A;Maguire S;Brough R;Fachal L;Michailidou K;Bolla MK;Wang Q;Dennis J;Ahearn TU;Andrulis IL;Anton-Culver H;Antonenkova NN;Arndt V;Aronson KJ;Augustinsson A;Becher H;Beckmann MW;Behrens S;Benitez J;Bermisheva M;Bogdanova NV;Bojesen SE;Brenner H;Brucker SY;Cai Q;Campa D;Canzian F;Castelao JE;Chan TL;Chang-Claude J;Chanock SJ;Chenevix-Trench G;Choi JY;Clarke CL;NBCS Collaborators;Colonna S;Conroy DM;Couch FJ;Cox A;Cross SS;Czene K;Daly MB;Devilee P;Dörk T;Dossus L;Dwek M;Eccles DM;Ekici AB;Eliassen AH;Engel C;Fasching PA;Figueroa J;Flyger H;Gago-Dominguez M;Gao C;García-Closas M;García-Sáenz JA;Ghoussaini M;Giles GG;Goldberg MS;González-Neira A;Guénel P;Gündert M;Haeberle L;Hahnen E;Haiman CA;Hall P;Hamann U;Hartman M;Hatse S;Hauke J;Hollestelle A;Hoppe R;Hopper JL;Hou MF;kConFab Investigators;ABCTB Investigators;Ito H;Iwasaki M;Jager A;Jakubowska A;Janni W;John EM;Joseph V;Jung A;Kaaks R;Kang D;Keeman R;Khusnutdinova E;Kim SW;Kosma VM;Kraft P;Kristensen VN;Kubelka-Sabit K;Kurian AW;Kwong A;Lacey JV;Lambrechts D;Larson NL;Larsson SC;Le Marchand L;Lejbkowicz F;Li J;Long J;Lophatananon A;Lubiński J;Mannermaa A;Manoochehri M;Manoukian S;Margolin S;Matsuo K;Mavroudis D;Mayes R;Menon U;Milne RL;Mohd Taib NA;Muir K;Muranen TA;Murphy RA;Nevanlinna H;O'Brien KM;Offit K;Olson JE;Olsson H;Park SK;Park-Simon TW;Patel AV;Peterlongo P;Peto J;Plaseska-Karanfilska D;Presneau N;Pylkäs K;Rack B;Rennert G;Romero A;Ruebner M;Rüdiger T;Saloustros E;Sandler DP;Sawyer EJ;Schmidt MK;Schmutzler RK;Schneeweiss A;Schoemaker MJ;Shah M;Shen CY;Shu XO;Simard J;Southey MC;Stone J;Surowy H;Swerdlow AJ;Tamimi RM;Tapper WJ;Taylor JA;Teo SH;Teras LR;Terry MB;Toland AE;Tomlinson I;Truong T;Tseng CC;Untch M;Vachon CM;van den Ouweland AMW;Wang SS;Weinberg CR;Wendt C;Winham SJ;Winqvist R;Wolk A;Wu AH;Yamaji T;Zheng W;Ziogas A;Pharoah PDP;Dunning AM;Easton DF;Pettitt SJ;Lord CJ;Haider S;Orr N;Fletcher O
遗传和功能方法的结合已经在2 q35上确定了三个独立的乳腺癌风险基因座。最近的一项精细定位分析，以完善这些协会导致1（信号1），5（信号2）和42（信号3）在这些位点的可信的因果变异。我们使用公开可用的计算机模拟DNA酶I和ChIP-seq数据以及体外报告基因和CRISPR测定来注释信号2和3。我们鉴定了在两个信号下增强IGFBP 5启动子的细胞类型特异性转录的推定调控元件（在信号2下推定调控元件的表达增加30至40倍，在信号3下推定调控元件的表达增加2至3倍）。我们进一步鉴定了信号2处的5个可信致病变体之一，即1.4 kb缺失（esv 3594306），作为可能的致病变体;该变体的缺失等位基因与IGFBP 5表达平均额外增加1.3倍（MCF-7）和2.2倍（T-47 D）相关。我们提出了一个模型，其中esv 3594306的缺失等位基因并置两个转录因子结合区（由雌激素受体α ChIP-seq峰注释），以产生一个单一的扩展调节元件。这种调控元件增加了肿瘤抑制基因IGFBP 5的细胞类型特异性表达，从而降低了雌激素受体阳性乳腺癌的风险（比值比= 0.77，95%CI 0.74-0.81，p = 3.1 × 10−31）。
A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74–0.81, p = 3.1 × 10−31).
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影响因子：
30.8
作者：
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 JI;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 VM;Mannermaa A;Tseng CC;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 AL;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 AM;Humphreys K;Gao YT;Shu XO;Cox A;Cross SS;Blot W;Cai Q;Ghoussaini M;Perkins BJ;Shah M;Choi JY;Kang D;Lee SC;Hartman M;Kabisch M;Torres D;Jakubowska A;Lubinski J;Brennan P;Sangrajrang S;Ambrosone CB;Toland AE;Shen CY;Wu PE;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 TV;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;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;Sinilnikova OM;Mazoyer S;Isaacs C;Claes KB;De Leeneer K;de la Hoya M;Caldes T;Nevanlinna H;Khan S;Mensenkamp AR;HEBON;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;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 KA;Piedmonte M;Mulligan AM;Glendon G;Bojesen A;Thomassen M;Caligo MA;Yoon SY;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 KT;Helland Å;Haakensen V;Dowsett M;Pharoah PD;Simard J;Hall P;García-Closas M;Vachon C;Chenevix-Trench G;Antoniou AC;Easton DF;Edwards SL
通讯作者：
Edwards SL
影响因子：
64.8
作者：
Michailidou K;Lindström S;Dennis J;Beesley J;Hui S;Kar S;Lemaçon A;Soucy P;Glubb D;Rostamianfar A;Bolla MK;Wang Q;Tyrer J;Dicks E;Lee A;Wang Z;Allen J;Keeman R;Eilber U;French JD;Qing Chen X;Fachal L;McCue K;McCart Reed AE;Ghoussaini M;Carroll JS;Jiang X;Finucane H;Adams M;Adank MA;Ahsan H;Aittomäki K;Anton-Culver H;Antonenkova NN;Arndt V;Aronson KJ;Arun B;Auer PL;Bacot F;Barrdahl M;Baynes C;Beckmann MW;Behrens S;Benitez J;Bermisheva M;Bernstein L;Blomqvist C;Bogdanova NV;Bojesen SE;Bonanni B;Børresen-Dale AL;Brand JS;Brauch H;Brennan P;Brenner H;Brinton L;Broberg P;Brock IW;Broeks A;Brooks-Wilson A;Brucker SY;Brüning T;Burwinkel B;Butterbach K;Cai Q;Cai H;Caldés T;Canzian F;Carracedo A;Carter BD;Castelao JE;Chan TL;David Cheng TY;Seng Chia K;Choi JY;Christiansen H;Clarke CL;NBCS Collaborators;Collée M;Conroy DM;Cordina-Duverger E;Cornelissen S;Cox DG;Cox A;Cross SS;Cunningham JM;Czene K;Daly MB;Devilee P;Doheny KF;Dörk T;Dos-Santos-Silva I;Dumont M;Durcan L;Dwek M;Eccles DM;Ekici AB;Eliassen AH;Ellberg C;Elvira M;Engel C;Eriksson M;Fasching PA;Figueroa J;Flesch-Janys D;Fletcher O;Flyger H;Fritschi L;Gaborieau V;Gabrielson M;Gago-Dominguez M;Gao YT;Gapstur SM;García-Sáenz JA;Gaudet MM;Georgoulias V;Giles GG;Glendon G;Goldberg MS;Goldgar DE;González-Neira A;Grenaker Alnæs GI;Grip M;Gronwald J;Grundy A;Guénel P;Haeberle L;Hahnen E;Haiman CA;Håkansson N;Hamann U;Hamel N;Hankinson S;Harrington P;Hart SN;Hartikainen JM;Hartman M;Hein A;Heyworth J;Hicks B;Hillemanns P;Ho DN;Hollestelle A;Hooning MJ;Hoover RN;Hopper JL;Hou MF;Hsiung CN;Huang G;Humphreys K;Ishiguro J;Ito H;Iwasaki M;Iwata H;Jakubowska A;Janni W;John EM;Johnson N;Jones K;Jones M;Jukkola-Vuorinen A;Kaaks R;Kabisch M;Kaczmarek K;Kang D;Kasuga Y;Kerin MJ;Khan S;Khusnutdinova E;Kiiski JI;Kim SW;Knight JA;Kosma VM;Kristensen VN;Krüger U;Kwong A;Lambrechts D;Le Marchand L;Lee E;Lee MH;Lee JW;Neng Lee C;Lejbkowicz F;Li J;Lilyquist J;Lindblom A;Lissowska J;Lo WY;Loibl S;Long J;Lophatananon A;Lubinski J;Luccarini C;Lux MP;Ma ESK;MacInnis RJ;Maishman T;Makalic E;Malone KE;Kostovska IM;Mannermaa A;Manoukian S;Manson JE;Margolin S;Mariapun S;Martinez ME;Matsuo K;Mavroudis D;McKay J;McLean C;Meijers-Heijboer H;Meindl A;Menéndez P;Menon U;Meyer J;Miao H;Miller N;Taib NAM;Muir K;Mulligan AM;Mulot C;Neuhausen SL;Nevanlinna H;Neven P;Nielsen SF;Noh DY;Nordestgaard BG;Norman A;Olopade OI;Olson JE;Olsson H;Olswold C;Orr N;Pankratz VS;Park SK;Park-Simon TW;Lloyd R;Perez JIA;Peterlongo P;Peto J;Phillips KA;Pinchev M;Plaseska-Karanfilska D;Prentice R;Presneau N;Prokofyeva D;Pugh E;Pylkäs K;Rack B;Radice P;Rahman N;Rennert G;Rennert HS;Rhenius V;Romero A;Romm J;Ruddy KJ;Rüdiger T;Rudolph A;Ruebner M;Rutgers EJT;Saloustros E;Sandler DP;Sangrajrang S;Sawyer EJ;Schmidt DF;Schmutzler RK;Schneeweiss A;Schoemaker MJ;Schumacher F;Schürmann P;Scott RJ;Scott C;Seal S;Seynaeve C;Shah M;Sharma P;Shen CY;Sheng G;Sherman ME;Shrubsole MJ;Shu XO;Smeets A;Sohn C;Southey MC;Spinelli JJ;Stegmaier C;Stewart-Brown S;Stone J;Stram DO;Surowy H;Swerdlow A;Tamimi R;Taylor JA;Tengström M;Teo SH;Beth Terry M;Tessier DC;Thanasitthichai S;Thöne K;Tollenaar RAEM;Tomlinson I;Tong L;Torres D;Truong T;Tseng CC;Tsugane S;Ulmer HU;Ursin G;Untch M;Vachon C;van Asperen CJ;Van Den Berg D;van den Ouweland AMW;van der Kolk L;van der Luijt RB;Vincent D;Vollenweider J;Waisfisz Q;Wang-Gohrke S;Weinberg CR;Wendt C;Whittemore AS;Wildiers H;Willett W;Winqvist R;Wolk A;Wu AH;Xia L;Yamaji T;Yang XR;Har Yip C;Yoo KY;Yu JC;Zheng W;Zheng Y;Zhu B;Ziogas A;Ziv E;ABCTB Investigators;ConFab/AOCS Investigators;Lakhani SR;Antoniou AC;Droit A;Andrulis IL;Amos CI;Couch FJ;Pharoah PDP;Chang-Claude J;Hall P;Hunter DJ;Milne RL;García-Closas M;Schmidt MK;Chanock SJ;Dunning AM;Edwards SL;Bader GD;Chenevix-Trench G;Simard J;Kraft P;Easton DF
通讯作者：
Easton DF
影响因子：
16.6
作者：
Ghoussaini M;Edwards SL;Michailidou K;Nord S;Cowper-Sal Lari R;Desai K;Kar S;Hillman KM;Kaufmann S;Glubb DM;Beesley J;Dennis J;Bolla MK;Wang Q;Dicks E;Guo Q;Schmidt MK;Shah M;Luben R;Brown J;Czene K;Darabi H;Eriksson M;Klevebring D;Bojesen SE;Nordestgaard BG;Nielsen SF;Flyger H;Lambrechts D;Thienpont B;Neven P;Wildiers H;Broeks A;Van't Veer LJ;Th Rutgers EJ;Couch FJ;Olson JE;Hallberg E;Vachon C;Chang-Claude J;Rudolph A;Seibold P;Flesch-Janys D;Peto J;Dos-Santos-Silva I;Gibson L;Nevanlinna H;Muranen TA;Aittomäki K;Blomqvist C;Hall P;Li J;Liu J;Humphreys K;Kang D;Choi JY;Park SK;Noh DY;Matsuo K;Ito H;Iwata H;Yatabe Y;Guénel P;Truong T;Menegaux F;Sanchez M;Burwinkel B;Marme F;Schneeweiss A;Sohn C;Wu AH;Tseng CC;Van Den Berg D;Stram DO;Benitez J;Zamora MP;Perez JI;Menéndez P;Shu XO;Lu W;Gao YT;Cai Q;Cox A;Cross SS;Reed MW;Andrulis IL;Knight JA;Glendon G;Tchatchou S;Sawyer EJ;Tomlinson I;Kerin MJ;Miller N;Haiman CA;Henderson BE;Schumacher F;Le Marchand L;Lindblom A;Margolin S;Teo SH;Yip CH;Lee DS;Wong TY;Hooning MJ;Martens JW;Collée JM;van Deurzen CH;Hopper JL;Southey MC;Tsimiklis H;Kapuscinski MK;Shen CY;Wu PE;Yu JC;Chen ST;Alnæs GG;Borresen-Dale AL;Giles GG;Milne RL;McLean C;Muir K;Lophatananon A;Stewart-Brown S;Siriwanarangsan P;Hartman M;Miao H;Buhari SA;Teo YY;Fasching PA;Haeberle L;Ekici AB;Beckmann MW;Brenner H;Dieffenbach AK;Arndt V;Stegmaier C;Swerdlow A;Ashworth A;Orr N;Schoemaker MJ;García-Closas M;Figueroa J;Chanock SJ;Lissowska J;Simard J;Goldberg MS;Labrèche F;Dumont M;Winqvist R;Pylkäs K;Jukkola-Vuorinen A;Brauch H;Brüning T;Koto YD;Radice P;Peterlongo P;Bonanni B;Volorio S;Dörk T;Bogdanova NV;Helbig S;Mannermaa A;Kataja V;Kosma VM;Hartikainen JM;Devilee P;Tollenaar RA;Seynaeve C;Van Asperen CJ;Jakubowska A;Lubinski J;Jaworska-Bieniek K;Durda K;Slager S;Toland AE;Ambrosone CB;Yannoukakos D;Sangrajrang S;Gaborieau V;Brennan P;McKay J;Hamann U;Torres D;Zheng W;Long J;Anton-Culver H;Neuhausen SL;Luccarini C;Baynes C;Ahmed S;Maranian M;Healey CS;González-Neira A;Pita G;Alonso MR;Alvarez N;Herrero D;Tessier DC;Vincent D;Bacot F;de Santiago I;Carroll J;Caldas C;Brown MA;Lupien M;Kristensen VN;Pharoah PD;Chenevix-Trench G;French JD;Easton DF;Dunning AM;Australian Ovarian Cancer Management Group;Australian Ovarian Cancer Management Group
通讯作者：
Australian Ovarian Cancer Management Group
影响因子：
4.4
作者：
Inoue F;Ahituv N
通讯作者：
Ahituv N
影响因子：
7
作者：
Dryden NH;Broome LR;Dudbridge F;Johnson N;Orr N;Schoenfelder S;Nagano T;Andrews S;Wingett S;Kozarewa I;Assiotis I;Fenwick K;Maguire SL;Campbell J;Natrajan R;Lambros M;Perrakis E;Ashworth A;Fraser P;Fletcher O
通讯作者：
Fletcher O