University of Oulu

Baxter, J. S., Johnson, N., Tomczyk, K., Gillespie, A., Maguire, S., Brough, R., Fachal, L., Michailidou, K., Bolla, M. K., Wang, Q., Dennis, J., Ahearn, T. U., Andrulis, I. L., Anton-Culver, H., Antonenkova, N. N., Arndt, V., Aronson, K. J., Augustinsson, A., Becher, H., … Fletcher, O. (2021). Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element. The American Journal of Human Genetics, 108(7), 1190–1203. https://doi.org/10.1016/j.ajhg.2021.05.013

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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Author: Baxter, Joseph S.1; Johnson, Nichola1; Tomczyk, Katarzyna1;
Gillespie, Andrea1; Maguire, Sarah2; Brough, Rachel1,3; Fachal, Laura4; Michailidou, Kyriaki5,6,7; Bolla, Manjeet K.7; Wang, Qin7; Dennis, Joe7; Ahearn, Thomas U.8; Andrulis, Irene L.9,10; Anton-Culver, Hoda11; Antonenkova, Natalia N.12; Arndt, Volker13; Aronson, Kristan J.14; Augustinsson, Annelie15; Becher, Heiko16; Beckmann, Matthias W.17; Behrens, Sabine18; Benitez, Javier19,20; Bermisheva, Marina21; Bogdanova, Natalia, V12,22,23; Bojesen, Stig E.24,25,26; Brenner, Hermann13,27,28,29; Brucker, Sara Y.30; Cai, Qiuyin31; Campa, Daniele18,32; Canzian, Federico33; Castelao, Jose E.34; Chan, Tsun L.35,36; Chang-Claude, Jenny18,37; Chanock, Stephen J.8; Chenevix-Trench, Georgia38; Choi, Ji-Yeob39,40,41; Clarke, Christine L.42; Collaborators, Nbcs43,44,45,46,47,48,49,50,51,52,53; Colonna, Sarah54; Conroy, Don M.4; Couch, Fergus J.55; Cox, Angela56; Cross, Simon S.57; Czene, Kamila58; Daly, Mary B.59; Devilee, Peter60,61; Doerk, Thilo23; Dossus, Laure62; Dwek, Miriam63; Eccles, Diana M.64; Ekici, Arif B.65; Eliassen, A. Heather66,67,68; Engel, Christoph69,70; Fasching, Peter A.17,71; Figueroa, Jonine8,72,73; Flyger, Henrik74; Gago-Dominguez, Manuela75,76; Gao, Chi68,77; Garcia-Closas, Montserrat8; Garcia-Saenz, Jose A.78; Ghoussaini, Maya4,79; Giles, Graham G.80,81,82; Goldberg, Mark S.83,84; Gonzalez-Neira, Anna20; Guenel, Pascal85; Guendert, Melanie86,87,88; Haeberle, Lothar17; Hahnen, Eric89,90,91; Haiman, Christopher A.92; Hall, Per58,93; Hamann, Ute94; Hartman, Mikael95,96,97; Hatse, Sigrid98; Hauke, Jan89,90,91,99; Hollestelle, Antoinette100; Hoppe, Reiner101,102; Hopper, John L.81; Hou, Ming-Feng103; Ito, Hidemi104,105; Iwasaki, Motoki106; Jager, Agnes100; Jakubowska, Anna107,108; Janni, Wolfgang109; John, Esther M.110,111; Joseph, Vijai112; Jung, Audrey18; Kaaks, Rudolf18; Kang, Daehee113; Keeman, Renske114; Khusnutdinova, Elza21,115; Kim, Sung-Won116; Kosma, Veli-Matti117,118,119; Kraft, Peter68,77; Kristensen, Vessela N.44,120,121; Kubelka-Sabit, Katerina122; Kurian, Allison W.110,111; Kwong, Ava35,123,124,125; Lacey, James, V126,127; Lambrechts, Diether128,129; Larson, Nicole L.130; Larsson, Susanna C.131,132; Le Marchand, Loic133; Lejbkowicz, Flavio134,135; Li, Jingmei97,136; Long, Jirong31; Lophatananon, Artitaya137; LubiNski, Jan107; Mannermaa, Arto117,118,119; Manoochehri, Mehdi94; Manoukian, Siranoush138; Margolin, Sara93,139; Matsuo, Keitaro104,105; Mavroudis, Dimitrios140; Mayes, Rebecca4; Menon, Usha141; Milne, Roger L.80,81,82; Taib, Nur Aishah Mohd142; Muir, Kenneth137; Muranen, Taru A.143; Murphy, Rachel A.144,145; Nevanlinna, Heli143; O'Brien, Katie M.146; Offit, Kenneth112,147; Olson, Janet E.130; Olsson, Hakan15; Park, Sue K.40,113,148; Park-Simon, Tjoung-Won23; Patel, Alpa, V149; Peterlongo, Paolo150; Peto, Julian151; Plaseska-Karanfilska, Dijana152; Presneau, Nadege63; Pylkäs, Katri153,154; Rack, Brigitte109; Rennert, Gad134,135; Romero, Atocha155; Ruebner, Matthias17; Ruediger, Thomas156; Saloustros, Emmanouil157; Sandler, Dale P.146; Sawyer, Elinor J.158; Schmidt, Marjanka K.114,159; Schmutzler, Rita K.89,90,91,99; Schneeweiss, Andreas87,160,161; Schoemaker, Minouk J.162; Shah, Mitul4; Shen, Chen-Yang163,164; Shu, Xiao-Ou31; Simard, Jacques165; Southey, Melissa C.80,82,166; Stone, Jennifer81,167; Surowy, Harald86,87; Swerdlow, Anthony J.162,168; Tamimi, Rulla M.68,169; Tapper, William J.64; Taylor, Jack A.146,170; Teo, Soo Hwang171,172; Teras, Lauren R.149; Terry, Mary Beth173; Toland, Amanda E.174; Tomlinson, Ian175,176,177; Truong, Therese85; Tseng, Chiu-Chen92; Untch, Michael178; Vachon, Celine M.179; van den Ouweland, Ans M. W.180; Wang, Sophia S.126,127; Weinberg, Clarice R.181; Wendt, Camilla139; Winham, Stacey J.182; Winqvist, Robert153,154; Wolk, Alicja131,132; Wu, Anna H.92; Yamaji, Taiki106; Zheng, Wei31; Ziogas, Argyrios11; Pharoah, Paul D. P.4,7; Dunning, Alison M.4; Easton, Douglas F.4,7; Pettitt, Stephen J.1,3; Lord, Christopher J.1,3; Haider, Syed1; Orr, Nick2; Fletcher, Olivia1
Organizations: 1Inst Canc Res, Breast Canc Now Toby Robins Res Ctr, London SW7 3RP, England.
2Queens Univ Belfast, Ctr Canc Res & Cell Biol, Belfast BT7 1NN, Antrim, North Ireland.
3Inst Canc Res, CRUK Gene Funct Lab, London SW3 6JB, England.
4Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge CB1 8RN, England.
5Cyprus Inst Neurol & Genet, Biostat Unit, CY-2371 Nicosia, Cyprus.
6Cyprus Inst Neurol & Genet, Cyprus Sch Mol Med, CY-2371 Nicosia, Cyprus.
7Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England.
8NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Bethesda, MD 20850 USA.
9Mt Sinai Hosp, Fred A Litwin Ctr Canc Genet, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada.
10Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada.
11Univ Calif Irvine, Genet Epidemiol Res Inst, Dept Med, Irvine, CA 92617 USA.
12NN Alexandrov Res Inst Oncol & Med Radiol, Minsk 223040, BELARUS.
13German Canc Res Ctr, Div Clin Epidemiol & Aging Res, D-69120 Heidelberg, Germany.
14Queens Univ, Canc Res Inst, Dept Publ Hlth Sci, Kingston, ON K7L 3N6, Canada.
15Lund Univ, Dept Canc Epidemiol, Clin Sci, S-22242 Lund, Sweden.
16Univ Med Ctr Hamburg Eppendorf, Inst Med Biometry & Epidemiol, D-20246 Hamburg, Germany.
17Friedrich Alexander Univ Erlangen Nuremberg FAU, Univ Hosp Erlangen, Comprehens Canc Ctr Erlangen EMN, Dept Gynecol & Obstet, D-91054 Erlangen, Germany.
18German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany.
19Biomed Network Rare Dis CIBERER, Madrid 28029, Spain.
20Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Programme, Madrid 28029, Spain.
21Russian Acad Sci, Inst Biochem & Genet, Ufa Fed Res Ctr, Ufa 450054, Russia.
22Hannover Med Sch, Dept Radiat Oncol, D-30625 Hannover, Germany.
23Hannover Med Sch, Gynaecol Res Unit, D-30625 Hannover, Germany.
24Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Copenhagen Gen Populat Study, DK-2730 Herlev, Denmark.
25Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Clin Biochem, DK-2730 Herlev, Denmark.
26Univ Copenhagen, Fac Hlth & Med Sci, DK-2200 Copenhagen, Denmark.
27German Canc Res Ctr, Div Prevent Oncol, D-69120 Heidelberg, Germany.
28Natl Ctr Tumor Dis NCT, D-69120 Heidelberg, Germany.
29German Canc Res Ctr, German Canc Consortium DKTK, D-69120 Heidelberg, Germany.
30Univ Tubingen, Dept Gynecol & Obstet, D-72076 Tubingen, Germany.
31Vanderbilt Univ, Vanderbilt Epidemiol Ctr, Vanderbilt Ingram Canc Ctr, Dept Med,Sch Med,Div Epidemiol, Nashville, TN 37232 USA.
32Univ Pisa, Dept Biol, I-56126 Pisa, Italy.
33German Canc Res Ctr, Genom Epidemiol Grp, D-69120 Heidelberg, Germany.
34Inst Invest Sanitaria Galicia Sur IISGS, Oncol & Genet Unit, Xerencia Xest Integrada Vigo SERGAS, Vigo 36312, Spain.
35Hong Kong Hereditary Breast Canc Family Registry, Hong Kong, Peoples R China.
36Hong Kong Sanat & Hosp, Dept Mol Pathol, Hong Kong, Peoples R China.
37Univ Med Ctr Hamburg Eppendorf, Univ Canc Ctr Hamburg UCCH, Canc Epidemiol Grp, D-20246 Hamburg, Germany.
38QIMR Berghofer Med Res Inst, Dept Genet & Computat Biol, Brisbane, Qld 4006, Australia.
39Seoul Natl Univ, Dept Biomed Sci, Grad Sch, Seoul 03080, South Korea.
40Seoul Natl Univ, Canc Res Inst, Seoul 03080, South Korea.
41Seoul Natl Univ, Inst Hlth Policy & Management, Med Res Ctr, Seoul 03080, South Korea.
42Univ Sydney, Westmead Inst Med Res, Sydney, NSW 2145, Australia.
43Oslo Univ Hosp, Inst Canc Res, Dept Canc Genet, Radiumhosp, N-0379 Oslo, Norway.
44Univ Oslo, Fac Med, Inst Clin Med, N-0450 Oslo, Norway.
45Vestre Viken Hosp, Dept Res, N-3019 Drammen, Norway.
46Oslo Univ Hosp Ulleval, Dept Canc, Div Surg Canc & Transplantat Med, Sect Breast & Endocrine Surg, N-0450 Oslo, Norway.
47Oslo Univ Hosp, Dept Radiol & Nucl Med, N-0379 Oslo, Norway.
48Akershus Univ Hosp, Dept Pathol, N-1478 Lorenskog, Norway.
49Oslo Univ Hosp, Inst Canc Res, Dept Tumor Biol, N-0379 Oslo, Norway.
50Oslo Univ Hosp Radiumhosp, Dept Oncol, Div Surg Canc & Transplantat Med, N-0379 Oslo, Norway.
51Oslo Univ Hosp, Natl Advisory Unit Late Effects Canc Treatment, Radiumhosp, N-0379 Oslo, Norway.
52Akershus Univ Hosp, Dept Oncol, N-1478 Lorenskog, Norway.
53Oslo Univ Hosp, Breast Canc Res Consortium, N-0379 Oslo, Norway.
54Huntsman Canc Inst, Dept Med, Salt Lake City, UT 84112 USA.
55Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA.
56Univ Sheffield, Sheffield Inst Nucle Acids SInFoNiA, Dept Oncol & Metab, Sheffield S10 2TN, S Yorkshire, England.
57Univ Sheffield, Acad Unit Pathol, Dept Neurosci, Sheffield S10 2TN, S Yorkshire, England.
58Karolinska Inst, Dept Med Epidemiol & Biostat, S-17165 Stockholm, Sweden.
59Fox Chase Canc Ctr, Dept Clin Genet, Philadelphia, PA 19111 USA.
60Leiden Univ Med Ctr, Dept Pathol, NL-2333 ZA Leiden, Netherlands.
61Leiden Univ Med Ctr, Dept Human Genet, NL-2333 ZA Leiden, Netherlands.
62Int Agcy Res Canc IARC WHO, Nutr & Metab Sect, F-69372 Lyon, France.
63Univ Westminster, Sch Life Sci, London W1B 2HW, England.
64Univ Southampton, Fac Med, Southampton SO17 1BJ, Hants, England.
65Friedrich Alexander Univ Erlangen Nuremberg, Univ Hosp Erlangen, Comprehens Canc Ctr Erlangen EMN, Inst Human Genet, D-91054 Erlangen, Germany.
66Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA.
67Harvard Med Sch, Boston, MA 02115 USA.
68Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.
69Univ Leipzig, Inst Med Informat Stat & Epidemiol, D-04107 Leipzig, Germany.
70Univ Leipzig, LIFE Leipzig Res Ctr Civilizat Dis, D-04103 Leipzig, Germany.
71Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA.
72Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh EH16 4UX, Midlothian, Scotland.
73Univ Edinburgh, Canc Res UK Edinburgh Ctr, Edinburgh EH4 2XR, Midlothian, Scotland.
74Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Breast Surg, DK-2730 Herlev, Denmark.
75Complejo Hosp Univ Santiago, SERGAS, Inst Invest Sanitaria Santiago de Compostela IDIS, Fdn Publ Galega Med Xenom, Santiago De Compostela 15706, Spain.
76Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92037 USA.
77Harvard TH Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA.
78Hosp Clin San Carlos, Inst Invest Sanitaria San Carlos IdISSC, Ctr Invest Biomed Red Canc CIBERONC, Med Oncol Dept, Madrid 28040, Spain.
79Wellcome Sanger Inst, Core Genet Team, Open Targets, Cambridge CB10 1SA, England.
80Canc Council Victoria, Canc Epidemiol Div, Melbourne, Vic 3004, Australia.
81Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne Sch Populat & Global Hlth, Melbourne, Vic 3010, Australia.
82Monash Univ, Sch Clin Sci, Precis Med, Monash Hlth, Clayton, Vic 3168, Australia.
83McGill Univ, Dept Med, Montreal, PQ H4A 3J1, Canada.
84McGill Univ, Royal Victoria Hosp, Div Clin Epidemiol, Montreal, PQ H4A 3J1, Canada.
85Univ Paris Saclay, Ctr Res Epidemiol & Populat Hlth CESP, INSERM, Team Exposome & Hered, F-94805 Villejuif, France.
86German Canc Res Ctr, Mol Epidemiol Grp, C080, D-69120 Heidelberg, Germany.
87Heidelberg Univ, Univ Womens Clin Heidelberg, Mol Biol Breast Canc, D-69120 Heidelberg, Germany.
88Helmholtz Zentrum Munchen, Inst Diabet Res, German Res Ctr Environm Hlth, D-85764 Neuherberg, Germany.
89Univ Cologne, Fac Med, Ctr Familial Breast & Ovarian Canc, D-50937 Cologne, Germany.
90Univ Cologne, Univ Hosp Cologne, D-50937 Cologne, Germany.
91Univ Cologne, Fac Med, Ctr Integrated Oncol CIO, D-50937 Cologne, Germany.
92Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA.
93Soder Sjukhuset, Dept Oncol, S-11883 Stockholm, Sweden.
94German Canc Res Ctr, Mol Genet Breast Canc, D-69120 Heidelberg, Germany.
95Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 119077, Singapore.
96Natl Univ Singapore Hosp, Dept Surg, Singapore 119228, Singapore.
97Natl Univ Singapore, Yong Loo Lin Sch Med, Singapore 119077, Singapore.
98Katholieke Univ Leuven, Dept Oncol, Lab Expt Oncol LEO, Leuven Canc Inst, B-3000 Leuven, Belgium.
99Univ Cologne, Fac Med, Ctr Mol Med Cologne CMMC, D-50931 Cologne, Germany.
100Erasmus MC Canc Inst, Dept Med Oncol, NL-3015 GD Rotterdam, Netherlands.
101Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-70376 Stuttgart, Germany.
102Univ Tubingen, D-72074 Tubingen, Germany.
103Kaohsiung Municipal Hsiaokang Hosp, Dept Surg, Kaohsiung 812, Taiwan.
104Aichi Canc Ctr Res Inst, Div Canc Epidemiol & Prevent, Nagoya, Aichi 4648681, Japan.
105Nagoya Univ, Div Canc Epidemiol, Grad Sch Med, Nagoya, Aichi 4668550, Japan.
106Natl Canc Ctr, Ctr Publ Hlth Sci, Div Epidemiol, Tokyo 1040045, Japan.
107Pomeranian Med Univ, Dept Genet & Pathol, PL-71252 Szczecin, Poland.
108Pomeranian Med Univ, Independent Lab Mol Biol & Genet Diagnost, PL-71252 Szczecin, Poland.
109Univ Hosp Ulm, Dept Gynaecol & Obstet, D-89075 Ulm, Germany.
110Stanford Univ, Dept Epidemiol & Populat Hlth, Sch Med, Stanford, CA 94305 USA.
111Stanford Univ, Stanford Canc Inst, Dept Med, Div Oncol,Sch Med, Stanford, CA 94304 USA.
112Mem Sloan Kettering Canc Ctr, Dept Canc Biol & Genet, Clin Genet Res Lab, New York, NY 10065 USA.
113Seoul Natl Univ, Dept Prevent Med, Coll Med, Seoul 03080, South Korea.
114Antoni van Leeuwenhoek Hosp, Div Mol Pathol, Netherlands Canc Inst, NL-1066 CX Amsterdam, Netherlands.
115Bashkir State Univ, Dept Genet & Fundamental Med, Ufa 450000, Russia.
116Daerim St Marys Hosp, Dept Surg, Seoul 07442, South Korea.
117Univ Eastern Finland, Translat Canc Res Area, Kuopio 70210, Finland.
118Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Kuopio 70210, Finland.
119Kuopio Univ Hosp, Biobank Eastern Finland, Kuopio, Finland.
120Oslo Univ Hosp, Dept Med Genet, N-0379 Oslo, Norway.
121Univ Oslo, N-0379 Oslo, Norway.
122Clin Hosp Acibadem Sistina, Dept Histopathol & Cytol, Skopje 1000, North Macedonia.
123Univ Hong Kong, Dept Surg, Hong Kong, Peoples R China.
124Hong Kong Sanat & Hosp, Dept Surg, Hong Kong, Peoples R China.
125Hong Kong Sanat & Hosp, Canc Genet Ctr, Hong Kong, Peoples R China.
126City Hope Natl Med Ctr, Dept Computat & Quantitat Med, Duarte, CA 91010 USA.
127City Hope Natl Med Ctr, City Hope Comprehens Canc Ctr, Duarte, CA 91010 USA.
128VIB Ctr Canc Biol, B-3001 Leuven, Belgium.
129Univ Leuven, Dept Human Genet, Lab Translat Genet, B-3000 Leuven, Belgium.
130Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA.
131Karolinska Inst, Inst Environm Med, S-17177 Stockholm, Sweden.
132Uppsala Univ, Dept Surg Sci, S-75105 Uppsala, Sweden.
133Univ Hawaii Canc Ctr, Epidemiol Program, Honolulu, HI 96813 USA.
134Carmel Hosp, Clalit Natl Canc Control Ctr, IL-35254 Haifa, Israel.
135Technion Fac Med, IL-35254 Haifa, Israel.
136Genome Inst Singapore, Human Genet Div, Singapore 138672, Singapore.
137Univ Manchester, Fac Biol Med & Hlth, Sch Hlth Sci, Div Populat Hlth Hlth Serv Res & Primary Care, Manchester M13 9PL, Lancs, England.
138Fdn IRCCS Ist Nazl Tumori Milano, Dept Med Oncol & Hematol, Unit Med Genet, I-20133 Milan, Italy.
139Karolinska Inst, Dept Clin Sci & Educ, Sodersjukhuset, S-11883 Stockholm, Sweden.
140Univ Hosp Heraklion, Dept Med Oncol, Iraklion 71110, Greece.
141UCL, Inst Clin Trials & Methodol, London WC1V 6LJ, England.
142Univ Malaya, Univ Malaya Canc Res Inst, Fac Med, Breast Canc Res Unit, Kuala Lumpur 50603, Malaysia.
143Univ Helsinki, Helsinki Univ Hosp, Dept Obstet & Gynecol, Helsinki 00290, Finland.
144Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC V6T 1Z4, Canada.
145BC Canc, Canc Control Res, Vancouver, BC V5Z 1L3, Canada.
146NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA.
147Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Serv, New York, NY 10065 USA.
148Seoul Natl Univ, Coll Med, Convergence Grad Program Innovat Med Sci, Seoul 03080, South Korea.
149Amer Canc Soc, Dept Populat Sci, Atlanta, GA 30303 USA.
150IFOM FIRC Inst Mol Oncol, Genome Diagnost Program, I-20139 Milan, Italy.
151London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London WC1E 7HT, England.
152MASA, Res Ctr Genet Engn & Biotechnol Georgi D Efremov, Skopje 1000, North Macedonia.
153Univ Oulu, Bioctr Oulu, Canc & Translat Med Res Unit, Lab Canc Genet & Tumor Biol, Oulu 90570, Finland.
154Northern Finland Lab Ctr Oulu, Lab Canc Genet & Tumor Biol, Oulu 90570, Finland.
155Hosp Univ Puerta de Hierro, Med Oncol Dept, Madrid 28222, Spain.
156Staedtisches Klinikum Karlsruhe, Inst Pathol, D-76133 Karlsruhe, Germany.
157Univ Hosp Larissa, Dept Oncol, Larisa 41110, Greece.
158Kings Coll London, Comprehens Canc Ctr, Sch Canc & Pharmaceut Sci, Guys Campus, London, England.
159Antoni van Leeuwenhoek Hosp, Div Psychosocial Res & Epidemiol, Netherlands Canc Inst, NL-1066 CX Amsterdam, Netherlands.
160Univ Hosp, Natl Ctr Tumor Dis, D-69120 Heidelberg, Germany.
161German Canc Res Ctr, D-69120 Heidelberg, Germany.
162Inst Canc Res, Div Genet & Epidemiol, London SM2 5NG, England.
163Acad Sinica, Inst Biomed Sci, Taipei 115, Taiwan.
164China Med Univ, Sch Publ Hlth, Taichung, Taiwan.
165Univ Laval, Genom Ctr, Ctr Hosp Univ Quebec, Res Ctr, Quebec City, PQ G1V 4G2, Canada.
166Univ Melbourne, Dept Clin Pathol, Melbourne, Vic 3010, Australia.
167Univ Western Australia, Sch Populat & Global Hlth, Genet Epidemiol Grp, Perth, WA 6000, Australia.
168Inst Canc Res, Div Breast Canc Res, London SW7 3RP, England.
169Weill Cornell Med, Dept Populat Hlth Sci, New York, NY 10065 USA.
170NIEHS, Epigenet & Stem Cell Biol Lab, NIH, Res Triangle Pk, NC 27709 USA.
171Canc Res Malaysia, Breast Canc Res Programme, Subang Jaya 47500, Selangor, Malaysia.
172Univ Malaya, Fac Med, Dept Surg, Kuala Lumpur 50603, Malaysia.
173Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA.
174Ohio State Univ, Dept Canc Biol & Genet, Columbus, OH 43210 USA.
175Univ Birmingham, Inst Canc & Genom Sci, Birmingham B15 2TT, W Midlands, England.
176Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.
177Univ Oxford, Oxford NIHR Biomed Res Ctr, Oxford OX3 7BN, England.
178Helios Clin Berlin Buch, Dept Gynecol & Obstet, D-13125 Berlin, Germany.
179Mayo Clin, Div Epidemiol, Dept Hlth Sci Res, Rochester, MN 55905 USA.
180Erasmus MC, Dept Clin Genet, NL-3015 GD Rotterdam, Netherlands.
181NIEHS, Biostat & Computat Biol Branch, NIH, Res Triangle Pk, NC 27709 USA.
182Mayo Clin, Div Biomed Stat & Informat, Dept Hlth Sci Res, Rochester, MN 55905 USA.
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.6 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2022040827781
Language: English
Published: Elsevier, 2021
Publish Date: 2022-04-08
Description:

Abstract

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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Series: American journal of human genetics
ISSN: 0002-9297
ISSN-E: 1537-6605
ISSN-L: 0002-9297
Volume: 108
Issue: 7
Pages: 1190 - 1203
DOI: 10.1016/j.ajhg.2021.05.013
OADOI: https://oadoi.org/10.1016/j.ajhg.2021.05.013
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
3122 Cancers
Subjects:
Funding: M.W.B. conducts research funded by Amgen, Novartis, and Pfizer. P.A.F. conducts research funded by Amgen, Novartis, and Pfizer and received honoraria from Roche, Novartis, and Pfizer. A.W.K. received research funding to her institution from Myriad Genetics for an unrelated project other authors declare no conflict of interest.
Copyright information: © 2021 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
  https://creativecommons.org/licenses/by/4.0/