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Stevens KN , Fredericksen Z , Vachon CM , Wang X , Margolin S , Lindblom A , Nevanlinna H , Greco D , Aittomaki K , Blomqvist C , Chang-Claude J , Vrieling A , Flesch-Janys D , Sinn HP , Wang-Gohrke S , Nickels S , Brauch H , Genica Network , Ko YD , Fischer HP , Schmutzler RK , Meindl A , Bartram CR , Schott S , Engel C , Godwin AK , Weaver J , Pathak HB , Sharma P , Brenner H , Muller H , Arndt V , Stegmaier C , Miron P , Yannoukakos D , Stavropoulou A , Fountzilas G , Gogas HJ , Swann R , Dwek M , Perkins A , Milne RL , Benitez J , Zamora MP , Perez JI , Bojesen SE , Nielsen SF , Nordestgaard BG , Flyger H , Guenel P , Truong T , Menegaux F , Cordina-Duverger E , Burwinkel B , Marme F , Schneeweiss A , Sohn C , Sawyer E , Tomlinson I , Kerin MJ , Peto J , Johnson N , Fletcher O , Dos Santos Silva I , Fasching PA , Beckmann MW , Hartmann A , Ekici AB , Lophatananon A , Muir K , Puttawibul P , Wiangnon S , Schmidt MK , Broeks A , Braaf LM , Rosenberg EH , Hopper JL , Apicella C , Park DJ , Southey MC , Swerdlow AJ , Ashworth A , Orr N , Schoemaker MJ , Anton-Culver H , Ziogas A , Bernstein L , Dur CC , Shen CY , Yu JC , Hsu HM , Hsiung CN , Hamann U , Dunnebier T , Rudiger T , Ulmer HU , Pharoah PP , Dunning AM , Humphreys MK , Wang Q , Cox A , Cross SS , Reed MW , Hall P , Czene K , Ambrosone CB , Ademuyiwa F , Hwang H , Eccles DM , Garcia-Closas M , Figueroa JD , Sherman ME , Lissowska J , Devilee P , Seynaeve C , Tollenaar RA , Hooning MJ , Andrulis IL , Knight JA , Glendon G , Mulligan AM , Winqvist R , Pylkas K , Jukkola-Vuorinen A , Grip M , John EM , Miron A , Alnaes GG , Kristensen V , Borresen-Dale AL , Giles GG , Baglietto L , McLean CA , Severi G , Kosel ML , Pankratz VS , Slager S , Olson JE , Radice P , Peterlongo P , Manoukian S , Barile M , Lambrechts D , Hatse S , Dieudonne AS , Christiaens MR , Chenevix-Trench G , kConFab Investigators , Aocs Group , Beesley J , Chen X , Mannermaa A , Kosma VM , Hartikainen JM , Soini Y , Easton DF , Couch FJ
19p13.1 is a triple-negative-specific breast cancer susceptibility locus
Cancer Res. 2012 Apr 1;72(7) :1795-803
PMID: 22331459    PMCID: PMC33199792    URL: https://www.ncbi.nlm.nih.gov/pubmed/22331459
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Abstract
The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05-1.15; P = 3.49 x 10(-5)] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13-1.31; P = 2.22 x 10(-7)). However, rs8170 was no longer associated with ER-negative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89-1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18-1.33; P = 3.31 x 10(-13)]. Thus, 19p13.1 is the first triple-negative-specific breast cancer risk locus and the first locus specific to a histologic subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple-negative tumors and other subtypes likely arise through distinct etiologic pathways.
Notes
Stevens, Kristen N Fredericksen, Zachary Vachon, Celine M Wang, Xianshu Margolin, Sara Lindblom, Annika Nevanlinna, Heli Greco, Dario Aittomaki, Kristiina Blomqvist, Carl Chang-Claude, Jenny Vrieling, Alina Flesch-Janys, Dieter Sinn, Hans-Peter Wang-Gohrke, Shan Nickels, Stefan Brauch, Hiltrud Ko, Yon-Dschun Fischer, Hans-Peter Schmutzler, Rita K Meindl, Alfons Bartram, Claus R Schott, Sarah Engel, Christoph Godwin, Andrew K Weaver, Joellen Pathak, Harsh B Sharma, Priyanka Brenner, Hermann Muller, Heiko Arndt, Volker Stegmaier, Christa Miron, Penelope Yannoukakos, Drakoulis Stavropoulou, Alexandra Fountzilas, George Gogas, Helen J Swann, Ruth Dwek, Miriam Perkins, Annie Milne, Roger L Benitez, Javier Zamora, Maria Pilar Perez, Jose Ignacio Arias Bojesen, Stig E Nielsen, Sune F Nordestgaard, Borge G Flyger, Henrik Guenel, Pascal Truong, Therese Menegaux, Florence Cordina-Duverger, Emilie Burwinkel, Barbara Marme, Frederick Schneeweiss, Andreas Sohn, Christof Sawyer, Elinor Tomlinson, Ian Kerin, Michael J Peto, Julian Johnson, Nichola Fletcher, Olivia Dos Santos Silva, Isabel Fasching, Peter A Beckmann, Matthias W Hartmann, Arndt Ekici, Arif B Lophatananon, Artitaya Muir, Kenneth Puttawibul, Puttisak Wiangnon, Surapon Schmidt, Marjanka K Broeks, Annegien Braaf, Linde M Rosenberg, Efraim H Hopper, John L Apicella, Carmel Park, Daniel J Southey, Melissa C Swerdlow, Anthony J Ashworth, Alan Orr, Nicholas Schoemaker, Minouk J Anton-Culver, Hoda Ziogas, Argyrios Bernstein, Leslie Dur, Christina Clarke Shen, Chen-Yang Yu, Jyh-Cherng Hsu, Huan-Ming Hsiung, Chia-Ni Hamann, Ute Dunnebier, Thomas Rudiger, Thomas Ulmer, Hans Ulrich Pharoah, Paul P Dunning, Alison M Humphreys, Manjeet K Wang, Qin Cox, Angela Cross, Simon S Reed, Malcom W Hall, Per Czene, Kamila Ambrosone, Christine B Ademuyiwa, Foluso Hwang, Helena Eccles, Diana M Garcia-Closas, Montserrat Figueroa, Jonine D Sherman, Mark E Lissowska, Jolanta Devilee, Peter Seynaeve, Caroline Tollenaar, Rob A E M Hooning, Maartje J Andrulis, Irene L Knight, Julia A Glendon, Gord Mulligan, Anna Marie Winqvist, Robert Pylkas, Katri Jukkola-Vuorinen, Arja Grip, Mervi John, Esther M Miron, Alexander Alnaes, Grethe Grenaker Kristensen, Vessela Borresen-Dale, Anne-Lise Giles, Graham G Baglietto, Laura McLean, Catriona A Severi, Gianluca Kosel, Matthew L Pankratz, V S Slager, Susan Olson, Janet E Radice, Paolo Peterlongo, Paolo Manoukian, Siranoush Barile, Monica Lambrechts, Diether Hatse, Sigrid Dieudonne, Anne-Sophie Christiaens, Marie-Rose Chenevix-Trench, Georgia Beesley, Jonathan Chen, Xiaoqing Mannermaa, Arto Kosma, Veli-Matti Hartikainen, Jaana M Soini, Ylermi Easton, Douglas F Couch, Fergus J eng CA116201/CA/NCI NIH HHS/ U01 CA69417/CA/NCI NIH HHS/ RFA-CA-06-503/CA/NCI NIH HHS/ CA92044/CA/NCI NIH HHS/ C490/A10124/CRUK_/Cancer Research UK/United Kingdom R01 CA77398/CA/NCI NIH HHS/ U01 CA69631/CA/NCI NIH HHS/ C8197/A10865/CRUK_/Cancer Research UK/United Kingdom P30 CA016056-32/CA/NCI NIH HHS/ CA122340/CA/NCI NIH HHS/ 5U01 CA113916/CA/NCI NIH HHS/ C8197/A10123/CRUK_/Cancer Research UK/United Kingdom C1287/A12014/CRUK_/Cancer Research UK/United Kingdom CA58860/CA/NCI NIH HHS/ U01 CA69638/CA/NCI NIH HHS/ ImNIH/Intramural NIH HHS/ C1287/A10118/CRUK_/Cancer Research UK/United Kingdom U01 CA69467/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Cancer Res. 2012 Apr 1;72(7):1795-803. doi: 10.1158/0008-5472.CAN-11-3364. Epub 2012 Feb 13.