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Blein, Sophie ; Bardel, Claire ; Danjean, Vincent ; McGuffog, Lesley ; Healay, Sue ; Barrowdale, Daniel ; Lee, Andrew ; Dennis, Joe ; Kuchenbaecker, Karoline B. ; Soucy, Penny ; Terry, Mary Beth ; Chung, Wendy K. ; Goldgar, David E. ; Buys, Saundra S. ; Janavicius, Ramunas ; Tihomirova, Laima ; Tung, Nadine ; Dorfling, Cecilia M. ; van Rensburg, Elizabeth J. ; Neuhausen, Susan L. ; Ding, Yuan Chun ; Gerdes, Anne-Marie ; Ejlertsen, Bent ; Nielsen, Finn C. ; Hansen, Thomas V. O. ; Osorio, Ana ; Benitez, Javier ; Andreas Conejero, Raquel ; Segota, Ena ; Weitzel, Jeffrey N. ; Thelander, Margo ; Peterlongo, Paolo ; Radice, Paolo ; Pensotti, Valeria ; Dolcetti, Riccardo ; Bonanni, Bernardo ; Peissel, Bernard ; Zaffaroni, Daniela ; Scuvera, Giulietta ; Manoukian, Siranoush ; Varesco, Liliana ; Capone, Gabriele L. ; Papi, Laura ; Ottini, Laura ; Yannoukakos, Drakoulis ; Konstantopoulou, Irene ; Garber, Judy ; Hamann, Ute ; Donaldson, Alan ; Brady, Angela ; Brewer, Carole ; Foo, Claire ; Evans, D. Gareth ; Frost, Debra ; Eccles, Diana ; Douglas, Fiona ; Cook, Jackie ; Adlard, Julian ; Barwell, Julian ; Walker, Lisa ; Izatt, Louise ; Side, Lucy E. ; Kennedy, M. John ; Tischkowitz, Marc ; Rogers, Mark T. ; Porteous, Mary E. ; Morrison, Patrick J. ; Platte, Radka ; Eeles, Ros ; Davidson, Rosemarie ; Hodgson, Shirley ; Cole, Trevor ; Godwin, Andrew K ; Isaacs, Claudine ; Claes, Kathleen ; De Leeneer, Kim ; Meindl, Alfons ; Gehrig, Andrea ; Wappenschmidt, Barbara ; Sutter, Christian ; Engel, Christoph ; Niederacher, Dieter ; Steinemann, Doris ; Plendl, Hansjoerg ; Kast, Karin ; Rhiem, Kerstin ; Ditsch, Nina ; Arnold, Norbert ; Varon-Mateeva, Raymonda ; Schmutzler, Rita K. ; Preisler-Adams, Sabine ; Markov, Nadja Bogdanova ; Wang-Gohrke, Shan ; de Pauw, Antoine ; Lefol, Cedrick ; Lasset, Christine ; Leroux, Dominique ; Rouleau, Etienne ; Damiola, Francesca ; Dreyfus, Helene ; Barjhoux, Laure ; Golmard, Lisa ; Uhrhammer, Nancy ; Bonadona, Valerie ; Sornin, Valerie ; Bignon, Yves-Jean ; Carter, Jonathan ; Van Le, Linda ; Piedmonte, Marion ; DiSilvestro, Paul A. ; de la Hoya, Miguel ; Caldes, Trinidad ; Nevanlinna, Heli ; Aittomäki, Kristiina ; Jager, Agnes ; van den Ouweland, Ans M. W. ; Kets, Carolien M. ; Aalfs, Cora M. ; van Leeuwen, Flora E. ; Hogervorst, Frans B. L. ; Meijers-Heijboer, Hanne E. J. ; Oosterwijk, Jan C. ; van Roozendaal, Kees E. P. ; Rookus, Matti A. ; Devilee, Peter ; van der Luijt, Rob B. ; Olah, Edith ; Diez, Orland ; Teule, Alex ; Lazaro, Conxi ; Blanco, Ignacio ; Del Valle, Jesus ; Jakubowska, Anna ; Sukiennicki, Grzegorz ; Gronwald, Jacek ; Spurdle, Amanda B. ; Foulkes, William ; Olswold, Curtis ; Lindor, Noralene M. ; Pankratz, Vernon S. ; Szabo, Csilla I. ; Lincoln, Anne ; Jacobs, Lauren ; Corines, Marina ; Robson, Mark ; Vijai, Joseph ; Berger, Andreas ; Fink-Retter, Anneliese ; Singer, Christian F. ; Rappaport, Christine ; Geschwantler Kaulich, Daphne ; Pfeiler, Georg ; Tea, Muy-Kheng ; Greene, Mark H. ; Mai, Phuong L. ; Rennert, Gad ; Imyanitov, Evgeny N. ; Mulligan, Anna Marie ; Glendon, Gord ; Andrulis, Irene L. ; Tchatchou, Andrine ; Toland, Amanda Ewart ; Pedersen, Inge Sokilde ; Thomassen, Mads ; Kruse, Torben A. ; Jensen, Uffe Birk ; Caligo, Maria A. ; Friedman, Eitan ; Zidan, Jamal ; Laitman, Yael ; Lindblom, Annika ; Melin, Beatrice ; Arver, Brita ; Loman, Niklas ; Rosenquist, Richard ; Olopade, Olufunmilayo I. ; Nussbaum, Robert L. ; Ramus, Susan J. ; Nathanson, Katherine L. ; Domchek, Susan M. ; Rebbeck, Timothy R. ; Arun, Banu K. ; Mitchell, Gillian ; Karlan, Bethy Y. ; Lester, Jenny ; Orsulic, Sandra ; Stoppa-Lyonnet, Dominique ; Thomas, Gilles ; Simard, Jacques ; Couch, Fergus J. ; Offit, Kenenth ; Easton, Douglas F. ; Chenevix-Trench, Georgia ; Antoniou, Antonis C. ; Mazoyer, Sylvie ; Phelan, Catherine M. ; Sinilnikova, Olga M. ; Cox, David G.
Introduction:
Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers.
Methods:
We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals.
Results:
We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk.
Conclusions:
This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.
Ferreira, Manuel A. ; Gamazon, Eric R. ; Al-Ejeh, Fares ; Aittomäki, Kristiina ; Andrulis, Irene L. ; Anton-Culver, Hoda ; Arason, Adalgeir ; Arndt, Volker ; Aronson, Kristan J. ; Arun, Banu K. ; Asseryanis, Ella ; Azzollini, Jacopo ; Balmaña, Judith ; Barnes, Daniel R. ; Barrowdale, Daniel ; Beckmann, Matthias W. ; Behrens, Sabine ; Benitez, Javier ; Bermisheva, Marina ; Bialkowska, Katarzyna ; Blomqvist, Carl ; Bogdanova, Natalia V. ; Bojesen, Stig E. ; Bolla, Manjeet K. ; Borg, Ake ; Brauch, Hiltrud ; Brenner, Hermann ; Broeks, Annegien ; Burwinkel, Barbara ; Caldés, Trinidad ; Caligo, Maria A. ; Campa, Daniele ; Campbell, Ian ; Canzian, Federico ; Carter, Jonathan ; Carter, Brian D. ; Castelao, Jose E. ; Chang-Claude, Jenny ; Chanock, Stephen J. ; Christiansen, Hans ; Chung, Wendy K. ; Claes, Kathleen B. M. ; Clarke, Christine L. ; Couch, Fergus J. ; Cox, Angela ; Cross, Simon S. ; Czene, Kamila ; Daly, Mary B. ; de la Hoya, Miguel ; Dennis, Joe ; Devilee, Peter ; Diez, Orland ; Dörk, Thilo ; Dunning, Alison M. ; Dwek, Miriam ; Eccles, Diana M. ; Ejlertsen, Bent ; Ellberg, Carolina ; Engel, Christoph ; Eriksson, Mikael ; Fasching, Peter A. ; Fletcher, Olivia ; Flyger, Henrik ; Friedman, Eitan ; Frost, Debra ; Gabrielson, Marike ; Gago-Dominguez, Manuela ; Ganz, Patricia A. ; Gapstur, Susan M. ; Garber, Judy ; García-Closas, Montserrat ; García-Sáenz, José A. ; Gaudet, Mia M. ; Giles, Graham G. ; Glendon, Gord ; Godwin, Andrew K. ; Goldberg, Mark S. ; Goldgar, David E. ; González-Neira, Anna ; Greene, Mark H. ; Gronwald, Jacek ; Guenél, Pascal ; Haimann, Christopher A. ; Hall, Per ; Hamann, Ute ; He, Wei ; Heyworth, Jane ; Hogervorst, Frans B. L. ; Hollestelle, Antoinette ; Hoover, Robert N. ; Hopper, John L. ; Hulick, Peter J. ; Humphreys, Keith ; Imyanitov, Evgeny N. ; Isaacs, Claudine ; Jakimovska, Milena ; Jakubowska, Anna ; James, Paul A. ; Janavicius, Ramunas ; Jankowitz, Rachel C. ; John, Esther M. ; Johnson, Nichola ; Joseph, Vijai ; Karlan, Beth Y. ; Khusnutdinova, Elza ; Kiiski, Johanna I. ; Ko, Yon-Dschun ; Jones, Michael E. ; Konstantopoulou, Irene ; Kristensen, Vessela N. ; Laitman, Yael ; Lambrechts, Diether ; Lazaro, Conxi ; Leslie, Goska ; Lester, Jenny ; Lesueur, Fabienne ; Lindström, Sara ; Long, Jirong ; Loud, Jennifer T. ; Lubiński, Jan ; Makalic, Enes ; Mannermaa, Arto ; Manoochehri, Mehdi ; Margolin, Sara ; Maurer, Tabea ; Mavroudis, Dimitrios ; McGuffog, Lesley ; Meindl, Alfons ; Menon, Usha ; Michailidou, Kyriaki ; Miller, Austin ; Montagna, Marco ; Moreno, Fernando ; Moserle, Lidia ; Mulligan, Anna Marie ; Nathanson, Katherine L. ; Neuhausen, Susan L. ; Nevanlinna, Heli ; Nevelsteen, Ines ; Nielsen, Finn C. ; Nikitina-Zake, Liene ; Nussbaum, Robert L. ; Offit, Kenneth ; Olah, Edith ; Olopade, Olufunmilayo I. ; Olsson, Håkan ; Osorio, Ana ; Papp, Janos ; Park-Simon, Tjoung-Won ; Parsons, Michael T. ; Pedersen, Inge Sokilde ; Peixoto, Ana ; Peterlongo, Paolo ; Pharaoh, Paul D. P. ; Plaseska-Karanfilska, Dijana ; Poppe, Bruce ; Presneau, Nadege ; Radice, Paolo ; Rantala, Johanna ; Rennert, Gad ; Risch, Harvey A. ; Saloustros, Emmanouil ; Sanden, Kristin ; Sawyer, Elinor J. ; Schmidt, Marjanka K. ; Schmutzler, Rita K. ; Sharma, Priyanka ; Shu, Xiao-Ou ; Simard, Jaques ; Singer, Christian F. ; Soucy, Penny ; Southey, Melissa C. ; Spinelli, John J. ; Spurdle, Amanda B. ; Stone, Jennifer ; Swerdlow, Anthony J. ; Tapper, William J. ; Taylor, Jack A. ; Teixeira, Manuel R. ; Terry, Mary Beth ; Teulé, Alex ; Thomassen, Mads ; Thöne, Kathrin ; Thull, Darcy L. ; Tischkowitz, Marc ; Toland, Amanda E. ; Torres, Diana ; Truong, Thérèse ; Tung, Nadine ; Vachon, Celine M. ; van Asperen, Christi J. ; van den Ouweland, Ans M. W. ; van Rensburg, Elizabeth J. ; Vega, Ana ; Viel, Alexandra ; Wang, Qin ; Wappenschmidt, Barbara ; Weitzel, Jeffrey N. ; Wendt, Camilla ; Winqvist, Robert ; Yang, Xiaohong R. ; Yannoukakos, Drakoulis ; Ziogas, Argyrios ; Kraft, Peter ; Antoniou, Antonis C. ; Zheng, Wei ; Easton, Douglas F. ; Milne, Roger L. ; Beesley, Jonathan ; Chenevix-Trench, Georgia
Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.