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An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

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Abstract
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.
Keywords
GENETIC MODIFIERS, SINGLE-NUCLEOTIDE POLYMORPHISMS, OXIDATIVE STRESS, DNA HAPLOGROUPS, SUSCEPTIBILITY, OVARIAN, CONSORTIUM, VARIANTS, MULTIPLE, DISEASES

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Chicago
Blein, Sophie, Claire Bardel, Vincent Danjean, Lesley McGuffog, Sue Healey, Daniel Barrowdale, Andrew Lee, et al. 2015. “An Original Phylogenetic Approach Identified Mitochondrial Haplogroup T1a1 as Inversely Associated with Breast Cancer Risk in BRCA2 Mutation Carriers.” Breast Cancer Research 17.
APA
Blein, S., Bardel, C., Danjean, V., McGuffog, L., Healey, S., Barrowdale, D., Lee, A., et al. (2015). An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers. BREAST CANCER RESEARCH, 17.
Vancouver
1.
Blein S, Bardel C, Danjean V, McGuffog L, Healey S, Barrowdale D, et al. An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers. BREAST CANCER RESEARCH. 2015;17.
MLA
Blein, Sophie, Claire Bardel, Vincent Danjean, et al. “An Original Phylogenetic Approach Identified Mitochondrial Haplogroup T1a1 as Inversely Associated with Breast Cancer Risk in BRCA2 Mutation Carriers.” BREAST CANCER RESEARCH 17 (2015): n. pag. Print.
@article{6886747,
  abstract     = {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.},
  articleno    = {61},
  author       = {Blein, Sophie and Bardel, Claire and Danjean, Vincent and McGuffog, Lesley and Healey, Sue and Barrowdale, Daniel and Lee, Andrew and Dennis, Joe and Kuchenbaecker, Karoline B and Soucy, Penny and Terry, Mary Beth and Chung, Wendy K and Goldgar, David E and Buys, Saundra S and Janavicius, Ramunas and Tihomirova, Laima and Tung, Nadine and Dorfling, Cecilia M and van Rensburg, Elizabeth J and Neuhausen, Susan L and Ding, Yuan Chun and Gerdes, Anne-Marie and Ejlertsen, Bent and Nielsen, Finn C and Hansen, Thomas VO and Osorio, Ana and Benitez, Javier and Andr{\'e}s Conejero, Raquel and Segota, Ena and Weitzel, Jeffrey N and Thelander, Margo and Peterlongo, Paolo and Radice, Paolo and Pensotti, Valeria and Dolcetti, Riccardo and Bonanni, Bernardo and Peissel, Bernard and Zaffaroni, Daniela and Scuvera, Giulietta and Manoukian, Siranoush and Varesco, Liliana and Capone, Gabriele L and Papi, Laura and Ottini, Laura and Yannoukakos, Drakoulis and Konstantopoulou, Irene and Garber, Judy and Hamann, Ute and Donaldson, Alan and Brady, Angela and Brewer, Carole and Foo, Claire and Evans, D Gareth and Frost, Debra and Eccles, Diana and Douglas, Fiona and Cook, Jackie and Adlard, Julian and Barwell, Julian and Walker, Lisa and Izatt, Louise and Side, Lucy E and Kennedy, M John and Tischkowitz, Marc and Rogers, Mark T and Porteous, Mary E and Morrison, Patrick J and Platte, Radka and Eeles, Ros and Davidson, Rosemarie and Hodgson, Shirley and Cole, Trevor and Godwin, Andrew K and Isaacs, Claudine and Claes, Kathleen and De Leeneer, Kim and Meindl, Alfons and Gehrig, Andrea and Wappenschmidt, Barbara and Sutter, Christian and Engel, Christoph and Niederacher, Dieter and Steinemann, Doris and Plendl, Hansjoerg and Kast, Karin and Rhiem, Kerstin and Ditsch, Nina and Arnold, Norbert and Varon-Mateeva, Raymonda and Schmutzler, Rita K and Preisler-Adams, Sabine and Markov, Nadja Bogdanova and Wang-Gohrke, Shan and de Pauw, Antoine and Lefol, C{\'e}drick and Lasset, Christine and Leroux, Dominique and Rouleau, Etienne and Damiola, Francesca and Dreyfus, Helene and Barjhoux, Laure and Golmard, Lisa and Uhrhammer, Nancy and Bonadona, Val{\'e}rie and Sornin, Val{\'e}rie and Bignon, Yves-Jean and Carter, Jonathan and Van Le, Linda and Piedmonte, Marion and DiSilvestro, Paul A and de la Hoya, Miguel and Caldes, Trinidad and Nevanlinna, Heli and Aittom{\"a}ki, Kristiina and Jager, Agnes and van den Ouweland, Ans MW and Kets, Carolien M and Aalfs, Cora M and van Leeuwen, Flora E and Hogervorst, Frans BL and Meijers-Heijboer, Hanne EJ and Oosterwijk, Jan C and van Roozendaal, Kees EP and Rookus, Matti A and Devilee, Peter and van der Luijt, Rob B and Olah, Edith and Diez, Orland and Teul{\'e}, Alex and Lazaro, Conxi and Blanco, Ignacio and Del Valle, Jes{\'u}s and Jakubowska, Anna and Sukiennicki, Grzegorz and Gronwald, Jacek and Lubinski, Jan and Durda, Katarzyna and Jaworska-Bieniek, Katarzyna and Agnarsson, Bjarni A and Maugard, Christine and Amadori, Alberto and Montagna, Marco and Teixeira, Manuel R and Spurdle, Amanda B and Foulkes, William and Olswold, Curtis and Lindor, Noralane M and Pankratz, Vernon S and Szabo, Csilla I and Lincoln, Anne and Jacobs, Lauren and Corines, Marina and Robson, Mark and Vijai, Joseph and Berger, Andreas and Fink-Retter, Anneliese and Singer, Christian F and Rappaport, Christine and Kaulich, Daphne Geschwantler and Pfeiler, Georg and Tea, Muy-Kheng and Greene, Mark H and Mai, Phuong L and Rennert, Gad and Imyanitov, Evgeny N and Mulligan, Anna Marie and Glendon, Gord and Andrulis, Irene L and Tchatchou, Sandrine and Toland, Amanda Ewart and Pedersen, Inge Sokilde and Thomassen, Mads and Kruse, Torben A and Jensen, Uffe Birk and Caligo, Maria A and Friedman, Eitan and Zidan, Jamal and Laitman, Yael and Lindblom, Annika and Melin, Beatrice and Arver, Brita and Loman, Niklas and Rosenquist, Richard and Olopade, Olufunmilayo I and Nussbaum, Robert L and Ramus, Susan J and Nathanson, Katherine L and Domchek, Susan M and Rebbeck, Timothy R and Arun, Banu K and Mitchell, Gillian and Karlan, Beth Y and Lester, Jenny and Orsulic, Sandra and Stoppa-Lyonnet, Dominique and Thomas, Gilles and Simard, Jacques and Couch, Fergus J and Offit, Kenneth and Easton, Douglas F and Chenevix-Trench, Georgia and Antoniou, Antonis C and Mazoyer, Sylvie and Phelan, Catherine M and Sinilnikova, Olga M and Cox, David G},
  issn         = {1465-542X},
  journal      = {BREAST CANCER RESEARCH},
  keyword      = {GENETIC MODIFIERS,SINGLE-NUCLEOTIDE POLYMORPHISMS,OXIDATIVE STRESS,DNA HAPLOGROUPS,SUSCEPTIBILITY,OVARIAN,CONSORTIUM,VARIANTS,MULTIPLE,DISEASES},
  language     = {eng},
  pages        = {15},
  title        = {An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers},
  url          = {http://dx.doi.org/10.1186/s13058-015-0567-2},
  volume       = {17},
  year         = {2015},
}

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