An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers
Creators: name: Blein, Sophie
name: Bardel, Claire
name: Danjean, Vincent
name: McGuffog, Lesley
name: Healey, Sue
name: Barrowdale, Daniel
name: Lee, Andrew
name: Dennis, Joe
name: Kuchenbaecker, Karoline B.
name: Soucy, Penny
name: Terry, Mary Beth
name: Chung, Wendy K.
name: Goldgar, David E.
name: Janavicius, Ramunas
name: Buys, Saundra S.
name: Tihomirova, Laima
name: Tung, Nadine
name: Dorfling, Cecilia M.
name: Neuhausen, Susan L.
name: Van Rensburg, Elizabeth J.
name: Ding, Yuan Chun
name: Gerdes, Anne-Marie
name: Ejlertsen, Bent
name: Nielsen, Finn C.
name: Hansen, Thomas V. O.
name: Osorio, Ana
name: Benitez, Javier
name: Conejero, Raquel Andrés
name: Segota, Ena
name: Weitzel, Jeffrey N.
name: Thelander, Margo
name: Peterlongo, Paolo
name: Radice, Paolo
name: Pensotti, Valeria
name: Dolcetti, Riccardo
name: Peissel, Bernard
name: Bonanni, Bernardo
name: Zaffaroni, Daniela
name: Scuvera, Giulietta
name: Manoukian, Siranoush
name: Capone, Gabriele L.
name: Varesco, Liliana
name: Papi, Laura
name: Ottini, Laura
name: Yannoukakos, Drakoulis
name: Konstantopoulou, Irene
name: Garber, Judy
name: Donaldson, Alan
name: Hamann, Ute
name: Brady, Angela
name: Brewer, Carole
name: Foo, Claire
name: Evans, D Gareth
name: Frost, Debra
name: Eccles, Diana
name: Douglas, Fiona
name: Cook, Jackie
name: Adlard, Julian
name: Barwell, Julian
name: Walker, Lisa
name: Izatt, Louise
name: Kennedy, M. John
name: Rogers, Mark T.
name: Side, Lucy E.
name: Tischkowitz, Marc
name: Porteous, Mary E.
name: Morrison, Patrick J.
name: Platte, Radka
name: Davidson, Rosemarie
name: Eeles, Ros
name: Hodgson, Shirley
name: Cole, Trevor
name: Godwin, Andrew K.
name: Isaacs, Claudine
name: Claes, Kathleen
name: Leeneer, Kim De
name: Meindl, Alfons
name: Gehrig, Andrea
name: Wappenschmidt, Barbara
name: Engel, Christoph
name: Sutter, Christian
name: Niederacher, Dieter
name: Steinemann, Doris
name: Plendl, Hansjoerg
name: Kast, Karin
name: Rhiem, Kerstin
name: Ditsch, Nina
name: Arnold, Norbert
name: Varon-Mateeva, Raymonda
name: Schmutzler, Rita K.
name: Preisler-Adams, Sabine
name: Markov, Nadja Bogdanova
name: Wang-Gohrke, Shan
name: De Pauw, Antoine
name: Lefol, Cédrick
name: Leroux, Dominique
name: Lasset, Christine
name: Rouleau, Etienne
name: Damiola, Francesca
name: Dreyfus, Hélène
name: Barjhoux, Laure
name: Golmard, Lisa
name: Uhrhammer, Nancy
name: Bonadona, Valérie
name: Bignon, Yves-Jean
name: Sornin, Valérie
name: Carter, Jonathan
name: Le, Linda Van
name: Piedmonte, Marion
name: DiSilvestro, Paul A.
name: De La Hoya, Miguel
name: Caldes, Trinidad
name: Nevanlinna, Heli
name: Aittomäki, Kristiina
name: Van Den Ouweland, Ans M. W.
name: Kets, Carolien M.
name: Aalfs, Cora M.
name: Jager, Agnes
name: Van Leeuwen, Flora E.
name: Hogervorst, Frans B. L.
name: Meijers-Heijboer, Hanne E. J.
name: Oosterwijk, Jan C.
name: Van Roozendaal, Kees E. P.
name: Rookus, Matti A.
name: Devilee, Peter
name: Van Der Luijt, Rob B.
name: Olah, Edith
name: Diez, Orland
name: Lazaro, Conxi
name: Teulé, Alex
name: Blanco, Ignacio
name: Del Valle, Jesús
name: Jakubowska, Anna
name: Sukiennicki, Grzegorz
name: Gronwald, Jacek
name: Lubinski, Jan
name: Durda, Katarzyna
name: Jaworska-Bieniek, Katarzyna
name: Agnarsson, Bjarni A.
name: Amadori, Alberto
name: Maugard, Christine
name: Montagna, Marco
name: Teixeira, Manuel R.
name: Spurdle, Amanda B.
name: Foulkes, William
name: Olswold, Curtis
name: Lindor, Noralane M.
name: Pankratz, Vernon S.
name: Szabo, Csilla I.
name: Lincoln, Anne
name: Jacobs, Lauren
name: Corines, Marina
name: Robson, Mark
name: Vijai, Joseph
name: Fink-Retter, Anneliese
name: Berger, Andreas
name: Singer, Christian F.
name: Rappaport, Christine
name: Kaulich, Daphne Geschwantler
name: Pfeiler, Georg
name: Tea, Muy-Kheng
name: Mai, Phuong L.
name: Greene, Mark H.
name: Rennert, Gad
name: Imyanitov, Evgeny N.
name: Mulligan, Anna Marie
name: Glendon, Gord
name: Andrulis, Irene L.
name: Tchatchou, Sandrine
name: Toland, Amanda Ewart
name: Pedersen, Inge Sokilde
name: Thomassen, Mads
name: Kruse, Torben A.
name: Caligo, Maria A.
name: Jensen, Uffe Birk
name: Friedman, Eitan
name: Zidan, Jamal
name: Laitman, Yael
name: Melin, Beatrice
name: Lindblom, Annika
name: Arver, Brita
name: Loman, Niklas
name: Rosenquist, Richard
name: Olopade, Olufunmilayo I.
name: Nussbaum, Robert L.
name: Ramus, Susan J.
name: Nathanson, Katherine L.
name: Domchek, Susan M.
name: Rebbeck, Timothy R.
name: Arun, Banu K.
name: Mitchell, Gillian
name: Karlan, Beth Y.
name: Lester, Jenny
name: Orsulic, Sandra
name: Stoppa-Lyonnet, Dominique
name: Thomas, Gilles
name: Simard, Jacques
name: Offit, Kenneth
name: Couch, Fergus J.
name: Easton, Douglas F.
name: Chenevix-Trench, Georgia
name: Antoniou, Antonis C.
name: Mazoyer, Sylvie
name: Phelan, Catherine M.
name: Sinilnikova, Olga M.
name: Cox, David G.
name: EMBRACE
name: HEBON
name: GEMO Study Collaborators
Publisher: name: Columbia University
Year: 2015
Subjects: Breast--Cancer--Genetic aspects
Mitochondrial DNA
Mutation (Biology)
Oncology

description: 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.