Blein, SophieBardel, ClaireDanjean, VincentMcGuffog, LesleyHealey, SueBarrowdale, DanielLee, AndrewDennis, JoeKuchenbaecker, Karoline B.Soucy, PennyTerry, Mary BethChung, Wendy K.Goldgar, David E.Buys, Saundra S.Breast Cancer Family RegistryJanavicius, RamunasTihomirova, LaimaTung, NadineDorfling, Cecilia MariaJansen van Rensburg, ElizabethNeuhausen, Susan L.Ding, Yuan ChunGerdes, Anne-MarieEjlertsen, BentNielsen, Finn C.Hansen, Thomas V.O.Osorio, AnaBenitez, JavierConejero, Raquel AndresSegota, EnaWeitzel, Jeffrey N.Thelander, MargoPeterlongo, PaoloRadice, PaoloPensotti, ValeriaDolcetti, RiccardoBonanni, BernardoPeissel, BernardZaffaroni, DanielaScuvera, GiuliettaManoukian, SiranoushVaresco, LilianaCapone, Gabriele LPapi, LauraOttini, LauraYannoukakos, DrakoulisKonstantopoulou, IreneGarber, JudyHamann, UteDonaldson, AlanBrady, A.Brewer, CaroleFoo, ClaireEvans, D. GarethFrost, DebraEccles, Diana M.EMBRACEDouglas, FionaCook, JackieAdlard, JulianBarwell, JulianWalker, LisaIzatt, LouiseSide, Lucy E.Kennedy, M.J.Tischkowitz, MarcRogers, Mark T.Porteous, Mary E.Morrison, Patrick J.Platte, RadkaEeles, Rosalind A.Davidson, RosemarieHodgson, ShirleyCole, TrevorGodwin, Andrew K.Isaacs, ClaudineClaes, KathleenDe Leeneer, KimMeindl, AlfonsGehrig, AndreaWappenschmidt, BarbaraSutter, ChristianEngel, ChristophNiederacher, DieterSteinemann, DorisPlendl, HansjoergKast, KarinRhiem, KerstinDitsch, NinaArnold, NorbertVaron-Mateeva, RaymondaSchmutzler, Rita KatharinaPreisler-Adams, SabineMarkov, Nadja BogdanovaWang-Gohrke, ShanDe Pauw, AntoineLefol, CedrickLasset, ChristineLeroux, DominiqueRouleau, EtienneDamiola, FrancescaGEMO Study CollaboratorsDreyfus, HeleneBarjhoux, LaureGolmard, LisaUhrhammer, NancyBonadona, ValerieSornin, ValerieBignon, Yves-JeanCarter, JonathanVan Le, LindaPiedmonte, MarionDiSilvestro, Paul A.De la Hoya, MiguelCaldes, TrinidadNevanlinna, HeliAittomaki, KristiinaJager, AgnesVan den Ouweland, Ans M.W.Kets, Carolien M.Aalfs, Cora M.Van Leeuwen, Flora E.Hogervorst, Frans B.L.Meijers-Heijboer, Hanne E.J.HEBONOosterwijk, JanVan Roozendaal, Kees E.P.Rookus, Matti A.Devilee, PeterVan der Luijt, Rob BOlah, EdithDiez, OrlandTeule, AlexLazaro, ConxiBlanco, IgnacioDel Valle, JesusJakubowska, AnnaSukiennicki, GrzegorzGronwald, JacekLubinski, JanDurda, KatarzynaJaworska-Bieniek, KatarzynaAgnarsson, Bjarni A.Maugard, ChristineAmadori, AlbertoMontagna, MarcoTeixeira, Manuel R.Spurdle, Amanda B.Foulkes, WilliamOlswold, CurtisLindor, Noralane M.Pankratz, Vernon S.Szabo, Csilla I.Lincoln, AnneJacobs, LaurenCorines, Marina J.Robson, Mark E.Vijai, JosephBerger, AndreasFink-Retter, AnnelieseSinger, Christian F.Rappaport, ChristineKaulich, D.G.Pfeiler, GeorgTea, Muy-Kheng M.Greene, Mark H.Mai, Phuong L.Rennert, GadImyanitov, Evgeny N.Mulligan, Anna MarieGlendon, GordAndrulis, Irene L.Tchatchou, SandrineToland, Amanda EwartPedersen, Inge SokildeThomassen, MadsKruse, Torben AJensen, Uffe BirkCaligo, Maria A.Friedman, EitanZidan, JamalLaitman, YaelLindblom, AnnikaMelin, B.Arver, BritaLoman, NiklasRosenquist, RichardOlopade, Olufunmilayo I.Nussbaum, Robert L.Ramus, Susan J.Nathanson, Katherine L.Domchek, Susan M.Rebbeck, Timothy R.Arun, Banu K.Mitchell, GillianKarlan, Beth Y.Lester, JennyOrsulic, SandraStoppa-Lyonnet, DominiqueThomas, GillesSimard, JacquesCouch, Fergus J.Offit, KennethEaston, Douglas F.Chenevix-Trench, GeorgiaAntoniou, Antonis C.Mazoyer, SylviePhelan, Catherine M.Sinilnikova, Olga M.Cox, David G.2015-11-262015-11-262015-04-25Blein 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, vol. 17, art. no. 61, pp. 1-15.1465-5411 (print)1465-542X (online)10.1186/s13058-015-0567-2http://hdl.handle.net/2263/50958Additional file 1: List of ethical committees that approved the access to the data analyzed in this study.Additional file 2: SNPs selected for downstream analyses.Additional file 3: Description and results of the procedure used to estimate the accuracy of our haplogroup inference methodology.Additional file 4: Absolute and relative frequencies of imputed haplogroups by population. Table containing absolute and relative frequencies of imputed haplogroups for BRCA1 and BRCA2 mutation carriers.Additional file 6: Details of haplogroups inference results for subclade T.Additional file 7: Methods used to compute coevolution index.Additional file 5: Correlated evolution index for all non-monomorphic sites observed in short haplotype sequences of subclade T. Table containing correlated evolution index for all non-monomorphic sites observed in short haplotypes sequences of subclade T.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.en© 2015 Blein et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License.Breast cancerPathogenic mutationsMitochondriaBRCA1BRCA2Deoxyribonucleic acid (DNA)Article