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    Breast cancer research : BCR. 2015 Apr 25. doi: 10.1186/s13058-015-0567-2. pii: 10.1186/s13058-015-0567-2. pmc: PMC4478717
    An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers.
    Blein S1,  Bardel C2,  Danjean V3,  McGuffog L4,  Healey S5,  Barrowdale D6,  Lee A7,  Dennis J8,  Kuchenbaecker KB9,  Soucy P10,  Terry MB11,  Chung WK12,  Goldgar DE13,  Buys SS14,  Janavicius R15,  Tihomirova L16,  Tung N17,  Dorfling CM18,  van Rensburg EJ19,  Neuhausen SL20,  Ding YC21,  Gerdes AM22,  Ejlertsen B23,  Nielsen FC24,  Hansen TV25,  Osorio A26,  Benitez J27,  Conejero RA28,  Segota E29,  Weitzel JN30,  Thelander M31,  Peterlongo P32,  Radice P33,  Pensotti V34,  Dolcetti R35,  Bonanni B36,  Peissel B37,  Zaffaroni D38,  Scuvera G39,  Manoukian S40,  Varesco L41,  Capone GL42,  Papi L43,  Ottini L44,  Yannoukakos D45,  Konstantopoulou I46,  Garber J47,  Hamann U48,  Donaldson A49,  Brady A50,  Brewer C51,  Foo C52,  Evans DG53,  Frost D54,  Eccles D55,  Douglas F56,  Cook J57,  Adlard J58,  Barwell J59,  Walker L60,  Izatt L61,  Side LE62,  Kennedy MJ63,  Tischkowitz M64,  Rogers MT65,  Porteous ME66,  Morrison PJ67,  Platte R68,  Eeles R69,  Davidson R70,  Hodgson S71,  Cole T72,  Godwin AK73,  Isaacs C74,  Claes K75,  De Leeneer K76,  Meindl A77,  Gehrig A78,  Wappenschmidt B79,  Sutter C80,  Engel C81,  Niederacher D82,  Steinemann D83,  Plendl H84,  Kast K85,  Rhiem K86,  Ditsch N87,  Arnold N88,  Varon-Mateeva R89,  Schmutzler RK90,  Preisler-Adams S91,  Markov NB92,  Wang-Gohrke S93,  de Pauw A94,  Lefol C95,  Lasset C96,  Leroux D97,  Rouleau E98,  Damiola F99,  Dreyfus H100,  Barjhoux L101,  Golmard L102,  Uhrhammer N103,  Bonadona V104,  Sornin V105,  Bignon YJ106,  Carter J107,  Van Le L108,  Piedmonte M109,  DiSilvestro PA110,  de la Hoya M111,  Caldes T112,  Nevanlinna H113,  Aittomäki K114,  Jager A115,  van den Ouweland AM116,  Kets CM117,  Aalfs CM118,  van Leeuwen FE119,  Hogervorst FB120,  Meijers-Heijboer HE121,  Oosterwijk JC122,  van Roozendaal KE123,  Rookus MA124,  Devilee P125,  van der Luijt RB126,  Olah E127,  Diez O128,  Teulé A129,  Lazaro C130,  Blanco I131,  Del Valle J132,  Jakubowska A133,  Sukiennicki G134,  Gronwald J135,  Lubinski J136,  Durda K137,  Jaworska-Bieniek K138,  Agnarsson BA139,  Maugard C140,  Amadori A141,  Montagna M142,  Teixeira MR143,  Spurdle AB144,  Foulkes W145,  Olswold C146,  Lindor NM147,  Pankratz VS148,  Szabo CI149,  Lincoln A150,  Jacobs L151,  Corines M152,  Robson M153,  Vijai J154,  Berger A155,  Fink-Retter A156,  Singer CF157,  Rappaport C158,  Kaulich DG159,  Pfeiler G160,  Tea MK161,  Greene MH162,  Mai PL163,  Rennert G164,  Imyanitov EN165,  Mulligan AM166,  Glendon G167,  Andrulis IL168,  Tchatchou S169,  Toland AE170,  Pedersen IS171,  Thomassen M172,  Kruse TA173,  Jensen UB174,  Caligo MA175,  Friedman E176,  Zidan J177,  Laitman Y178,  Lindblom A179,  Melin B180,  Arver B181,  Loman N182,  Rosenquist R183,  Olopade OI184,  Nussbaum RL185,  Ramus SJ186,  Nathanson KL187,  Domchek SM188,  Rebbeck TR189,  Arun BK190,  Mitchell G191,  Karlan BY192,  Lester J193,  Orsulic S194,  Stoppa-Lyonnet D195,  Thomas G196,  Simard J197,  Couch FJ198,  Offit K199,  Easton DF200,  Chenevix-Trench G201,  Antoniou AC202,  Mazoyer S203,  Phelan CM204,  Sinilnikova OM205,  Cox DG206
    Author information
    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.


    Publikations ID: 25925750
    Quelle: öffnen
     
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