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.
An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers / Blein S; Bardel C; Danjean V; McGuffog L; Healey S; Barrowdale D; Lee A; Dennis J; Kuchenbaecker KB; Soucy P; Terry MB; Chung WK; Goldgar DE; Buys SS; Breast Cancer Family Registry.; Janavicius R; Tihomirova L; Tung N; Dorfling CM; van Rensburg EJ; Neuhausen SL; Ding YC; Gerdes AM; Ejlertsen B; Nielsen FC; Hansen TV; Osorio A; Benitez J; Conejero RA; Segota E; Weitzel JN; Thelander M; Peterlongo P; Radice P; Pensotti V; Dolcetti R; Bonanni B; Peissel B; Zaffaroni D; Scuvera G; Manoukian S; Varesco L; Capone GL; Papi L; Ottini L; Yannoukakos D; Konstantopoulou I; Garber J; Hamann U; Donaldson A; Brady A; Brewer C; Foo C; Evans DG; Frost D; Eccles D; EMBRACE.; Douglas F; Cook J; Adlard J; Barwell J; Walker L; Izatt L; Side LE; Kennedy MJ; Tischkowitz M; Rogers MT; Porteous ME; Morrison PJ; Platte R; Eeles R; Davidson R; Hodgson S; Cole T; Godwin AK; Isaacs C; Claes K; De Leeneer K; Meindl A; Gehrig A; Wappenschmidt B; Sutter C; Engel C; Niederacher D; Steinemann D; Plendl H; Kast K; Rhiem K; Ditsch N; Arnold N; Varon-Mateeva R; Schmutzler RK; Preisler-Adams S; Markov NB; Wang-Gohrke S; de Pauw A; Lefol C; Lasset C; Leroux D; Rouleau E; Damiola F; GEMO Study Collaborators.; Dreyfus H; Barjhoux L; Golmard L; Uhrhammer N; Bonadona V; Sornin V; Bignon YJ; Carter J; Van Le L; Piedmonte M; DiSilvestro PA; de la Hoya M; Caldes T; Nevanlinna H; Aittomäki K; Jager A; van den Ouweland AM; Kets CM; Aalfs CM; van Leeuwen FE; Hogervorst FB; Meijers-Heijboer HE; HEBON.; Oosterwijk JC; van Roozendaal KE; Rookus MA; Devilee P; van der Luijt RB; Olah E; Diez O; Teulé A; Lazaro C; Blanco I; Del Valle J; Jakubowska A; Sukiennicki G; Gronwald J; Lubinski J; Durda K; Jaworska-Bieniek K; Agnarsson BA; Maugard C; Amadori A; Montagna M; Teixeira MR; Spurdle AB; Foulkes W; Olswold C; Lindor NM; Pankratz VS; Szabo CI; Lincoln A; Jacobs L; Corines M; Robson M; Vijai J; Berger A; Fink-Retter A; Singer CF; Rappaport C; Kaulich DG; Pfeiler G; Tea MK; Greene MH; Mai PL; Rennert G; Imyanitov EN; Mulligan AM; Glendon G; Andrulis IL; Tchatchou S; Toland AE; Pedersen IS; Thomassen M; Kruse TA; Jensen UB; Caligo MA; Friedman E; Zidan J; Laitman Y; Lindblom A; Melin B; Arver B; Loman N; Rosenquist R; Olopade OI; Nussbaum RL; Ramus SJ; Nathanson KL; Domchek SM; Rebbeck TR; Arun BK; Mitchell G; Karlan BY; Lester J; Orsulic S; Stoppa-Lyonnet D; Thomas G; Simard J; Couch FJ; Offit K; Easton DF; Chenevix-Trench G; Antoniou AC; Mazoyer S; Phelan CM; Sinilnikova OM; Cox DG.. - In: BREAST CANCER RESEARCH. - ISSN 1465-542X. - STAMPA. - 17:(2015), pp. 61-75. [10.1186/s13058-015-0567-2]
An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers.
PAPI, LAURA;
2015
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.
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