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

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

doi: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.

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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Journal	Breast cancer research : BCR
Volume	17
DOIs	https://doi.org/10.1186/s13058-015-0567-2
Publication status	Published - 2015

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Cite this

Blein, S., Bardel, C., Danjean, V., McGuffog, L., Healey, S., Barrowdale, D., Lee, A., Dennis, J., Kuchenbaecker, K. B., Soucy, P., Terry, M. B., Chung, W. K., Goldgar, D. E., Buys, S. S., Janavicius, R., Tihomirova, L., Tung, N., Dorfling, C. M., van Rensburg, E. J., ... Cox, D. G. (2015). An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers. Breast cancer research : BCR, 17. https://doi.org/10.1186/s13058-015-0567-2

@article{1d10c257026d4e6aaf820be0eb51cb43,

title = "An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers.",

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.",

author = "Sophie Blein and Claire Bardel and Vincent Danjean and Lesley McGuffog and Sue Healey and Daniel Barrowdale and Andrew Lee and Joe Dennis and Kuchenbaecker, {Karoline B} and Penny Soucy and Terry, {Mary Beth} and Chung, {Wendy K} and Goldgar, {David E} and Buys, {Saundra S} and Ramunas Janavicius and Laima Tihomirova and Nadine Tung and Dorfling, {Cecilia M} and {van Rensburg}, {Elizabeth J} and Neuhausen, {Susan L} and Ding, {Yuan Chun} and Anne-Marie Gerdes and Bent Ejlertsen and Nielsen, {Finn C} and Hansen, {Thomas Vo} and Ana Osorio and Javier Benitez and Conejero, {Raquel Andr{\'e}s} and Ena Segota and Weitzel, {Jeffrey N} and Margo Thelander and Paolo Peterlongo and Paolo Radice and Valeria Pensotti and Riccardo Dolcetti and Bernardo Bonanni and Bernard Peissel and Daniela Zaffaroni and Giulietta Scuvera and Siranoush Manoukian and Liliana Varesco and Capone, {Gabriele L} and Laura Papi and Laura Ottini and Drakoulis Yannoukakos and Irene Konstantopoulou and Judy Garber and Ute Hamann and Alan Donaldson and Angela Brady and Carole Brewer and Claire Foo and Evans, {D Gareth} and Debra Frost and Diana Eccles and Fiona Douglas and Jackie Cook and Julian Adlard and Julian Barwell and Lisa Walker and Louise Izatt and Side, {Lucy E} and Kennedy, {M John} and Marc Tischkowitz and Rogers, {Mark T} and Porteous, {Mary E} and Morrison, {Patrick J} and Radka Platte and Ros Eeles and Rosemarie Davidson and Shirley Hodgson and Trevor Cole and Godwin, {Andrew K} and Claudine Isaacs and Kathleen Claes and {De Leeneer}, Kim and Alfons Meindl and Andrea Gehrig and Barbara Wappenschmidt and Christian Sutter and Christoph Engel and Dieter Niederacher and Doris Steinemann and Hansjoerg Plendl and Karin Kast and Kerstin Rhiem and Nina Ditsch and Norbert Arnold and Raymonda Varon-Mateeva and Schmutzler, {Rita K} and Sabine Preisler-Adams and Markov, {Nadja Bogdanova} and Shan Wang-Gohrke and {de Pauw}, Antoine and C{\'e}drick Lefol and Christine Lasset and Dominique Leroux and Etienne Rouleau and Francesca Damiola and H{\'e}l{\`e}ne Dreyfus and Laure Barjhoux and Lisa Golmard and Nancy Uhrhammer and Val{\'e}rie Bonadona and Val{\'e}rie Sornin and Yves-Jean Bignon and Jonathan Carter and {Van Le}, Linda and Marion Piedmonte and DiSilvestro, {Paul A} and {de la Hoya}, Miguel and Trinidad Caldes and Heli Nevanlinna and Kristiina Aittom{\"a}ki and Agnes Jager 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 Peter Devilee and {van der Luijt}, {Rob B} and Edith Olah and Orland Diez and Alex Teul{\'e} and Conxi Lazaro and Ignacio Blanco and {Del Valle}, Jes{\'u}s and Anna Jakubowska and Grzegorz Sukiennicki and Jacek Gronwald and Jan Lubinski and Katarzyna Durda and Katarzyna Jaworska-Bieniek and Agnarsson, {Bjarni A} and Christine Maugard and Alberto Amadori and Marco Montagna and Teixeira, {Manuel R} and Spurdle, {Amanda B} and William Foulkes and Curtis Olswold and Lindor, {Noralane M} and Pankratz, {Vernon S} and Szabo, {Csilla I} and Anne Lincoln and Lauren Jacobs and Marina Corines and Mark Robson and Joseph Vijai and Andreas Berger and Anneliese Fink-Retter and Singer, {Christian F} and Christine Rappaport and Kaulich, {Daphne Geschwantler} and Georg Pfeiler and Muy-Kheng Tea and Greene, {Mark H} and Mai, {Phuong L} and Gad Rennert and Imyanitov, {Evgeny N} and Mulligan, {Anna Marie} and Gord Glendon and Andrulis, {Irene L} and Sandrine Tchatchou and Toland, {Amanda Ewart} and Pedersen, {Inge Sokilde} and Mads Thomassen and Kruse, {Torben A} and Jensen, {Uffe Birk} and Caligo, {Maria A} and Eitan Friedman and Jamal Zidan and Yael Laitman and Annika Lindblom and Beatrice Melin and Brita Arver and Niklas Loman and Richard Rosenquist 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 Gillian Mitchell and Karlan, {Beth Y} and Jenny Lester and Sandra Orsulic and Dominique Stoppa-Lyonnet and Gilles Thomas and Jacques Simard and Couch, {Fergus J} and Kenneth Offit and Easton, {Douglas F} and Georgia Chenevix-Trench and Antoniou, {Antonis C} and Sylvie Mazoyer and Phelan, {Catherine M} and Sinilnikova, {Olga M} and Cox, {David G}",

note = "P30 CA168524, NCI NIH HHS, United StatesR01 CA140323, NCI NIH HHS, United StatesRC4 CA153828, NCI NIH HHS, United StatesU01 CA113916, NCI NIH HHS, United StatesUM1 CA164920, NCI NIH HHS, United States",

year = "2015",

doi = "10.1186/s13058-015-0567-2",

language = "English",

volume = "17",

journal = "Breast cancer research : BCR",

publisher = "Springer Nature",

}

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, Janavicius, R, Tihomirova, L, Tung, N, Dorfling, CM, van Rensburg, EJ, Neuhausen, SL, Ding, YC, Gerdes, A-M, 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, 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, Dreyfus, H, Barjhoux, L, Golmard, L, Uhrhammer, N, Bonadona, V, Sornin, V, Bignon, Y-J, 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, 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, M-K, 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 2015, 'An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers.', Breast cancer research : BCR, vol. 17. https://doi.org/10.1186/s13058-015-0567-2

TY - JOUR

T1 - An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers.

AU - Blein, Sophie

AU - Bardel, Claire

AU - Danjean, Vincent

AU - McGuffog, Lesley

AU - Healey, Sue

AU - Barrowdale, Daniel

AU - Lee, Andrew

AU - Dennis, Joe

AU - Kuchenbaecker, Karoline B

AU - Soucy, Penny

AU - Terry, Mary Beth

AU - Chung, Wendy K

AU - Goldgar, David E

AU - Buys, Saundra S

AU - Janavicius, Ramunas

AU - Tihomirova, Laima

AU - Tung, Nadine

AU - Dorfling, Cecilia M

AU - van Rensburg, Elizabeth J

AU - Neuhausen, Susan L

AU - Ding, Yuan Chun

AU - Gerdes, Anne-Marie

AU - Ejlertsen, Bent

AU - Nielsen, Finn C

AU - Hansen, Thomas Vo

AU - Osorio, Ana

AU - Benitez, Javier

AU - Conejero, Raquel Andrés

AU - Segota, Ena

AU - Weitzel, Jeffrey N

AU - Thelander, Margo

AU - Peterlongo, Paolo

AU - Radice, Paolo

AU - Pensotti, Valeria

AU - Dolcetti, Riccardo

AU - Bonanni, Bernardo

AU - Peissel, Bernard

AU - Zaffaroni, Daniela

AU - Scuvera, Giulietta

AU - Manoukian, Siranoush

AU - Varesco, Liliana

AU - Capone, Gabriele L

AU - Papi, Laura

AU - Ottini, Laura

AU - Yannoukakos, Drakoulis

AU - Konstantopoulou, Irene

AU - Garber, Judy

AU - Hamann, Ute

AU - Donaldson, Alan

AU - Brady, Angela

AU - Brewer, Carole

AU - Foo, Claire

AU - Evans, D Gareth

AU - Frost, Debra

AU - Eccles, Diana

AU - Douglas, Fiona

AU - Cook, Jackie

AU - Adlard, Julian

AU - Barwell, Julian

AU - Walker, Lisa

AU - Izatt, Louise

AU - Side, Lucy E

AU - Kennedy, M John

AU - Tischkowitz, Marc

AU - Rogers, Mark T

AU - Porteous, Mary E

AU - Morrison, Patrick J

AU - Platte, Radka

AU - Eeles, Ros

AU - Davidson, Rosemarie

AU - Hodgson, Shirley

AU - Cole, Trevor

AU - Godwin, Andrew K

AU - Isaacs, Claudine

AU - Claes, Kathleen

AU - De Leeneer, Kim

AU - Meindl, Alfons

AU - Gehrig, Andrea

AU - Wappenschmidt, Barbara

AU - Sutter, Christian

AU - Engel, Christoph

AU - Niederacher, Dieter

AU - Steinemann, Doris

AU - Plendl, Hansjoerg

AU - Kast, Karin

AU - Rhiem, Kerstin

AU - Ditsch, Nina

AU - Arnold, Norbert

AU - Varon-Mateeva, Raymonda

AU - Schmutzler, Rita K

AU - Preisler-Adams, Sabine

AU - Markov, Nadja Bogdanova

AU - Wang-Gohrke, Shan

AU - de Pauw, Antoine

AU - Lefol, Cédrick

AU - Lasset, Christine

AU - Leroux, Dominique

AU - Rouleau, Etienne

AU - Damiola, Francesca

AU - Dreyfus, Hélène

AU - Barjhoux, Laure

AU - Golmard, Lisa

AU - Uhrhammer, Nancy

AU - Bonadona, Valérie

AU - Sornin, Valérie

AU - Bignon, Yves-Jean

AU - Carter, Jonathan

AU - Van Le, Linda

AU - Piedmonte, Marion

AU - DiSilvestro, Paul A

AU - de la Hoya, Miguel

AU - Caldes, Trinidad

AU - Nevanlinna, Heli

AU - Aittomäki, Kristiina

AU - Jager, Agnes

AU - van den Ouweland, Ans Mw

AU - Kets, Carolien M

AU - Aalfs, Cora M

AU - van Leeuwen, Flora E

AU - Hogervorst, Frans Bl

AU - Meijers-Heijboer, Hanne Ej

AU - Oosterwijk, Jan C

AU - van Roozendaal, Kees Ep

AU - Rookus, Matti A

AU - Devilee, Peter

AU - van der Luijt, Rob B

AU - Olah, Edith

AU - Diez, Orland

AU - Teulé, Alex

AU - Lazaro, Conxi

AU - Blanco, Ignacio

AU - Del Valle, Jesús

AU - Jakubowska, Anna

AU - Sukiennicki, Grzegorz

AU - Gronwald, Jacek

AU - Lubinski, Jan

AU - Durda, Katarzyna

AU - Jaworska-Bieniek, Katarzyna

AU - Agnarsson, Bjarni A

AU - Maugard, Christine

AU - Amadori, Alberto

AU - Montagna, Marco

AU - Teixeira, Manuel R

AU - Spurdle, Amanda B

AU - Foulkes, William

AU - Olswold, Curtis

AU - Lindor, Noralane M

AU - Pankratz, Vernon S

AU - Szabo, Csilla I

AU - Lincoln, Anne

AU - Jacobs, Lauren

AU - Corines, Marina

AU - Robson, Mark

AU - Vijai, Joseph

AU - Berger, Andreas

AU - Fink-Retter, Anneliese

AU - Singer, Christian F

AU - Rappaport, Christine

AU - Kaulich, Daphne Geschwantler

AU - Pfeiler, Georg

AU - Tea, Muy-Kheng

AU - Greene, Mark H

AU - Mai, Phuong L

AU - Rennert, Gad

AU - Imyanitov, Evgeny N

AU - Mulligan, Anna Marie

AU - Glendon, Gord

AU - Andrulis, Irene L

AU - Tchatchou, Sandrine

AU - Toland, Amanda Ewart

AU - Pedersen, Inge Sokilde

AU - Thomassen, Mads

AU - Kruse, Torben A

AU - Jensen, Uffe Birk

AU - Caligo, Maria A

AU - Friedman, Eitan

AU - Zidan, Jamal

AU - Laitman, Yael

AU - Lindblom, Annika

AU - Melin, Beatrice

AU - Arver, Brita

AU - Loman, Niklas

AU - Rosenquist, Richard

AU - Olopade, Olufunmilayo I

AU - Nussbaum, Robert L

AU - Ramus, Susan J

AU - Nathanson, Katherine L

AU - Domchek, Susan M

AU - Rebbeck, Timothy R

AU - Arun, Banu K

AU - Mitchell, Gillian

AU - Karlan, Beth Y

AU - Lester, Jenny

AU - Orsulic, Sandra

AU - Stoppa-Lyonnet, Dominique

AU - Thomas, Gilles

AU - Simard, Jacques

AU - Couch, Fergus J

AU - Offit, Kenneth

AU - Easton, Douglas F

AU - Chenevix-Trench, Georgia

AU - Antoniou, Antonis C

AU - Mazoyer, Sylvie

AU - Phelan, Catherine M

AU - Sinilnikova, Olga M

AU - Cox, David G

N1 - P30 CA168524, NCI NIH HHS, United StatesR01 CA140323, NCI NIH HHS, United StatesRC4 CA153828, NCI NIH HHS, United StatesU01 CA113916, NCI NIH HHS, United StatesUM1 CA164920, NCI NIH HHS, United States

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

U2 - 10.1186/s13058-015-0567-2

DO - 10.1186/s13058-015-0567-2

M3 - Article

C2 - 25925750

VL - 17

JO - Breast cancer research : BCR

JF - Breast cancer research : BCR

ER -

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

Abstract

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