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