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

Sophie Blein; Christine June Jacobs; 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; HEBON

doi:10.1186/s13058-015-0567-2

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

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

Sophie Blein, Christine June Jacobs, Claire Bardel, Vincent Danjean, Lesley McGuffog, Sue Healey, Daniel Barrowdale, Andrew Lee, Joe Dennis, Karoline B Kuchenbaecker, …

Breast cancer research : BCR, Vol.17(1), pp.61-61

25/04/2015

DOI: https://doi.org/10.1186/s13058-015-0567-2

PMCID: PMC4478717

PMID: 25925750

Abstract

BRCA1 Protein - genetics

Breast Neoplasms - genetics

Female

Genes, BRCA2

Genes, Mitochondrial

Genetic Predisposition to Disease

Haplotypes

Heterozygote

Humans

Phylogeny

Risk

Mutation

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. 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. 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. 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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Title: An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers
Creators: Sophie Blein - Inserm
Christine June Jacobs - School of Health Sciences
Claire Bardel - Claude Bernard University Lyon 1
Vincent Danjean - Grenoble Computer Science Laboratory
Lesley McGuffog - University of Cambridge
Sue Healey - QIMR Berghofer Medical Research Institute
Daniel Barrowdale - University of Cambridge
Andrew Lee - University of Cambridge
Joe Dennis - University of Cambridge
Karoline B Kuchenbaecker - University of Cambridge
Penny Soucy - Centre Hospitalier Universitaire de Québec
Mary Beth Terry - Columbia University
Wendy K Chung - Columbia University
David E Goldgar - University of Utah
Saundra S Buys - Huntsman Cancer Institute
Ramunas Janavicius - Vilnius University
Laima Tihomirova - Latvian Biomedical Research and Study Centre
Nadine Tung - Beth Israel Deaconess Medical Center
Cecilia M Dorfling - University of Pretoria
Elizabeth J van Rensburg - University of Pretoria
Susan L Neuhausen - City of Hope
Yuan Chun Ding - City of Hope
Anne-Marie Gerdes - Copenhagen University Hospital
Bent Ejlertsen - Copenhagen University Hospital
Finn C Nielsen - Copenhagen University Hospital
Thomas Vo Hansen - Copenhagen University Hospital
Ana Osorio - Spanish National Cancer Research Centre
Javier Benitez - Center for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain. jbenitez@cnio.es
Raquel Andrés Conejero - Hospital Clínico Universitario Lozano Blesa
Ena Segota - Holy Cross Hospital
Jeffrey N Weitzel - City of Hope
Margo Thelander - John Muir Health
Paolo Peterlongo - FIRC Institute of Molecular Oncology
Paolo Radice - Fondazione IRCCS Istituto Nazionale dei Tumori
Valeria Pensotti - City of Hope
Riccardo Dolcetti - Centro di Riferimento Oncologico
Bernardo Bonanni - European Institute of Oncology
Bernard Peissel - Istituti di Ricovero e Cura a Carattere Scientifico
Daniela Zaffaroni - Istituti di Ricovero e Cura a Carattere Scientifico
Giulietta Scuvera - Istituti di Ricovero e Cura a Carattere Scientifico
Siranoush Manoukian - Istituti di Ricovero e Cura a Carattere Scientifico
Liliana Varesco - Istituti di Ricovero e Cura a Carattere Scientifico
Gabriele L Capone - University of Florence
Laura Papi - University of Florence
Laura Ottini - Sapienza University of Rome
Drakoulis Yannoukakos - Papageorgiou General Hospital
Irene Konstantopoulou - National Centre of Scientific Research "Demokritos"
Judy Garber - Dana-Farber Cancer Institute
Ute Hamann - DKFZ-ZMBH Alliance
Alan Donaldson - St Michael's Hospital
Angela Brady - Wessex Regional Genetics Laboratory
Carole Brewer - Exeter Hospital
Claire Foo - Liverpool Womens NHS Foundation Trust
D Gareth Evans - Manchester Academic Health Science Centre
Debra Frost - University of Cambridge
Diana Eccles - University of Southampton
Fiona Douglas - Centre for Life
Jackie Cook - Sheffield Children's Hospital
Julian Adlard - Leeds General Infirmary
Julian Barwell - University Hospitals of Leicester NHS Trust
Lisa Walker - Churchill Hospital
Louise Izatt - Guy's and St Thomas' NHS Foundation Trust
Lucy E Side - Great Ormond Street Hospital
M John Kennedy - Great Ormond Street Hospital
Marc Tischkowitz - Addenbrooke's Hospital
Mark T Rogers - University Hospital of Wales
Mary E Porteous - Western General Hospital
Patrick J Morrison - Queen's University Belfast
Radka Platte - University of Cambridge
Ros Eeles - Royal Marsden NHS Foundation Trust
Rosemarie Davidson - Woolmanhill Hospital
Shirley Hodgson - St George's, University of London
Trevor Cole - Birmingham Women's Hospital
Andrew K Godwin - University of Kansas Medical Center
Claudine Isaacs - MedStar Georgetown University Hospital
Kathleen Claes - Ghent University Hospital
Kim De Leeneer - Ghent University Hospital
Alfons Meindl - Rechts der Isar Hospital
Andrea Gehrig - University of Würzburg
Barbara Wappenschmidt - University Hospital Cologne
Christian Sutter - Heidelberg University
Christoph Engel - Leipzig University
Dieter Niederacher - Heinrich Heine University Düsseldorf
Doris Steinemann - Medizinische Hochschule Hannover
Hansjoerg Plendl - Institute of Human Genetics, University Medical Center Schleswig-Holstein, Campus Kiel, Arnold-Heller-Strasse 3, D-24105, Kiel, Germany. plendl@medgen.uni-kiel.de
Karin Kast - University Hospital Carl Gustav Carus
Kerstin Rhiem - University Hospital Cologne
Nina Ditsch - Rechts der Isar Hospital
Norbert Arnold - University Hospital Schleswig-Holstein
Raymonda Varon-Mateeva - Charité - Universitätsmedizin Berlin
Rita K Schmutzler - University Hospital Cologne
Sabine Preisler-Adams - University Hospital Münster
Nadja Bogdanova Markov - University Hospital Münster
Shan Wang-Gohrke - University Hospital Ulm
Antoine de Pauw - Institute Curie
Cédrick Lefol - Institute Curie
Christine Lasset - Claude Bernard University Lyon 1
Dominique Leroux - Centre Hospitalier Universitaire de Grenoble
Etienne Rouleau - Hôpital René Huguenin
Francesca Damiola - Inserm
Hélène Dreyfus - Centre Hospitalier Universitaire de Grenoble
Laure Barjhoux - Inserm
Lisa Golmard - Institute Curie
Nancy Uhrhammer - Centre Jean Perrin
Valérie Bonadona - Biometry and Evolutionary Biology Laboratory
Valérie Sornin - Inserm
Yves-Jean Bignon - Centre Jean Perrin
Jonathan Carter - Royal Prince Alfred Hospital
Linda Van Le - Gynecologic Oncology Group
Marion Piedmonte - Gynecologic Oncology Group
Paul A DiSilvestro - Women & Infants Hospital of Rhode Island
Miguel de la Hoya - Instituto de Investigación Sanitaria del Hospital Clínico San Carlos
Trinidad Caldes - Instituto de Investigación Sanitaria del Hospital Clínico San Carlos
Heli Nevanlinna - Helsinki University Hospital
Kristiina Aittomäki - Helsinki University Hospital
Agnes Jager - Erasmus MC
Ans Mw van den Ouweland - Erasmus MC
Carolien M Kets - Radboud University Medical Center
Cora M Aalfs - Academic Medical Center
Flora E van Leeuwen - Oncode Institute
Frans Bl Hogervorst - The Netherlands Cancer Institute
Hanne Ej Meijers-Heijboer - Amsterdam UMC Location VUmc
Jan C Oosterwijk - University Medical Center Groningen
Kees Ep van Roozendaal - Maastricht University
Matti A Rookus - Oncode Institute
Peter Devilee - Leiden University Medical Center
Rob B van der Luijt - University Medical Center Utrecht
Edith Olah - National Institute of Oncology
Orland Diez - Vall d'Hebron Institut de Recerca
Alex Teulé - Duran i Reynals Hospital
Conxi Lazaro - Duran i Reynals Hospital
Ignacio Blanco - Institut Català d'Oncologia
Jesús Del Valle - Duran i Reynals Hospital
Anna Jakubowska - Pomeranian Medical University
Grzegorz Sukiennicki - Pomeranian Medical University
Jacek Gronwald - Pomeranian Medical University
Jan Lubinski - Pomeranian Medical University
Katarzyna Durda - Pomeranian Medical University
Katarzyna Jaworska-Bieniek - Pomeranian Medical University
Bjarni A Agnarsson - National University Hospital of Iceland
Christine Maugard - Hôpital Civil, Strasbourg
Alberto Amadori - University of Padua
Marco Montagna - Istituto Oncologico Veneto
Manuel R Teixeira - Universidade do Porto
Amanda B Spurdle - QIMR Berghofer Medical Research Institute
William Foulkes - McGill University
Curtis Olswold - Mayo Clinic in Florida
Noralane M Lindor - Mayo Clinic in Arizona
Vernon S Pankratz - Mayo Clinic in Florida
Csilla I Szabo - National Human Genome Research Institute
Anne Lincoln - Memorial Sloan Kettering Cancer Center
Lauren Jacobs - Memorial Sloan Kettering Cancer Center
Marina Corines - Memorial Sloan Kettering Cancer Center
Mark Robson - Memorial Sloan Kettering Cancer Center
Joseph Vijai - Memorial Sloan Kettering Cancer Center
Andreas Berger - Medical University of Vienna
Anneliese Fink-Retter - Medical University of Vienna
Christian F Singer - Comprehensive Cancer Center Vienna
Christine Rappaport - Medical University of Vienna
Daphne Geschwantler Kaulich - Medical University of Vienna
Georg Pfeiler - Medical University of Vienna
Muy-Kheng Tea - Medical University of Vienna
Mark H Greene - National Cancer Institute
Phuong L Mai - National Institutes of Health
Gad Rennert - Carmel Medical Center
Evgeny N Imyanitov - Institute of Oncology NN Petrov
Anna Marie Mulligan - University of Toronto
Gord Glendon - Cancer Care Ontario
Irene L Andrulis - University of Toronto
Sandrine Tchatchou - Lunenfeld-Tanenbaum Research Institute
Amanda Ewart Toland - Cancer Genetics
Inge Sokilde Pedersen - Aalborg University Hospital
Mads Thomassen - Odense University Hospital
Torben A Kruse - Odense University Hospital
Uffe Birk Jensen - Aarhus University Hospital
Maria A Caligo - Azienda Ospedaliera Universitaria Pisana
Eitan Friedman - Sheba Medical Center
Jamal Zidan - Rebecca Sieff Hospital
Yael Laitman - Sheba Medical Center
Annika Lindblom - Karolinska University Hospital
Beatrice Melin - Umeå University
Brita Arver - Sophiahemmet Hospital
Niklas Loman - Lund University
Richard Rosenquist - Uppsala University
Olufunmilayo I Olopade - University of Chicago
Robert L Nussbaum - University of California, San Francisco
Susan J Ramus - University of Southern California
Katherine L Nathanson - University of Pennsylvania
Susan M Domchek - University of Pennsylvania
Timothy R Rebbeck - University of Pennsylvania
Banu K Arun - The University of Texas MD Anderson Cancer Center
Gillian Mitchell - Peter MacCallum Cancer Centre
Beth Y Karlan - Cedars-Sinai Medical Center
Jenny Lester - Cedars-Sinai Medical Center
Sandra Orsulic - Cedars-Sinai Medical Center
Dominique Stoppa-Lyonnet - Sorbonne Paris Cité
Gilles Thomas - Centre Léon Bérard
Jacques Simard - Centre Hospitalier Universitaire de Québec
Fergus J Couch - Mayo Clinic in Florida
Kenneth Offit - Memorial Sloan Kettering Cancer Center
Douglas F Easton - University of Cambridge
Georgia Chenevix-Trench - QIMR Berghofer Medical Research Institute
Antonis C Antoniou - University of Cambridge
Sylvie Mazoyer - Inserm
Catherine M Phelan - Moffitt Cancer Center
Olga M Sinilnikova - Inserm
David G Cox - Inserm
HEBON
Publication Details: Breast cancer research : BCR, Vol.17(1), pp.61-61
Date published: 25/04/2015
Grant note: U10 CA180868 / NCI NIH HHS N02CP65504 / NCI NIH HHS UG1 CA189867 / NCI NIH HHS U24 CA196067 / NCI NIH HHS P30 CA168524 / NCI NIH HHS RC4 CA153828 / NCI NIH HHS UM1 CA164920 / NCI NIH HHS U10 CA037517 / NCI NIH HHS R01 CA142996 / NCI NIH HHS P30 CA016672 / NCI NIH HHS R01 CA128978 / NCI NIH HHS R01 CA102776 / NCI NIH HHS N02CP11019 / NCI NIH HHS P50 CA116201 / NCI NIH HHS U10 CA027469 / NCI NIH HHS R01 CA116167 / NCI NIH HHS P30 CA008748 / NCI NIH HHS U01 CA116167 / NCI NIH HHS R01 CA083855 / NCI NIH HHS 11174 / Cancer Research UK R01 CA176785 / NCI NIH HHS P50 CA125183 / NCI NIH HHS U01 CA113916 / NCI NIH HHS R01 CA140323 / NCI NIH HHS U10 CA101165 / NCI NIH HHS U01 CA161032 / NCI NIH HHS
Identifiers: 99822358802346
Academic Unit: School of Health Sciences
Language: English
Resource Type: Journal article

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

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