The University of Southampton
University of Southampton Institutional Repository

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

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers
An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers
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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Blein, Sophie
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Blein, Sophie, Bardel, Claire and Danjean, Vincent et al. (2015) An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers. Breast Cancer Research, 17 (1), 1-15. (doi:10.1186/s13058-015-0567-2). (PMID:25925750)

Record type: Article

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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Accepted/In Press date: 25 March 2015
Published date: 27 April 2015
Organisations: Cancer Sciences

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Local EPrints ID: 382468
URI: http://eprints.soton.ac.uk/id/eprint/382468
PURE UUID: 317dcb68-d0e6-4715-b360-b8c7668d7912
ORCID for Diana Eccles: ORCID iD orcid.org/0000-0002-9935-3169

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Date deposited: 05 Oct 2015 13:57
Last modified: 15 Mar 2024 02:40

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Contributors

Author: Sophie Blein
Author: Claire Bardel
Author: Vincent Danjean
Author: Lesley McGuffog
Author: Sue Healey
Author: Daniel Barrowdale
Author: Andrew Lee
Author: Joe Dennis
Author: Karoline B. Kuchenbaecker
Author: Penny Soucy
Author: Mary Beth Terry
Author: Wendy K. Chung
Author: David E. Goldgar
Author: Saundra S. Buys
Author: Ramunas Janavicius
Author: Laima Tihomirova
Author: Nadine Tung
Author: Cecilia M. Dorfling
Author: Elizabeth J. van Rensburg
Author: Susan L. Neuhausen
Author: Yuan Chun Ding
Author: Anne-Marie Gerdes
Author: Bent Ejlertsen
Author: Finn C Nielsen
Author: Thomas VO Hansen
Author: Ana Osorio
Author: Javier Benitez
Author: Raquel Andrés Conejero
Author: Ena Segota
Author: Jeffrey N Weitzel
Author: Margo Thelander
Author: Paolo Peterlongo
Author: Paolo Radice
Author: Valeria Pensotti
Author: Riccardo Dolcetti
Author: Bernardo Bonanni
Author: Bernard Peissel
Author: Daniela Zaffaroni
Author: Giulietta Scuvera
Author: Siranoush Manoukian
Author: Liliana Varesco
Author: Gabriele L. Capone
Author: Laura Papi
Author: Laura Ottini
Author: Drakoulis Yannoukakos
Author: Irene Konstantopoulou
Author: Judy Garber
Author: Ute Hamann
Author: Alan Donaldson
Author: Angela Brady
Author: Carole Brewer
Author: Claire Foo
Author: D. Gareth Evans
Author: Debra Frost
Author: Diana Eccles ORCID iD
Author: Fiona Douglas
Author: Jackie Cook
Author: Julian Adlard
Author: Julian Barwell
Author: Lisa Walker
Author: Louise Izatt
Author: Lucy E. Side
Author: M. John Kennedy
Author: Marc Tischkowitz
Author: Mark T. Rogers
Author: Mary E. Porteous
Author: Patrick J. Morrison
Author: Radka Platte
Author: Ros Eeles
Author: Rosemarie Davidson
Author: Shirley Hodgson
Author: Trevor Cole
Author: Andrew K. Godwin
Author: Claudine Isaacs
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