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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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  • 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
  • Breast Cancer Family Registry
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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.

OriginalsprogEngelsk
TidsskriftBreast Cancer Research Review
Vol/bind17
Sider (fra-til)61
DOI
StatusUdgivet - 2015

ID: 45843610