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.
Additional file 1: List of ethical committees that approved the
access to the data analyzed in this study.
Additional file 2: SNPs selected for downstream analyses.
Additional file 3: Description and results of the procedure used to
estimate the accuracy of our haplogroup inference methodology.
Additional file 4: Absolute and relative frequencies of imputed
haplogroups by population. Table containing absolute and relative
frequencies of imputed haplogroups for BRCA1 and BRCA2 mutation carriers.
Additional file 6: Details of haplogroups inference results for
Additional file 7: Methods used to compute coevolution index.
Additional file 5: Correlated evolution index for all non-monomorphic
sites observed in short haplotype sequences of subclade T. Table
containing correlated evolution index for all non-monomorphic sites
observed in short haplotypes sequences of subclade T.