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 chainefficiency and reactive oxygen speciesproduction. Individuals with different mitochondrial haplogroupsdiffer in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen speciesproduction, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroupsmodify 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. Haplogroupinference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subcladesenriched in affected or unaffected individuals. Results: We discovered that subcladeT1a1 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 haplogroupin the general population (that is, H and T clades), the T1a1 haplogrouphas 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 cancerrisk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiologicalstudies aimed at identifying association or risk modification effects.