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.Peer reviewe

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

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

"Respect when you can, resect when you should": A realistic approach to posterior leaflet mitral valve repair.

OBJECTIVE: Avoiding resection to treat posterior leaflet prolapse has become popular to repair degenerative mitral regurgitation. We never subscribed to such simplification but advocated an alternative approach based on the "respect when you can, resect when you should" concept. The present study reviewed posterior leaflet prolapse in degenerative disease with the aim to expose the 10-year experience with this surgical policy, in particular long-term outcomes such as survival, recurrent/severe mitral regurgitation, and reoperation. METHODS: From January 2005 to December 2015, 701 consecutive patients with severe mitral regurgitation underwent mitral valve repair in 2 distinct institutions. Mitral regurgitation was degenerative in 441 patients, of whom the 376 with posterior leaflet prolapse constituted the study population. Patients were followed up by echocardiograms until December 2017. Longitudinal data stratified by institution were analyzed by mixed-effects models. Outcome measures were analyzed by Kaplan-Meier test. RESULTS: Patients with posterior leaflet prolapse (24.7% isolated P2 and 75.3% P2 associated with other segments) were aged 65.8 +/- 13 years, and 70.5% were male. Median follow-up was 61.1 months. There were 3 hospital deaths (0.8%). Reoperation was necessary in 7 patients (1.9%). After 1, 5, and 10 years, overall survival was 97.8%, 93.6%, and 86.7%, respectively; the overall survival of the proportion of patients with recurrent/residual >2+ mitral regurgitation was estimated at 0.7%, 1.9%, and 5.9% and that of patients with New York Heart Association III/IV at 0.8%, 1.9%, and 5.3%. CONCLUSIONS: The "resect with respect" approach yields low operative mortality, no systolic anterior motion, good surface of coaptation, and low incidence of residual/recurrent mitral regurgitation and of reoperation, thus supporting resection when required concept