TY - JOUR
T1 - An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers
AU - GEMO Study Collaborators
AU - HEBON
AU - Blein, Sophie
AU - Bardel, Claire
AU - Danjean, Vincent
AU - McGuffog, Lesley
AU - Healey, Sue
AU - Barrowdale, Daniel
AU - Lee, Andrew
AU - Dennis, Joe
AU - Kuchenbaecker, Karoline B.
AU - Soucy, Penny
AU - Terry, Mary Beth
AU - Chung, Wendy K.
AU - Goldgar, David E.
AU - Buys, Saundra S.
AU - Janavicius, Ramunas
AU - Tihomirova, Laima
AU - Tung, Nadine
AU - Dorfling, Cecilia M.
AU - van Rensburg, Elizabeth J.
AU - Neuhausen, Susan L.
AU - Ding, Yuan Chun
AU - Gerdes, Anne Marie
AU - Ejlertsen, Bent
AU - Nielsen, Finn C.
AU - Hansen, Thomas V.O.
AU - Osorio, Ana
AU - Benitez, Javier
AU - Conejero, Raquel Andrés
AU - Segota, Ena
AU - Weitzel, Jeffrey N.
AU - Thelander, Margo
AU - Peterlongo, Paolo
AU - Radice, Paolo
AU - Pensotti, Valeria
AU - Dolcetti, Riccardo
AU - Bonanni, Bernardo
AU - Peissel, Bernard
AU - Zaffaroni, Daniela
AU - Scuvera, Giulietta
AU - Manoukian, Siranoush
AU - Varesco, Liliana
AU - Capone, Gabriele L.
AU - Papi, Laura
AU - Ottini, Laura
AU - Yannoukakos, Drakoulis
AU - Konstantopoulou, Irene
AU - Garber, Judy
AU - Hamann, Ute
AU - Donaldson, Alan
AU - Caron, Olivier
N1 - Publisher Copyright:
© 2015 Blein et al.
PY - 2015/4/25
Y1 - 2015/4/25
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84932607033&partnerID=8YFLogxK
U2 - 10.1186/s13058-015-0567-2
DO - 10.1186/s13058-015-0567-2
M3 - Article
C2 - 25925750
AN - SCOPUS:84932607033
SN - 1465-5411
VL - 17
JO - Breast Cancer Research
JF - Breast Cancer Research
IS - 1
M1 - 61
ER -