TY - JOUR

T1 - An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

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 VO

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 - Brady, Angela

AU - Breast Cancer Family Registry

PY - 2015

Y1 - 2015

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.

U2 - 10.1186/s13058-015-0567-2

DO - 10.1186/s13058-015-0567-2

M3 - Journal article

C2 - 25925750

VL - 17

SP - 1

EP - 15

JO - Breast Cancer Research

JF - Breast Cancer Research

SN - 1465-5411

IS - 1

M1 - 61

ER -