title: Targeted Sequencing of the Mitochondrial Genome of Women at High Risk of Breast Cancer without Detectable Mutations in BRCA1/2.
abstract: Breast Cancer is a complex multifactorial disease for which high-penetrance mutations have been identified. Approaches used to date have identified genomic features explaining about 50% of breast cancer heritability. A number of low- to medium penetrance alleles (per-allele odds ratio < 1.5 and 4.0, respectively) have been identified, suggesting that the remaining heritability is likely to be explained by the cumulative effect of such alleles and/or by rare high-penetrance alleles. Relatively few studies have specifically explored the mitochondrial genome for variants potentially implicated in breast cancer risk. For these reasons, we propose an exploration of the variability of the mitochondrial genome in individuals diagnosed with breast cancer, having a positive breast cancer family history but testing negative for BRCA1/2 pathogenic mutations. We sequenced the mitochondrial genome of 436 index breast cancer cases from the GENESIS study. As expected, no pathogenic genomic pattern common to the 436 women included in our study was observed. The mitochondrial genes MT-ATP6 and MT-CYB were observed to carry the highest number of variants in the study. The proteins encoded by these genes are involved in the structure of the mitochondrial respiration chain, and variants in these genes may impact reactive oxygen species production contributing to carcinogenesis. More functional and epidemiological studies are needed to further investigate to what extent variants identified may influence familial breast cancer risk.
authors.affiliation: INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Blein
authors.affiliation: INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Barjhoux
authors.affiliation: INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
authors.forename: Francesca
authors.initials: F
authors.lastname: Damiola
authors.affiliation: Inserm, U900, Paris, France; Institut Curie, Paris, France; Mines ParisTech, Fontainebleau, France.
authors.forename: Marie-Gabrielle
authors.initials: MG
authors.lastname: Dondon
authors.affiliation: Inserm, U900, Paris, France; Institut Curie, Paris, France; Mines ParisTech, Fontainebleau, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Eon-Marchais
authors.affiliation: Inserm, U900, Paris, France.
authors.forename: Morgane
authors.initials: M
authors.lastname: Marcou
authors.affiliation: Consultation de Génétique, Département de Médecine, Institut de Cancérologie Gustave Roussy, Villejuif, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Caron
authors.affiliation: Centre Catherine de Sienne, Nantes, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Lortholary
authors.affiliation: Institut Curie, Department of Tumour Biology, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Buecher
authors.affiliation: Département de Cancérologie sénologique, CLCC Oscar Lambret, Lille, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Vennin
authors.affiliation: Centre François Baclesse, Caen, France.
authors.forename: Pascaline
authors.initials: P
authors.lastname: Berthet
authors.affiliation: Oncogénétique Clinique, Hôpital René Huguenin/Institut Curie, Saint-Cloud, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Noguès
authors.affiliation: Université Lyon 1, CNRS UMR5558, Lyon, France; Unité de Prévention et d'Epidémiologie Génétique, Centre Léon Bérard, Lyon, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Lasset
authors.affiliation: Consultation de Génétique, Département de Médecine, Institut de Cancérologie Gustave Roussy, Villejuif, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Gauthier-Villars
authors.affiliation: INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Mazoyer
authors.affiliation: Consultation de Génétique, Département de Médecine, Institut de Cancérologie Gustave Roussy, Villejuif, France; Institut Curie, INSERM U830, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Stoppa-Lyonnet
authors.affiliation: Inserm, U900, Paris, France; Institut Curie, Paris, France; Mines ParisTech, Fontainebleau, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Andrieu
authors.affiliation: Université Lyon 1, INCa-Synergie, Centre Léon Bérard, 28 rue Laennec, Lyon Cedex 08, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Thomas
authors.affiliation: INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France; Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon - Centre Léon Bérard, Lyon, France.
authors.forename: Olga M
authors.initials: OM
authors.lastname: Sinilnikova
authors.affiliation: INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
authors.forename: David G
authors.initials: DG
authors.lastname: Cox
mesh_terms: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D054629:Genome, Mitochondrial / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics*; D009154:Mutation; D019683:Penetrance
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; C501005:MT-ATP6 protein, human; D025261:Mitochondrial Proton-Translocating ATPases