title: Genomic Analyses of Breast Cancer Progression Reveal Distinct Routes of Metastasis Emergence.
abstract: A main controversy in cancer research is whether metastatic abilities are present in the most advanced clone of the primary tumor or result from independently acquired aberrations in early disseminated cancer cells as suggested by the linear and the parallel progression models, respectively. The genetic concordance between different steps of malignant progression is mostly unexplored as very few studies have included cancer samples separated by both space and time. We applied whole exome sequencing and targeted deep sequencing to 26 successive samples from six patients with metastatic estrogen receptor (ER)-positive breast cancer. Our data provide support for both linear and parallel progression towards metastasis. We report for the first time evidence of metastasis-to-metastasis seeding in breast cancer. Our results point to three distinct routes of metastasis emergence. This may have profound clinical implications and provides substantial novel molecular insights into the timing and mutational evolution of breast cancer metastasis.
authors.affiliation: Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.|Human Genetics, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
authors.forename: Anne Bruun
authors.initials: AB
authors.lastname: Krøigård
authors.affiliation: Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.|Human Genetics, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
authors.forename: Martin Jakob
authors.initials: MJ
authors.lastname: Larsen
authors.affiliation: Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.|Human Genetics, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Brasch-Andersen
authors.affiliation: Department of Pathology, Slagelse Hospital, Slagelse, Denmark.
authors.forename: Anne-Vibeke
authors.initials: AV
authors.lastname: Lænkholm
authors.affiliation: Department of Oncology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Ann S
authors.initials: AS
authors.lastname: Knoop
authors.affiliation: Department of Oncology, Odense University Hospital, Odense, Denmark.
authors.forename: Jeanette Dupont
authors.initials: JD
authors.lastname: Jensen
authors.affiliation: Department of Pathology, Odense University Hospital, Odense, Denmark.
authors.forename: Martin
authors.initials: M
authors.lastname: Bak
authors.affiliation: Lundbeckfonden Center of Excellence NanoCAN, Odense, Denmark.|Molecular Oncology Group, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Jan
authors.initials: J
authors.lastname: Mollenhauer
authors.affiliation: Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.|Human Genetics, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.|Lundbeckfonden Center of Excellence NanoCAN, Odense, Denmark.
authors.forename: Mads
authors.initials: M
authors.lastname: Thomassen
authors.affiliation: Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.|Human Genetics, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.|Lundbeckfonden Center of Excellence NanoCAN, Odense, Denmark.
authors.forename: Torben A
authors.initials: TA
authors.lastname: Kruse
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001859:Bone Neoplasms / Q000235:genetics* / Q000556:secondary; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000235:genetics; D018450:Disease Progression; D005260:Female; D023281:Genomics; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics* / Q000556:secondary; D008875:Middle Aged; D009154:Mutation; D012097:Repressor Proteins / Q000235:genetics; D000073359:Exome Sequencing / Q000379:methods
chemical_list: C486398:BCL6B protein, human; D003598:Cytoskeletal Proteins; D060588:LIM Domain Proteins; D012097:Repressor Proteins; C108627:ZNF185 protein, human