title: From latent disseminated cells to overt metastasis: genetic analysis of systemic breast cancer progression.
abstract: According to the present view, metastasis marks the end in a sequence of genomic changes underlying the progression of an epithelial cell to a lethal cancer. Here, we aimed to find out at what stage of tumor development transformed cells leave the primary tumor and whether a defined genotype corresponds to metastatic disease. To this end, we isolated single disseminated cancer cells from bone marrow of breast cancer patients and performed single-cell comparative genomic hybridization. We analyzed disseminated tumor cells from patients after curative resection of the primary tumor (stage M0), as presumptive progenitors of manifest metastasis, and from patients with manifest metastasis (stage M1). Their genomic data were compared with those from microdissected areas of matched primary tumors. Disseminated cells from M0-stage patients displayed significantly fewer chromosomal aberrations than primary tumors or cells from M1-stage patients (P < 0.008 and P < 0.0001, respectively), and their aberrations appeared to be randomly generated. In contrast, primary tumors and M1 cells harbored different and characteristic chromosomal imbalances. Moreover, applying machine-learning methods for the classification of the genotypes, we could correctly identify the presence or absence of metastatic disease in a patient on the basis of a single-cell genome. We suggest that in breast cancer, tumor cells may disseminate in a far less progressed genomic state than previously thought, and that they acquire genomic aberrations typical of metastatic cells thereafter. Thus, our data challenge the widely held view that the precursors of metastasis are derived from the most advanced clone within the primary tumor.
authors.affiliation: Institut für Immunologie, Ludwig-Maximilians-Universität München, 80336 München, Germany.
authors.forename: Oleg
authors.initials: O
authors.lastname: Schmidt-Kittler
authors.forename: Thomas
authors.initials: T
authors.lastname: Ragg
authors.forename: Angela
authors.initials: A
authors.lastname: Daskalakis
authors.forename: Martin
authors.initials: M
authors.lastname: Granzow
authors.forename: Andre
authors.initials: A
authors.lastname: Ahr
authors.forename: Thomas J F
authors.initials: TJ
authors.lastname: Blankenstein
authors.forename: Manfred
authors.initials: M
authors.lastname: Kaufmann
authors.forename: Joachim
authors.initials: J
authors.lastname: Diebold
authors.forename: Hans
authors.initials: H
authors.lastname: Arnholdt
authors.forename: Peter
authors.initials: P
authors.lastname: Muller
authors.forename: Joachim
authors.initials: J
authors.lastname: Bischoff
authors.forename: Detlev
authors.initials: D
authors.lastname: Harich
authors.forename: Gunter
authors.initials: G
authors.lastname: Schlimok
authors.forename: Gert
authors.initials: G
authors.lastname: Riethmuller
authors.forename: Roland
authors.initials: R
authors.lastname: Eils
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Klein
mesh_terms: D000465:Algorithms; D000071183:Autophagy-Related Proteins; D001853:Bone Marrow / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D015820:Cadherins / Q000235:genetics; D002869:Chromosome Aberrations; D002885:Chromosomes, Human, Pair 16; D019295:Computational Biology; D018450:Disease Progression; D015536:Down-Regulation; D016678:Genome; D005838:Genotype; D006801:Humans; D017403:In Situ Hybridization; D019656:Loss of Heterozygosity; D008207:Lymphatic Metastasis; D008957:Models, Genetic; D009362:Neoplasm Metastasis; D009693:Nucleic Acid Hybridization; D010802:Phylogeny; D011505:Protein-Tyrosine Kinases; D016160:Retinoblastoma Protein / Q000235:genetics; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D000071183:Autophagy-Related Proteins; D015820:Cadherins; C407704:RB1CC1 protein, human; D016160:Retinoblastoma Protein; D011505:Protein-Tyrosine Kinases