title: Inferring tumor progression from genomic heterogeneity.
abstract: Cancer progression in humans is difficult to infer because we do not routinely sample patients at multiple stages of their disease. However, heterogeneous breast tumors provide a unique opportunity to study human tumor progression because they still contain evidence of early and intermediate subpopulations in the form of the phylogenetic relationships. We have developed a method we call Sector-Ploidy-Profiling (SPP) to study the clonal composition of breast tumors. SPP involves macro-dissecting tumors, flow-sorting genomic subpopulations by DNA content, and profiling genomes using comparative genomic hybridization (CGH). Breast carcinomas display two classes of genomic structural variation: (1) monogenomic and (2) polygenomic. Monogenomic tumors appear to contain a single major clonal subpopulation with a highly stable chromosome structure. Polygenomic tumors contain multiple clonal tumor subpopulations, which may occupy the same sectors, or separate anatomic locations. In polygenomic tumors, we show that heterogeneity can be ascribed to a few clonal subpopulations, rather than a series of gradual intermediates. By comparing multiple subpopulations from different anatomic locations, we have inferred pathways of cancer progression and the organization of tumor growth.
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Navin
authors.forename: Alexander
authors.initials: A
authors.lastname: Krasnitz
authors.forename: Linda
authors.initials: L
authors.lastname: Rodgers
authors.forename: Kerry
authors.initials: K
authors.lastname: Cook
authors.forename: Jennifer
authors.initials: J
authors.lastname: Meth
authors.forename: Jude
authors.initials: J
authors.lastname: Kendall
authors.forename: Michael
authors.initials: M
authors.lastname: Riggs
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Eberling
authors.forename: Jennifer
authors.initials: J
authors.lastname: Troge
authors.forename: Vladimir
authors.initials: V
authors.lastname: Grubor
authors.forename: Dan
authors.initials: D
authors.lastname: Levy
authors.forename: Pär
authors.initials: P
authors.lastname: Lundin
authors.forename: Susanne
authors.initials: S
authors.lastname: Månér
authors.forename: Anders
authors.initials: A
authors.lastname: Zetterberg
authors.forename: James
authors.initials: J
authors.lastname: Hicks
authors.forename: Michael
authors.initials: M
authors.lastname: Wigler
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000473:pathology; D056905:Chromosome Breakpoints; D055028:Comparative Genomic Hybridization / Q000379:methods*; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry / Q000379:methods*; D018628:Gene Dosage; D018740:Genetic Heterogeneity; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D048088:Informatics; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D011003:Ploidies; D017422:Sequence Analysis, DNA