Inferring tumor progression from genomic heterogeneity
- Nicholas Navin1,
- Alexander Krasnitz1,
- Linda Rodgers1,
- Kerry Cook1,
- Jennifer Meth1,
- Jude Kendall1,
- Michael Riggs1,
- Yvonne Eberling1,
- Jennifer Troge1,
- Vladimir Grubor1,
- Dan Levy1,
- Pär Lundin2,
- Susanne Månér2,
- Anders Zetterberg2,
- James Hicks1 and
- Michael Wigler1,3
- * Corresponding author; email: wigler{at}cshl.edu
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: (I) monogenomic and (II) 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 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.
Footnotes
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- Received August 12, 2009.
- Accepted October 14, 2009.
- Copyright © 2009, Cold Spring Harbor Laboratory Press
