Darryl Shibata, USC, "Reconstruction Human Cancer Evolution with Epigenetic Somatic Cell Molecular Clocks"

How did a tumor form?

1. Sequential evolution?
2. Single clonal expansion ("Big-bang"? (from a single cell)

To study, using tools from pop. gen.

Molecular Clock Hypothesis:

• Genomes are almost perfect copies of copies
• Measurements

1. Pairwise distances (PWD) (comparative genomics)
2. Selection: Hard to measure
• use PWD to infer selection
• between tumor/germline; <1 per 100,000 bp (~70 years difference estimated)
• doesn't work for comparing tumor to germline, or tumor to tumor
• but we can use methylation for this comparison!
• changes faster

Testing sequential vs. big bang theory:

• sequential evolution: wide heterogeneity of ages = wide variety in methylation patters
• single clonal expansion: narrow range of ages  = similar methylation patterns
• differs for individual cancers

Also: can test physical vs. pairwise distances

• sequential evolution: neighbors are more related than distant cells
• single clonal expansion: methylation similarity not related to physical distance

Side notes:

• Using genetic clock analysis, metastatic cells are generally found to be quite old
• Collection process may introduce homogeneity (e.g., can use microenvironments to influence methylation patterns)