title: Inferring clonal expansion and cancer stem cell dynamics from DNA methylation patterns in colorectal cancers.
abstract: Cancers are clonal expansions, but how a single, transformed human cell grows into a billion-cell tumor is uncertain because serial observations are impractical. Potentially, this history is surreptitiously recorded within genomes that become increasingly numerous, polymorphic, and physically separated after transformation. To correlate physical with epigenetic pairwise distances, small 2,000- to 10,000-cell gland fragments were sampled from left and right sides of 12 primary colorectal cancers, and passenger methylation at 2 CpG-rich regions was measured by bisulfite sequencing. Methylation patterns were polymorphic but differences were similar between different parts of the same tumor, consistent with relatively isotropic or "flat" clonal expansions that could be simulated by rapid initial population expansions. Methylation patterns were too diverse to be consistent with very rare cancer stem cells but were more consistent with multiple ( approximately 4 to 1,000) long-lived cancer stem cell lineages per cancer gland. Our study illustrates the potential to reconstruct the unperturbed biology of human cancers from epigenetic passenger variations in their present-day genomes.
authors.affiliation: Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA.
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Siegmund
authors.forename: Paul
authors.initials: P
authors.lastname: Marjoram
authors.forename: Yen-Jung
authors.initials: YJ
authors.lastname: Woo
authors.forename: Simon
authors.initials: S
authors.lastname: Tavaré
authors.forename: Darryl
authors.initials: D
authors.lastname: Shibata
mesh_terms: D002452:Cell Count; D019070:Cell Lineage; D049109:Cell Proliferation; D002999:Clone Cells; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D003198:Computer Simulation; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D006801:Humans; D018613:Microscopy, Confocal; D008938:Mitosis; D014411:Neoplastic Stem Cells / Q000473:pathology*; D010641:Phenotype