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(American Journal of Pathology. 1999;154:1815-1824.)
© 1999 American Society for Investigative Pathology

Regular Articles

Colorectal Adenoma and Cancer Divergence

Evidence of Multilineage Progression

Jen-Lan Tsao*, Simon Tavaré{dagger}, Reijo Salovaara{ddagger}, Jeremy R. Jass§, Lauri A. Aaltonen|| and Darryl Shibata*

From the Department of Pathology,*
Norris Cancer Center, University of Southern California School of Medicine, Los Angeles, California; the Departments of Biological Sciences and Mathematics,{dagger}
University of Southern California, Los Angeles, California; the Departments of Pathology and Medical Genetics,{ddagger}
Haartman Institute, University of Helsinki, Helsinki, Finland; the Department of Pathology,§
University of Queensland Medical School, Herston, Australia, and the Department of Medical Genetics,||
Haartman Institute, University of Helsinki, Helsinki, Finland

Colorectal cancer progression involves changes in phenotype and genotype. Although usually illustrated as a linear process, more complex underlying pathways have not been excluded. The object of this paper is to apply modern quantitative principles of molecular evolution to multistep tumor progression. To reconstruct progression lineages, the genotypes of two adjacent adenoma-cancer pairs were determined by serial dilution and polymerase chain reaction at 28–30 microsatellite (MS) loci and then traced back to their most recent common ancestor. The tumors were mismatch repair deficient, and therefore relatively large numbers of MS mutations should accumulate during progression. As expected, the MS genotypes were similar (correlation coefficients >0.9) between different parts of the same adenoma or cancer, but very different (correlation coefficients <0.2) between unrelated metachronous adenoma-cancer pairs. Unexpectedly, the genotypes of the adjacent adenoma-cancer pairs were also very different (correlation coefficients of 0.30 and 0.36), consistent with early adenoma-cancer divergence rather than direct linear progression. More than 60% of the divisions occurred after this early adenoma-cancer divergence. Therefore, the tumor phylogenies were not consistent with sequential stepwise selection along a single most "fit" and frequent lineage from adenoma to cancer. Instead, one effective early progression strategy creates and maintains multiple evolving candidate lineages, which are subsequently selected for terminal clonal expansion.




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