Colorectal adenoma and cancer divergence - Evidence of multilineage progression

Colorectal cancer progression involves changes in phenotype and genotype. A lthough usually illustrated as a linear process, more complex underlying pa thways have not been excluded. The object of this paper is to apply modern quantitative principles of molecular evolution to multistep tumor progressi on. To reconstruct progression Lineages, the genotypes of two adjacent aden oma-cancer pairs were determined by serial dilution and polymerase chain re action at 28-30 microsatellite (MS) loci and then traced back to their most recent common ancestor. The tumors were mismatch repair deficient, and the refore relatively large numbers of MS mutations should accumulate during pr ogression. As expected, the MS genotypes were similar (correlation coeffici ents >0.9) between different parts of the same adenoma or cancer, but very different (correlation coefficients <0.2) between unrelated metachronous ad enoma-cancer pairs. Unexpectedly, the genotypes of the adjacent adenoma-can cer pairs were also very different (correlation coefficients of 0.30 and 0. 36), consistent with early adenoma-cancer divergence rather than direct lin ear progression, More than 60% of the divisions occurred after this early a denoma-cancer divergence. Therefore, the tumor phylogenies were not consist ent with sequential stepwise selection along a single most "fit" and freque nt 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.