Abstract
BackgroundIt is possible to infer the past of populations by comparing genomes between individuals. In general, older populations have more genomic diversity than younger populations. The force of selection can also be inferred from population diversity. If selection is strong and frequently eliminates less fit variants, diversity will be limited because new, initially homogeneous populations constantly emerge.Methodology and ResultsHere we translate a population genetics approach to human somatic cancer cell populations by measuring genomic diversity within and between small colorectal cancer (CRC) glands. Control tissue culture and xenograft experiments demonstrate that the population diversity of certain passenger DNA methylation patterns is reduced after cloning but subsequently increases with time. When measured in CRC gland populations, passenger methylation diversity from different parts of nine CRCs was relatively high and uniform, consistent with older, stable lineages rather than mixtures of younger homogeneous populations arising from frequent cycles of selection. The diversity of six metastases was also high, suggesting dissemination early after transformation. Diversity was lower in DNA mismatch repair deficient CRC glands, possibly suggesting more selection and the elimination of less fit variants when mutation rates are elevated.Conclusion/SignificanceThe many hitchhiking passenger variants observed in primary and metastatic CRC cell populations are consistent with relatively old populations, suggesting that clonal evolution leading to selective sweeps may be rare after transformation. Selection in human cancers appears to be a weaker than presumed force after transformation, consistent with the observed rarity of driver mutations in cancer genomes. Phenotypic plasticity rather than the stepwise acquisition of new driver mutations may better account for the many different phenotypes within human tumors.
Highlights
A barrier to a better understanding of human cancer is the inability to directly observe how cancers evolve
Passenger methylation patterns should be initially homogeneous and subsequently become increasingly polymorphic after a clonal evolution bottleneck. We verify that these passenger methylation patterns or tags can record a simple clonal evolution cycle: polyclonal population R monoclonal population R polyclonal population
Clonal evolution depends on new driver mutations, which should be readily generated by the genomic ‘‘instability’’ thought to be present in many cancers [17]
Summary
A barrier to a better understanding of human cancer is the inability to directly observe how cancers evolve. A logical presumption is that progression occurs stepwise after transformation (Fig 1) with the sequential selection of new driver mutations and more malignant phenotypes by clonal evolution [1] as tumor cells encounter and colonize new microenvironments. A recent cancer genome sequencing study [2] illustrated that metastases have relatively few additional mutations compared to their primary colorectal cancers (CRCs). Positive or negative selection is difficult to quantify, there is a long history of using the variation at neutral or hitchhiking passenger loci within a population to measure the force of selection, which opposes drift by eliminating less fit variants [8]. If selection is strong and frequently eliminates less fit variants, diversity will be limited because new, initially homogeneous populations constantly emerge
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