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Population Size May Enable Cancer Cell to Avoid Mutational Meltdown

NEW YORK (GenomeWeb) – Cancer cell populations may avoid extinction from mutation accumulation because of their population size, a new analysis has found.

Cancer cells rapidly accrue deleterious mutations — more quickly than they can be purged through natural selection. But in spite of that, cancer cell populations don't die out.

Researchers from Beijing and Taipei used HeLa cells to examine the genetic load of cancer cells and their growth rate. As they reported in Molecular Biology and Evolution yesterday, the researchers found cell lines established from a single ancestral HeLa cell population had differing mutational and growth rates, but also that a portion of cells remain free of mutations.

"High deleterious mutation rate would raise an impression that the HeLa cell lines may have gone extinct long ago," senior author Xuemei Lu from the Chinese Academy of Sciences said in a statement, adding that these mutation-free cells seem to enable the population to avoid extinction.

The researchers established a HeLa cell line, E6, generated from the ancestral JF line. After about 15 to 16 divisions, they generated five single-cell clones from E6 and established those in culture. These newly generated lines had different proliferation rates — at day 7, the mean cell number of one group was 62, while it was 17.3 for another — indicating that heterogeneity in cell proliferation rate can occur quickly in a short amount of time. The proliferation rate also appeared to be somewhat heritable.

The researchers also monitored the genetic load of these five newly generated lines and their ancestral line by sequencing the cell lines to develop copy-number profiles. The slower-growing clones had a higher number and longer CNVs as compared to the ancestral E6 line.

This indicated to the researchers that CNVs could be generated quickly. For one of these slow-growing lines, B8, the researchers derived 11 clones, with varying growth rates and found they developed aneuploidy within 20 cell divisions to 30 cell divisions.

As the slow-growing lines had more chromosomes than the fast-growing and ancestral groups, this also suggested to the researchers that many of the CNVs are deleterious and affect cells' ability to proliferate.

By modeling cell growth and mutation accumulation, the researchers further found that approximately one deleterious mutation arises every three to four cell divisions and that HeLa cells have a 5 percent reduction in fitness every generation. This, they said, means that the cells could be at risk for a mutational meltdown.

They isolated 39 cells from a fast-growing clone and 40 from a slow-growing clone. After a week, about 23 percent of the fast-growing cells and 50 percent of the slow-growing cells died out. Most of the cell lines with growth rate of less than 0.6 died out within two months, they noted.

However, in 200 simulations of long-term growth based on populations starting from a single cell, the researchers found that about 10 percent of clones survived after 180 generations.

They then randomly chose one clone that they allowed to grow to a population size of a million. Most, 87 percent of the cells, had by then accumulated at least one deleterious mutation not in the ancestral cell, with the slowest growing ones accumulating five more deleterious mutations than the fast-growing cells.

However, about 13 percent of cells were free of mutations. This portion of cells could then be allowing the population to avoid extinction, the researchers said. It could also account for why killing 90 percent of cancer cell through chemotherapy may not be enough, the researchers noted.

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