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Cancer May Be Driven by DNA Outside of Chromosomes

In the spring of 2012, my colleagues and I began to notice something strange in tumor cells from patients with glioblastoma, a highly aggressive form of brain cancer, who were coming into our clinic at the University of California, Los Angeles. From genomic sequencing of their tumors, we knew they displayed amplification of a specific growth-promoting oncogene.

Despite being treated with drugs designed to target this gene, the patients were not getting better, and when we interrogated the genomes of their cancers after the tumors were surgically removed following treatment, we saw that they had changed. The tumors had dramatically reduced the number of copies of the targeted epidermal growth factor receptor (EGFR) gene, presumably giving them an advantage to escape the drugs, and they had evolved these genetic differences at a rate that seemed to make no sense—within just one to two weeks.

Normally, we think of cancers evolving over many cell divisions, as the cells carrying genetic changes that provide a fitness advantage—such as an ability to resist a particular treatment—will be more likely to survive and divide. Here, we were noticing a change in the copy number of the gene within just a few generations. There was no way that we could explain how the tumors were altering their DNA so quickly.

Even stranger, we could take any cell from the tumor, and whether it had high or undetectable protein levels of EGFR, it would give rise to a new tumor when cultured in the lab or implanted into a mouse. Each of these new tumors would then display the full spectrum of cells found in the original tumor, varied in their EGFR copy number. This makes no sense according to what we know about classical genetics. We would have expected that tumors arising from a cell with low levels of EGFR would give rise to a tumor with low EGFR levels, whereas a tumor arising from a cell with high levels of EGFR would give rise to a tumor with high EGFR levels.

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