DNA flaws can stack up as cancer grows

Acute myeloid leukemia appears to progress by accumulating mutations

VANCOUVER — As a man’s cells grew cancerous, a wide range of mutations gradually emerged too, a new gene sequencing study finds. The results provide a deep understanding of the genetic changes that allowed an aggressive form of leukemia to set in and take hold in one patient, Elaine Mardis of Washington University in St. Louis said in a March 28 presentation at the annual conference on Research in Computational Molecular Biology.

“Cancers’ origins lie in the genome,” Mardis said. “These genetic approaches are really addressing the underlying questions of cancer biology.”

In the new study, Mardis and her colleagues collected cells from a 68-year-old man with a blood disease called myelodysplastic syndrome. About one in four people with this disorder go on to develop a fast-moving and dangerous type of cancer called acute myeloid leukemia. Two years after those samples were taken the man was diagnosed with full-blown acute myeloid leukemia, and the researchers harvested a second batch of cells. By reading the letter-by-letter DNA sequences in the two samples of cells, the team could pinpoint genetic changes as the cells turned cancerous.

Over time, the cells accumulated new genetic mutations, the team found. The early mutations didn’t seem to run rampant and overtake all of the cancerous cells, but they didn’t disappear, either. These early mutations became present in less and less of the cancer-cell population.

Watching the same cancer in the same person over time allows the team to see just how this cancer evolves, says computational biologist Cenk Sahinalp of Simon Fraser University in Canada.

“Maybe they don’t die out, but in time, their proportion gets lower and lower.”  

The finding helps answer a long-standing question: In leukemia, does a group of cells with a particular mutation rapidly spread, or do additional mutations pop up along the way and result in a cancer that’s more genetically mixed? In colon cancer, for instance, most cells in the final tumors contain mutations that are the same as the early mutations, suggesting that these mutations quickly spread. Yet in this particular patient and for this particular leukemia, more mutations occurred.

This steady accumulation of multiple mutations — and the genetically complex mishmash of cells that results — may confound treatment options, which are typically aimed at one select problem, Mardis says. But it’s important for doctors to be aware of the likely genetic complexities of leukemia when they’re deciding on a treatment. “Physicians need to know what they’re up against,” she says. 

The researchers now have cell samples from 25 patients who developed myelodysplastic syndrome and then AML, and preliminary tests show similar accumulation of new mutations. Comparing how these individual cancers change genetically over time may allow the researchers to identify common mutations.

Knowing what genes change, and when, may lead to more specific and effective treatments for leukemia, Mardis says. “At the end of the day, we want to inform how patients are treated — and better treated — for this disease.” 

Laura Sanders is the neuroscience writer. She holds a Ph.D. in molecular biology from the University of Southern California.

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