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DNA Sequencing Extended to Cancer Treatment Decisions

Elaine Mardis (Washington University in St. Louis)

Elaine Mardis (Washington University in St. Louis)

Medical researchers at Washington University in St. Louis have adapted DNA sequencing technology to map the genetic evolution of disease and monitor response to treatment. Up to now, researchers have used genomic sequencing to identify mutations at the root of a patient’s tumor, but that technology can also help guide treatment decisions, according to Elaine Mardis, co-director of the Genome Institute at Washington University’s medical school (pictured right). Mardis described some of her team’s findings yesterday at the opening plenary session of the American Association for Cancer Research annual meeting in Chicago.

Mardis and colleagues have so far sequenced the genome of tumor cells from more than 700 cancer patients. By comparing the genetic sequences in the tumor cells to healthy cells from the same patient, they can identify mutations underlying each patient’s cancer. The Genome Institute researchers use a technique developed in their labs known as deep digital sequencing that sequences individual mutations in tumor samples more than 1,000 times. This more intensive sequencing identifies the frequency of each mutation in a patient’s tumor genome and allows the researchers to map the genetic evolution of cancer cells as the disease progressed.

This whole-genome approach, says Mardis, leads to different ways of thinking about cancer, with many potential benefits to patients. “We are finding genetic mutations in multiple tumor types,” says Mardis, “that could potentially be targeted with drugs that are already available.” In patients with breast cancer, for example, Mardis and her colleagues have found numerous driver mutations in genes that have not previously been associated with breast tumors.

Another key benefit to patients of whole-genome sequencing is the added understanding of the way cancers form and evolve. The researchers have discovered that as cancer evolves, tumors acquire new mutations but still retain the original cluster of mutations that made the cells cancerous in the first place.

Their discovery suggests that drugs targeted to cancer may be more effective if directed toward genetic changes that occur early in the course of cancer. The findings also suggest that sequencing all of the tumor DNA is needed to get an accurate picture of how the cancer cells evolve. The researchers say that if they sequenced only the small portion (1 to 2%) of the genome that involves genes, they would not have gained the statistical power to track the frequency of mutations over time.

Mardis says that the traditional concept of the clinical trial may need to be adjusted to evaluate the benefits to patients of whole-genome sequencing. Clinical trials typically involve randomly assigning patients to a particular treatment regimen, but a personalized medicine approach calls for choosing drugs based on the underlying mutations in each patient’s tumor. “Having all treatment options available for every patient doesn’t fit neatly into the confines of a carefully designed clinical trial,” notes Mardis. “We’re going to need more flexibility.”

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