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Whole-Genome Testing Could Become Diagnosis Tool

Less than a decade after the first human genome was sequenced at a cost of hundreds of millions of dollars, whole-genome sequencing is poised to become a useful and affordable diagnostic tool, experts say.

April 19, 2011 -- Less than a decade after the first human genome was sequenced at a cost of hundreds of millions of dollars, whole-genome sequencing is poised to become a useful and affordable diagnostic tool, experts say.

Technological advances allow researchers to sequence entire genomes at a speed and cost that was unimaginable just a few years ago.

Now two new case studies appearing this week in TheJournal of the American Medical Association show the value of whole-genome sequencing in the management of certain cancers.

“My expectation is that within just a few years whole-genome sequencing will be no more expensive than targeted sequencing and it will tell us much more,” cancer genetics researcher Boris Pasche, MD, PhD, of the University of Alabama at Birmingham tells WebMD.

How Whole-Genome Sequencing Works

Testing for specific mutations, such as BRCA1 and BRCA2 in breast cancer and ovarian cancer, is now commonly performed when the mutations are suspected.

But these tests focus on genes, which make up a very small percentage of the genome. Whole-genome sequencing searches for all genetic alterations in DNA that can affect susceptibility to cancer and other diseases.

Washington University oncology professor Timothy Ley, MD, calls whole-genome sequencing the most powerful diagnostic tool ever for understanding specific mutations that influence cancer susceptibility.

“We are in the very early stages of understanding what to do with the data provided by whole-genome sequencing,” he tells WebMD. “The more genomes we sequence, the more we will understand about how mutations influence outcomes.”

He says the two cases reported in The Journal of the American Medical Association highlight the potential value of whole-genome sequencing for providing meaningful information.

Testing Reveals Unsuspected Mutations

One case involved a woman who developed breast cancer at age 37, followed by ovarian cancer at age 39. Despite treatment, the ovarian cancer returned. The woman died at the age of 42, just days after being diagnosed with acute myeloid leukemia.

The woman had little family history of cancer, and testing for known susceptibility genes, such as BRCA1 and BRCA2, proved negative.

Genomic testing identified an unexpected mutation in the tumor suppressor gene TP53, which caused a rare disorder known as Li-Fraumeni syndrome.

“The syndrome carries a 90% lifetime risk of developing breast cancer and a 50% chance of developing cancer before the age of 40,” Pasche says. “It is a ticking time bomb.”

The discovery did not help the patient, but it could have major implications for her three young children, who have a 50% chance of inheriting the genetic error.

“We now know that aggressive screening and a variety of interventions, such as prophylactic mastectomy, can have a real impact on outcomes,” Pasche says.

Testing Helps Identify Treatment

The second case involved a young woman with acute myeloid leukemia.

The question was whether the woman needed a bone marrow transplant. Traditional testing left her doctors unsure about the answer.

A transplant was recommended based on the outcome of one test, which suggested that her odds of long-term survival were less than 15%.

Genome sequencing revealed a specific genetic error that was associated with a much better prognosis and a highly effective drug treatment.

“Without this information she might very well have received a bone marrow transplant,” Ley says.

In both cases, the whole genomic sequencing provided clinically useful information within six weeks. Technological advances will soon allow even faster sequencing.

“The technology is very close to being clinically applicable,” Ley says. “Many groups, including our own, are working to bring it into the clinical setting.”

Cost of Genomic Sequencing Dropping

He says whole-genome sequencing will initially benefit patients with high-risk cancers with no clear tools for identifying the best treatment.

One candidate is triple-negative breast cancer, which does not respond to targeted hormone therapies and tends to have a poor prognosis. Another is acute myeloid leukemia.

In an editorial accompanying the studies, Pasche writes that the cost of whole-genome sequencing has dropped 100-fold in less than three years. He writes that “the trend suggests that we are a lot closer to cost-effective, clinical genomics than most physicians realize.”

Lay predicts the cost will drop to around $10,000 to $15,000 within a few years.

The cheaper the cost, the more often the test will be performed. And greater use will mean more data to help researchers understand the mutations that influence susceptibility to cancer and other diseases.

“I think this will have enormous benefits from a research point of view for understanding a variety of inherited diseases,” Lay says.

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