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Finding the Hidden Mutations That Control Cancer

New sequencing technologies that can detect rare mutations in tumors might allow personalized treatments for cancer.
June 28, 2006

The DNA of cancer cells is littered with mutations – tiny genetic missteps that can make cells grow out of control or become resistant to certain medicines. Identifying those mutations could speed up the development of new drugs or new diagnostics that could match an individual with the most effective treatment.

But sorting out the key mutations from the surrounding reams of normal DNA in tumor samples is a challenge, partly because it’s difficult to isolate and sequence single molecules of DNA.

Now a team from MIT, Harvard, and the Dana-Farber Cancer Institute in Boston has demonstrated a technique for isolating and quickly sequencing single snippets of DNA. And that advance could be crucial for cancer patients, since some cancer therapies work almost miraculously in some patients whose tumors contain a specific mutation, while other mutations make certain drugs ineffective on tumors.

“We want to know the mutational profile of a tumor, and then make informed decisions about the best therapy,” says William Pao, a physician scientist at the Memorial Sloan-Kettering Cancer Center in New York, who has previously identified key mutations in lung cancer tumors. “The ultimate goal is molecularly tailored therapy.”

In a paper published online this week in Nature Medicine, scientists at the Dana-Farber Cancer Institute and Broad Institute of MIT and Harvard showed that a new type of sequencing technology, known as “parallel picoliter reactor sequencing,” could identify mutations in a gene targeted by lung cancer drugs, while traditional sequencing technologies could not. (Specific mutations in this gene make patients responsive or resistant to two cancer therapies, Iressa and Tarceva.)

Matthew Meyerson at Dana-Farber and colleagues studied tumor samples collected from patients with lung cancer. They first amplified the tumor cell DNA from a specific gene – the epidermal growth factor receptor (EGFR) – and then sequenced the gene using technology developed by 454 Life Sciences, a sequencing company based in Branford, CT.

Amplified DNA from a tumor sample contains snippets from both normal and cancer cells. Traditional sequencing methods would generate the sequence of the region containing the gene from this soup of DNA. But because the cancer mutations occur much less frequently than the normal sequence, the signal from the mutated sequence is likely to get lost. With the new method, in contrast, different DNA snippets are isolated by attaching them to tiny beads.

Only one strand from each double-stranded DNA snippet is attached to each bead. To sequence the DNA, each bead is placed in a tiny well, or “reactor,” filled with nucleotides, the building blocks that make up DNA, as well as the chemical reagents that spur the building process. Then a microfluidic system introduces four different nucleotides (G, C, A, and T) into the wells sequentially. When a nucleotide attaches to its complementary nucleotide on the DNA snippet, it causes a biochemical reaction that releases a brief flash of light. A computerized camera records the flashes and correlates them with the types of nucleotides washed across the well, calculating the sequence. Because each sequencing reaction takes place in an isolated reactor, scientists can detect rare mutations, which might occur in only a few wells.

“We found that using the 454 [Life Sciences] method, we could find mutations we would miss with conventional sequencing,” says Meyerson. “The key is to be able to sequence a gene from a single DNA molecule.”

Kettering’s Pao, who was not involved with the new research, says the results are promising. “If this kind of technique can be applied in the clinic, it would be very useful,” he says. “A lot of tumor samples from patients are limited in quantity, so it’s crucial to be able to take a minute amount of tumor cells and detect mutations.”

The technology was launched commercially last year, and 20 or so systems have already been sold, according to Michael Egholm, the company’s vice president of molecular biology.

The outfit is one of several companies striving to create fast, accurate, and affordable sequencing methods, which could ultimately have a broad impact on both cancer research and clinical practice. Last year, the National Institutes of Health (the nation’s premier biomedical funding agency) announced a project to create an atlas of genetic mutations in selected types of tumors. The number and types of tumors that can be sequenced will depend largely on the speed, accuracy, and cost of new sequencing methods (see “Genomic War on Cancer”).

“We think in a few years, we’ll have a catalogue of genes involved in cancer,” says Larry Thompson, a spokesman for the National Human Genome Research Institute, one of the sponsors of the atlas project. “Then we should be able to develop new diagnostic tests and new targets.”

“The more these technology companies move forward with improving the technology and driving down the cost,” he adds, “the more rapidly they will reach the clinic.”

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