Finding the Hidden Mutations That Control Cancer

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

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.