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Genome-Based Blood Tests May Usher in Personalized Medicine for Cancer

Data from the whole-genome sequencing of tumors from individual cancer patients may be used to develop individualized blood tests that can help physicians tailor treatments to the individual patient, according to results reported by researchers from Johns Hopkins and Life Technologies. The genome-based blood tests, believed to be the first of their kind, may be used to monitor tumor levels after therapy and determine cancer recurrence. This ground-breaking work may help bring the age of personalized medicine right to the cancer patient’s bedside. The sequencing in this project was carried out using the SOLiD next-generation sequencing platform (photo) from Life Technologies."We believe this is the first application of newer generations of whole-genome sequencing that could be clinically useful for cancer patients," says Dr. Victor Velculescu, co-director of the cancer biology program at Johns Hopkins and senior author of the report. "Using this approach, we can develop biomarkers for potentially any cancer patient." In their study, the scientists scanned the genomes of patients' tumors looking for alterations that they say most researchers have not been looking for—i.e., rearrangements of large chunks of DNA rather than changes in a single DNA letter among billions of others. Such DNA rearrangements are widely known to occur exclusively in cancer cells, not normal ones, making them ideal biomarkers for cancer. The researchers call their new approach Personalized Analysis of Rearranged Ends (PARE). "PARE uses genetic characteristics unique to the tumor to monitor disease progression. By exploiting rearrangements specific to the patient's tumor, we have developed a personalized approach for detection of residual disease," said lead author Rebecca Leary, a graduate student at the Johns Hopkins Kimmel Cancer Center.

"In sequencing individuals' genomes in the past, we focused on single-letter changes, but in this study, we looked for the swapping of entire sections of the tumor genome," said Dr. Bert Vogelstein, co-director of the Ludwig Institute at Johns Hopkins. "These alterations, like the reordering of chapters of a book, are easier to identify and detect in the blood than single-letter changes."

In one colon cancer patient, for example, the scientists found a section of chromosome four fused to a section of chromosome eight. "We developed a biomarker that could span this rearrangement and used a blood test to evaluate biomarker levels as the patient received a variety of cancer therapies," said Leary.

After an initial surgery, the patient's biomarker levels initially dropped due to the removal of the majority of the tumor. The biomarker levels then rose again, indicating that additional cancer remained in the patient's body. After chemotherapy and a second surgery, levels of the biomarker dropped substantially, but still showed a small, but measurable, level of the biomarker. This was consistent with a small metastatic lesion that remained in the patient's liver.

The investigators envision that PARE-based biomarkers could also be used to determine whether cancer cells are present in surgical margins or lymph node tissue removed during surgery and possibly for diagnosing early disease. "Eventually, we believe this type of approach could be used to detect recurrent cancers before they are found by conventional imaging methods, like CT scans," said Dr. Luis Diaz, assistant professor of oncology at Johns Hopkins.

The technology used to examine the patients' genomes will become inexpensive, Dr. Velculescu predicted. He said the genome scans in this study cost about $5,000 per patient, but noted that sequencing costs continue to drop. CT scans currently cost $1,500 per scan and are limited in their ability to detect microscopic cancers.

"If current trends in genome sequencing continue, PARE will be more cost-effective than CT scans and could prove to be more informative," said Dr. Kenneth Kinzler, co-director of the Ludwig Center at Johns Hopkins.

The researchers concluded that the new form of testing provides an exquisitely sensitive and broadly applicable approach for the development of personalized biomarkers to enhance the clinical management of cancer patients.

The scientists plan on testing more patient samples and refining their techniques to produce a commercially viable genome-based blood test. They have filed for patents on the technology.

Under a licensing agreement between Johns Hopkins University and Genzyme, Drs. Velculescu, Vogelstein, and Kinzler, are entitled to a share of royalties received by Johns Hopkins on sales of products related to research described in this paper. The terms of these arrangements are managed by Johns Hopkins University in accordance with its conflict-of-interest policies.

This report was published online on February 18, 2010 in Science Translational Medicine and was announced in a press conference at the opening of the American Association for the Advancement of Science (AAAS) annual meeting on that same day. The work is scheduled for publication in the print version of Science Translational Medicine on February 24, 2010. [Johns Hopkins press release] [AAAS press release]