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Researchers have developed a simple assay that appears to be able to reveal the evolutionary relationships among various tumor sites within a patient. "If we could build a 'family tree' of all cancer nodules in a patient, we could determine how different tumors are related to each other and reconstruct how the cancer evolved," Kamila Naxerova, PhD, a postdoctoral research fellow in the Steele Laboratory for Tumor Biology at Massachusetts General Hospital, explained in a news release about the study published in PNAS Early Edition (doi:10.1073/pnas.1400179111).

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"Usually that would require extensive genetic analysis with complex sequencing methods, but our methodology achieves that goal quickly and with minimal experimental effort."


The approach developed by the MGH team focused on small areas of the human genome-so-called polyguanine (poly-G) repeats that are particularly susceptible to mutation, with genetic "mistakes" occurring frequently during cell division. While these mutations do not directly relate to the development or progression of a tumor, they can reveal its lineage.


As described in the news release, Naxerova and her colleagues for the first time adapted poly-G repeat analysis-initially developed to study lineage relationships between single cells in mice-to the study of human cancer. Analyzing the poly-G profiles of primary and metastatic colon cancer samples from 22 patients showed that how the primary and metastatic tumors related to each other was different for each patient.


In some individuals there were significant genetic differences between tumor sites, suggesting early metastatic spread; in others, there was little difference between a primary tumor and its metastases.


The investigators also identified instances in which the genetic profiles of metastases were similar to those of only some cells in the primary tumor, suggesting that those cells were the source of the metastases, and other cases in which the genetic profiles of metastases from the same primary differed depending on their location.


"We found that there are several paths that can lead to metastatic disease," Naxerova said. "We are now applying this methodology to address specific clinically relevant questions about the biology of metastasis in larger numbers of patients. The method is fast and inexpensive and should be applicable to other types of tumors other than colon cancer."


One of her coauthors, Elena Brachtel, MD, of the Department of Pathology at MGH, noted that archival tissues from the files of the department were used for the study: "After diagnostic studies on tissue removed during a patient's operation are completed, the formalin-fixed paraffin tissue blocks are stored for several years. Increasingly, new molecular tests can be performed on tissue that was removed from a patient several years earlier, at a time when these tests were not yet available."


The study's senior author, Rakesh K. Jain, PhD, Director of the Steele Lab and Cook Professor of Radiation Oncology (Tumor Biology) at Harvard Medical School, said that the assay has many potential clinical applications: "For example, it could be used to reliably and quickly distinguish a metastasis from a second, independent tumor. Or it could identify the primary tumor in situations where multiple lesions are present and it is ambiguous which one is responsible for seeding metastases."