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    Genetic evidence explains why some tumors get more aggressive

    Alberto Broniscer, MD, PhD

    A team of St. Jude researchers have taken an important first step in understanding why certain cancers that arise in children’s brains can become more aggressive.

    These cancers start out as so-called low-grade gliomas, slow-growing tumors that represent the most common type of primary brain tumor in children. In some children these tumors undergo a process called malignant transformation, which turns them into deadly cancers called high-grade gliomas. While the progression of low-grade gliomas to high-grade gliomas occurs frequently and has been studied extensively in young adults, little is known about malignant transformation in children.

    Based on medical records and tissue samples of patients treated at St. Jude from 1985–2003, the researchers identified 11 patients whose low-grade gliomas turned to high-grade gliomas within several years. Among 65 patients with low-grade gliomas treated during the same period, the expected risk to undergo malignant transformation within 15 years was about 7 percent.

    The St. Jude researchers decided to look for genetic abnormalities in tissue specimens from patients with gliomas that might represent red flags that could warn clinicians in the future that a child’s low-grade tumor was likely to undergo malignant transformation.

    The team found that either the RB1 or the CDKN2A gene—or both—were deleted in 71 percent of low-grade glioma samples and in 90 percent of tumors after the gliomas had undergone malignant transformation.

    Abnormalities linked to the PTEN biochemical pathway occurred in 76 percent of the patients. The abnormalities found in these cancers before and after malignant transformation are linked to important growth and cell division regulatory mechanisms in cells, according to Alberto Broniscer, MD, Oncology. Broniscer is first author of a report on this work that recently appeared in the Journal of Clinical Oncology.

    The genetic abnormalities found in low-grade glioma from the pediatric tumors in this study were similar to those seen in adults who have these tumors.

    “This was the largest study to analyze malignant transformation of gliomas in children,” Broniscer said. “But it’s still a preliminary finding that requires a larger study to be validated.”

    The paper’s other St. Jude authors include Suzanne Baker, PhD, Melissa Fraser, PhD, and Richard Gilbertson, MD, PhD, all of Developmental Neurobiology; Mehmet Kocak, Biostatistics; Gerard Zambetti, PhD, Biochemistry; James Dalton and David Ellison, MD, PhD, both of Pathology; Amar Gajjar, MD, Oncology co-chair; and Larry Kun, MD, Radiological Sciences chair.

    April 2007