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NHGRI's Trent Delves into Genetics of Melanoma

By Peggy Vaughn

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DNA microarrays and high-throughput genotyping are Dr. Jeffrey M. Trent's everyday tools in his role as scientific director of the National Human Genome Research Institute and chief of its Cancer Genetics Branch.

Continued...

But it's the talent and dedication of his staff and colleagues worldwide that truly aided his work in locating the genes associated with the malignant progression of tumor cells, he told the audience at the G. Burroughs Mider Lecture in Masur Auditorium on Oct. 9. "It's nice to have tools and mathematical equations, but it's essential to have people," he said during his presentation on "Integrating Genetics, Genomics and Biology of Malignant Melanoma."

Trent arrived at NHGRI in 1993 and helped establish its Division of Intramural Research. Under his guidance, it is now a major research center in human genetics investigating the molecular changes behind the predisposition to, and progression of, human cancers. Much of his work has focused on the dire problem of malignant melanoma, the deadliest form of skin cancer, which is reaching epidemic proportions worldwide.

Mider lecturer Dr. Jeffrey Trent (r) of NHGRI meets with NIH director Dr. Elias Zerhouni before the talk in Masur Auditorium.

"One in 75 Americans born in the year 2000 will develop melanoma in their lifetime," he said. "Melanoma, as an entity, has increased more rapidly than any other cancer except lung cancer in women. It often afflicts young people — the median age of patients is 45. It is estimated the cost of the disease exceeds $1 billion a year in the United States alone."

The genetics of melanoma genesis and progression are not completely understood even today. But two decades ago, when Trent first began in the field as a cytogeneticist, it was known that chromosome 6 played a primary role in the progression of the disease. Investigators began to build on that knowledge, Trent said.

"Disorders of chromosome 6 are almost universally happening in the overwhelming majority of the tumors in this disease," he said. "Investigators began to look at it for solutions to the problem, to not just stare at cytogenic patterns but to dissect them."

Using new chromosome microdissection technology, researchers began to identify the genes that caused the disorder, hybridized them, and in animal studies showed that transferring an extra chromosome 6 into a melanoma could reduce tumorigenicity. Array-based technologies also allowed researchers to begin looking at tens of thousands of genes and to analyze gene expression in cancer. This generated a new taxonomy of the disease, Trent said.

"Melanoma had been looked at as a single entity," he said. "We wanted to get into the molecular taxonomy of it and find cancer pathways. We worked on tests to distinguish tumors as leads into the biology of the disease. From that we were able to elucidate some hints as to what these genes were involved in."

Trent said he was particularly interested in bringing these discoveries into the realm of patient care. He used gene-based technology to address the highly toxic side effects of using IL-2 in the high dose cell therapy pioneered by NCI's Dr. Steve Rosenberg. Using microarray and computational biology, Trent's team looked at literally billions of genes to find the three that separated the patients who would respond to IL-2 therapy from those who would not respond.

"Ultimately, we hope to use this (technology) to distinguish survival patterns and the genes important to this," Trent said.

The factors involved in susceptibility to melanoma are well known, with sun exposure, skin types and family history topping the list. However Trent, teaming with fellow NHGRI researcher Paul Meltzer, recently confirmed the finding that B-RAF gene mutations are a critical component of malignant melanomas, and for the first time presented evidence that even common moles (called nevi) have mutations in this gene.

"Up to 60 percent of melanomas have this mutated gene," he said, with almost 80 percent of nevi showing the identical genetic change. Work continues on investigating a particular gene, wnt5a, as a possible pathway to melanoma. Trent said there can be little doubt for the clinical need to develop molecular-based approaches to augment the routine surgical pathology of the disease.

At the conclusion of a lecture highlighted with dozens of photos of his colleagues, Trent spoke again of the asset he most valued during his years of genome research. "None of this would have been possible without a myriad of workers in a myriad of areas," he said.

Trent also formally announced that he would be leaving NHGRI to lead the private, non-profit Translational Genomics Research Institute in Phoenix. He will remain scientific director while a search is conducted to find his replacement.


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