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Vol. LXVI, No. 3
January 31, 2014

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Kidney Cancer Genes Identified Through Trans-NIH Effort

NCI’s Dr. Marston Linehan said of his branch’s work, “We could not have done this anywhere other than here at the Clinical Center.”
NCI’s Dr. Marston Linehan said of his branch’s work, “We could not have done this anywhere other than here at the Clinical Center.”
When Dr. W. Marston Linehan came to NIH in 1982, kidney cancer was thought to be a single disease. Now, kidney cancer is known to be a number of different cancers that happen to occur in the kidney.

Linehan, chief of the Urologic Oncology Branch in NCI’s Center for Cancer Research, reviewed progress made in understanding the genetic basis of kidney cancer when he gave the Astute Clinician Lecture in Masur Auditorium recently.

Linehan began his career at NIH as a senior investigator and urologist-in-charge at NCI. Early in his career, when he and his colleague Dr. Berton Zbar examined the tumors of patients with kidney cancer, they found the same chromosomal abnormality, a loss of a segment of chromosome 3. Their next step was to find the location of the chromosome 3 gene.

Linehan and his colleagues devoted a number of years to searching for the gene’s location before they concluded that his strategy was too slow. At the rate they were going, it could’ve taken almost 55 years to pinpoint the gene and determine its sequence. A colleague advised him that if there were a hereditary version of kidney cancer, he might find the gene by studying kidney cancer families.

“We set up a hereditary cancer program here at NIH to bring in families and evaluate them and determine who is affected and who wasn’t, so we could perform a genetic linkage analysis to identify the disease,” Linehan said. “Over the years, we have had the unbelievable opportunity to evaluate nearly 1,000 families.”

The program brings families to the Clinical Center, where NIH researchers can study them. Linehan assembled a team of urologic and general surgeons, geneticists, radiologists, nurses, data managers, urologic oncology fellows, neurosurgeons, ophthalmologists, basic scientists and statisticians to work together to find the genetic basis.

Since the program began, Linehan and his colleagues have discovered 5 different types of inherited kidney cancers and identified the genetic basis of 5 different types of kidney cancer. Each is caused by a different genetic mutation that interferes with cells’ ability to recognize and react to abnormalities in oxygen, iron, nutrients or energy.

Linehan and his colleagues have used what they learned to provide the foundation for the development of individual targeted therapeutic approaches for each type of kidney cancer. The FDA has since approved seven drugs for the treatment of advanced kidney cancer. “As thrilled as we are about this, we are not home yet,” Linehan said. “We still have a ways to go before we will see the development of effective forms of therapy for every patient with this disease.”

Linehan stressed that his research could not have taken place anywhere else. “We could not have done this anywhere other than here at the Clinical Center,” he said. “It is truly an NIH project. My assistant told me the other day, ‘You work with 137 different people from 29 labs and branches, from 9 different institutes.’”

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