2019 Science, Technology and Environment

W. Marston Linehan, M.D.

Discovered six different genetic origins of kidney cancer and provided the foundation for the development of targeted therapies that have saved thousands of lives

When Dr. Marston Linehan arrived at the National Institutes of Health more than 30 years ago, kidney cancer was considered a single disease. All patients underwent the same surgical procedures and were treated with the same drugs, but 80 percent of those with advanced kidney disease died within two years.

During his years of research and work with patients and their families, Linehan, now chief of the Urologic Oncology Branch, discovered that there are different types of kidney cancer, each with unique genetic characteristics that respond to different therapies. These findings have revolutionized the treatment of this deadly disease to the benefit of thousands of patients.

“Dr. Linehan is the leading researcher in the country and the world when it comes to finding treatments and cures for kidney cancer,” said NIH Director Francis Collins. “By studying members of families, he was able to identify the genes at the DNA level, which have helped with targeted treatments.”

Dr. Norman Sharpless, the former director of the National Cancer Institute and now acting director of the Food and Drug Administration, described Linehan as “a world expert” and “a father figure in the field.”

“Kidney cancer is a terrible cancer,” Sharpless said. “He has made a lot of progress identifying what drives this cancer and how to manage the treatment in patients.”

Each year, more than 100,000 people die from kidney cancer and 300,000 individuals worldwide are diagnosed with the disease.

Since pioneering the study of the genetic basis of kidney cancers, Linehan and his team of researchers have identified six kidney cancer genes and five new inherited kidney diseases, and they defined the clinical features and the surgical and medical management for these cancers. Linehan also laid the groundwork for targeted therapies for both hereditary and nonhereditary kidney cancers.

“My approach to finding genes and studying therapies has been studying families in which kidney cancer runs,” Linehan said.

To date, researchers have discovered a total of 16 different genes that cause kidney cancer and at least 13 different types of inherited kidney cancer.

Linehan came to the NIH in 1982 to set up a program to develop better methods of diagnosis and treatment for patients with urinary tract and genital malignancies. He soon began studying tumors from patients with noninherited kidney cancer, aiming to identify a gene that could lay a foundation for developing a targeted therapy.

“We spent years trying to find the genes,” Linehan said. “We identified the location of the first kidney cancer gene, but this was decades prior to any human genome project so it was a huge obstacle.”

With his goal in mind, Linehan changed his focus to study families with the disease, setting up a hereditary cancer program at the National Cancer Institute and enlisting physicians and scientists across the NIH to evaluate patients and map the gene in families.

“We found the gene for the most common form kidney cancer [clear cell] genes by studying kidney cancer in families,” he said. Subsequent studies of the gene led scientists worldwide to develop nine different therapeutic agents targeting the pathway of that gene in patients with advanced clear cell kidney cancer.

Success with this first gene led Linehan and his team to extend their work to thousands of patients, which led to the discovery of other major genes for familial as well as nonfamilial kidney cancer.

“His work on understanding the genetic basis of kidney cancer has led to novel surgical and precision therapeutic approaches for patients with advanced kidney cancer worldwide,” said Dr. Tom Mistelli, director of NIH’s Center for Cancer Research. “He was ahead of his time. He changed the way people think about kidney cancer.”

One particular family has been a driving force in Linehan’s research. In 1989, he was treating an 18-year-old woman who had a very aggressive and rare form of cancer. He removed her kidney, but she died several months later. Her mother, who had the same cancer, died 14 months after her daughter.

“She was the first patient in the world known to have this type of cancer,” Linehan said. “It took us 18 years to find out the type of kidney cancer she had, but our research identified the type of cancer and we have developed the treatment targeting this specific gene pathway.”

Today, Linehan follows 525 people at risk for this type of kidney cancer. Those with the cancer are being treated with the therapy Linehan and his team developed.

“Dr. Linehan is dedicated and compassionate, and he is continuing to look for treatments,” said Collins. “He is unique because he is a surgeon who still works in the operating room, but he also does cutting-edge research in the laboratory.”

Linehan said he is now working on a number of new projects, including one dealing with a very aggressive and deadly type of kidney cancer. Like his other work, this project has been a collaborative effort among team members and across the NIH, he said.

“Team science is the way to make progress.”