Dr. W. Marston Linehan
Understanding the Genetic Basis of RCC
Since 1982, Dr. Linehan’s clinical research career has been focused on the identification of tumor suppressor genes and oncogenes in familial and sporadic genitourinary malignancies. His greatest contribution to the field so far is the discovery of the genetic basis of RCC, specifically the genes and gene pathways involved in the development of this disease.
In an interview with the Genitourinary Cancers Symposium Daily News, Dr. Linehan debunked some of the common misconceptions about RCC.
“When we started studying kidney cancer in the early 1980s, it was considered to be a single disease,” he said.
This view resulted in uniform treatment strategies for all patients with RCC and, consequently, with some poor outcomes.
“We performed the same operation for all types of kidney cancer, and we gave the same drugs, none of which were effective, to all patients with metastatic disease,” Dr. Linehan explained.
Largely owing to the continued research efforts of Dr. Linehan and his team, we now know that RCC is not a single disease.
“It is made up of a number of different types of cancer, each with a distinct histology, each with a different clinical course, each responding differently to therapy, and each caused by a different gene,” he said.
At least 15 different genes have been identified as RCC-causing genes. Dr. Linehan said that most insights about the genetic basis of RCC stem from studies of families with the disease.
“There are a number of different types of genetically defined familial RCC, including VHL, HPRCC, BHD, and HLRCC,” he said. “For example, VHL is a hereditary cancer syndrome in which affected individuals are at risk of developing tumors in a number of organs, including the kidneys.”
Dr. Linehan’s team is credited with the discovery of genes associated with the development of some of these hereditary malignancies, including the VHL gene in VHL and clear cell RCC, the MET gene in HPRCC, and the FLCN gene in BHD.
In addition, his work describing the clinical phenotype and delineation of the fumarate hydratase pathway in patients affected by HLRCC “has provided clinicians with clinical and surgical approaches for the management of VHL-, HPRCC-, BHD-, and HLRCC-associated RCC and has provided the foundation for the development of novel therapeutic approaches for patients with clear cell, type 1 papillary, chromophobe, and type 2 papillary RCC.”
During his lecture, Dr. Linehan will discuss the risks associated with carrying a mutation in any of these genes, as well as the recommended treatment of patients who develop associated malignancies. He also will delve deeper into the current research strategies aimed at finding novel RCC therapies that target these gene pathways. Finally, he will talk about the ongoing and planned clinical trials in patients with VHL-, HPRCC-, BHD-, and HLRCC-associated RCC.
Improving the Diagnosis, Treatment, and Prevention of RCC
With more than 700 peer-reviewed publications in the field, Dr. Linehan is a well-respected member of the oncology community. He has put his knowledge and expertise to work by serving on numerous professional and editorial boards of acclaimed journals including the Journal of the National Cancer Institute, the Kidney Cancer Journal, and Nature Reviews Urology. In addition, he has helped communicate the importance of oncology research by serving as a panelist on the 2016 White House Precision Medicine Initiative Summit and by holding scientific briefings on a range of oncology topics.
During the past 30 years at NCI, Dr. Linehan’s research has focused on identifying the genes that cause RCC, studying the pathways of RCC genes, and developing and evaluating novel therapeutic approaches to treat RCC. His current research builds on his past findings.
“The focus and goals of our current research projects are to develop better methods for diagnosis, treatment, and, ultimately, prevention of RCC,” he said.
Among his collaborators in this research effort are Adam Metwalli, MD, who directs the surgical treatment of patients with localized/locally advanced RCC at NCI, and Ramaprasad Srinivasan, MD, PhD, who directs the therapeutic studies in patients with advanced RCC treated at the Urologic Oncology Branch at NCI.
The Outlook for RCC Research
Understanding the genetic basis of RCC has had direct implications on the effective treatment of patients with the disease, as well as on the search for new treatment options. In the next decade, Dr. Linehan expects to see continued progress in research focused on understanding RCC’s complex genetics.
“Advances in genomics will continue to provide insights in the RCC pathways and will provide the foundation for the development of effective forms of treatment, as well as prevention, in the near and distant future,” he said.
He also believes that mutation testing will play an important role in monitoring families at risk of developing RCC.
“The availability of rapid and inexpensive mutation testing will significantly simplify the characterization of families with RCC,” he said.
–Jasenka Piljac Žegarac, PhD