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Expert Stresses Significance of Genetic Differences in Kidney Cancer

Angelica Welch
Published: Thursday, May 04, 2017

W. Marston Linehan, MD

W. Marston Linehan, MD

There are 16 different known genes that cause kidney cancer and at least 13 different types of inherited kidney cancer, says W. Marston Linehan, MD, emphasizing the need to understand the genetic differences between these diseases.

Starting with the investigation of Von Hippel-Lindau (VHL) hereditary cancer syndrome in the 1980s, researchers began studying the genetics of hereditary kidney cancers in an effort to better understand the differences between various forms of the disease. Lessons learned from VHL, hereditary papillary renal cell carcinoma (PRCC), and hereditary leiomyomatosis and renal cell carcinoma (HLRCC) over the past 3 decades have lead oncologists further away from surgical intervention and closer to novel targeted therapies, for each disease, and possibly immunotherapy in a few.

In an interview with OncLive, Linehan, chief, Urologic Oncology Branch, National Cancer Institute, discussed the landscape of kidney cancer, current clinical trials, and hope for the future of immunotherapy in this disease.

OncLive: Can you describe the current landscape of kidney cancer?

Linehan: We started working on kidney cancer 33 years ago. Our goal was to understand the genes that cause kidney cancer, with the idea of studying their pathways and then developing therapies to target those pathways in patients with advanced, sporadic, non-inherited kidney cancer. What we've learned is that kidney cancer is not a single disease—it is a number of different diseases with different histologies, different clinical courses, responding differently to therapy, and of course, caused by different genes. We know now that kidney cancer is caused by at least 16 different genes. A huge amount has been learned about kidney cancer by studying families, because they are really the window to understanding therapy in patients with sporadic, non-inherited kidney cancer. 

When we started looking at kidney cancer in the 1980s, we started on a hereditary type called VHL hereditary cancer syndrome, in which patients are at risk to develop tumors in a number of organs, including, of course, the kidney. We studied these patients and these families—these very brave people—and we managed them, learned how to treat them surgically and learned how to do active surveillance. And what we found out was that we should recommend against surgery in patients with VHL whose kidney tumors are smaller than 3 cm—the so-called "3 centimeter rule."

And to date, we have not had 1 patient develop metastatic disease when managed in that fashion. We are very happy about that, and we really want to develop therapies so that we do not have to do surgery. We have managed nearly 800 patients with VHL, and so many of those have had to have so many kidney surgeries, so we are very enthusiastic about the potential to target that gene pathway. 

Another topic of hereditary kidney cancer that we studied that is very helpful in understanding non-inherited non-hereditary kidney cancer is PRCC. We defined it in the 1990s, and then discovered the gene for this disease was called MET—and those patients with PRCC that have a germline MET-gene mutation are highly likely to develop bilateral, multifocal, type 1 papillary kidney cancer. We also know that that gene is mutated in a pretty significant number of patients with non-inherited kidney cancer. There are different types of alterations or increase copy numbers in over 80% of tumors from patients with type 1 papillary kidney cancer. So, we are very interested in targeted that pathway—the MET pathway. We have run a multicenter trial at the NCI targeting MET in patients with hereditary PRCC and we saw really dramatic responses. We are now doing trials of another MET drug targeting this population, but also in patients with non-inherited PRCC.

The third one that I will tell you about, which is the most humbling disease that I work with, is a hereditary cancer syndrome called HLRCC. This is a not uncommon hereditary cancer syndrome in which patients are at risk to develop cutaneous leiomyomas and uterine leiomyomas, and a very aggressive form of type 2 papillary kidney cancer. We know now that HLRCC is caused by a gene for the Krebs cycle enzyme fumarate hydratase (FH). It is really pretty amazing when you think about it—a Krebs cycle enzyme gene mutated cancer. We know now that there are at least 3 different Krebs cycle enzyme mutation cancers—FH, succinate dehydrogenase (SDH), IDH 1 and IDH 2, and the first 2 of those cause hereditary kidney cancer—FH and SDH.

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