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Recent advances in the genetics of renal cell carcinoma (RCC) have pointed the way to better characterization of tumors and to therapeutic strategies that could substantially improve outcomes, according to a researcher in the field.

In contrast to certain other malignancies, RCC has proven stubborn about giving up its genetic mysteries. Consequently, conventional therapeutic strategies had an underlying presumption that all tumors were alike. That viewpoint has since been discounted.

, of the National Cancer Institute (NCI) in Bethesda, Md., said during a telephone interview that when he started studying kidney cancer 32 years ago, it was considered a single disease, and all patients were treated the same surgically. Linehan is chief of the NCI urologic oncology branch and a pioneer in the study of kidney cancer genetics.

Patients with advanced disease were given the same drugs, none of which worked, he told 乌鸦传媒. As time would prove, kidney cancer is not a single disease but a heterogeneous cancer that has multiple histologic subtypes, each with a different clinical course that responds differently to same therapy.

"So we set out in the early '80s to see if we could develop an effective therapy for this disease," Linehan said. "We showed there was an abnormality, a loss of a segment of chromosome 3, in patients with clear cell kidney cancer. There was no Human Genome Project back then, and we came to the realization that, using the best molecular techniques available at the time, we could definitely find a kidney cancer gene in that location," he recalled.

His team then switched gears overnight, reasoning that studying patients with inherited forms of kidney cancer would allow the power of genetics to identify kidney cancer genes. Understanding the genetic basis of a disease would be the first step in developing therapies to target that kidney cancer pathway. For the next decade, Linehan studied patients with (VHL) syndrome, a hereditary kidney cancer.

Starting Point

"Using genetic linkage analysis, in the spring of 1993 we identified the gene," Linehan said. "Then the following year we showed that the VHL gene was mutated in the nonhereditary, sporadic, nonfamilial type of clear cell kidney cancer."

More recent studies from NCI and elsewhere have shown an activating mutation of VHL in 90% of clear cell kidney cancer, he added. The next step was to figure out how the gene worked, and his lab eventually identified proteins that bind the VHL protein, providing a hint about its potential function.

Building off that work, other investigators found that the VHL complex targets a protein called hypoxia-inducible factor (HIF) for degradation. When HIF is mutated in patients with VHL or nonhereditary clear cell kidney cancer, it becomes the target of the VHL protein complex that accumulates and drives other genes to be expressed, Linehan said. The work provided the foundation for the development of targeted therapeutic approaches, leading to seven FDA-approved drugs for advanced kidney cancer.

Nonetheless, the therapies do not offer a cure for the disease, which could mean "we're not doing a good enough job targeting this pathway." Other genes and pathways are involved, and there's a "little bit of a Manhattan Project going on to target these other genes."

"What has changed is that survival has definitely improved overall with these targeted agents, but few patients are actually cured," Linehan said. "But with interleukin-2 based therapy over 12 years, there was no recurrent disease in about 85% of the patients here in . There is a lot of excitement about targeting the metabolic basis of cancer as well as about the new immunological forms of therapy."

"Notable progress has been made in the development of targeted therapeutic approaches as well as immunologic approaches in patients with advanced kidney disease and we're very optimistic about the potential of new immunologic therapies including agents that target PD-1 and those targeting metabolic tumors," he added.

Continued Progress

Linehan's predictions have proven accurate in recent work to determine the genetic basis of RCC. In addition to VHL, two other genes -- also located on the short terminal of chromosome 3 -- have been identified as key players in the clinical course of clear cell (cc) RCC: PBRM1 and BAP1. However, pathogenesis appears to begin with VHL mutation, said , of the University of Texas Southwestern Medical Center in Dallas. Another gene, 3p, also is affected.

"We believe that renal cell carcinoma begins with an in VHL, followed by loss of 3p and concomitant loss of VHL, PBRM1, and BAP1," Brugarolas said at the in New York City. "Our model predicts that patients whose tumors have different mutations will have different outcomes."

"With a single deletion, the kidney cell is in fact losing one copy of four different tumor suppressor genes," he added.

Investigators in other laboratories have corroborated the findings and supported the model of different outcomes associated with different types of mutations.

Using immunohistochemistry (IHC), Brugarolas and colleagues in Dallas and at the Mayo Clinic in Rochester, Minn., evaluated specimens from about 1,300 patients in an RCC registry at Mayo. The test can evaluate simultaneously tumors' mutation status with respect to BAP1 and PBRM1.

The study showed that patients with BAP1-positive tumors have better outcomes as compared with patients whose tumors are BAP1-negative. Mutation status for PBRM1 did not correlate significantly with outcome.

"We believe we can separate clear cell RCC into four different molecular subtypes, which are associated with different outcomes," Brugarolas said. "Patients with BAP1 and PBRM1 wild-type tumors have the best outcomes, followed by patients with tumors deficient in PBRM1, BAP1-deficient tumors, and deficiency in both PBRM1 and BAP1."

As compared with the wild-type tumors, the three remaining subtypes are associated with hazard ratios of 1.3, 3.2, and 5.2, with respect to less favorable outcomes.

The research has shown that PBRM1 mutations occur in 55% of clear cell RCC, BAP1 in 12%, and both in 3%.

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