Gene mutation findings classify renal cell carcinoma

Feb 20 2013

By Lucy Piper, Senior medwireNews Reporter

Researchers have identified mutation-defined subtypes of clear cell renal cell carcinoma (ccRCC) that have distinct clinical outcomes.

They found that patients with ccRCC positive for BAP1 gene mutations presented with more aggressive tumors and had significantly worse overall survival than patients with ccRCC positive for PBRM1 mutations.

The findings "establish the basis for a molecular genetic classification of clear-cell renal-cell carcinoma that could influence treatment decisions in the future," say James Brugarolas (University of Texas Southwestern [UTSW] Medical Center, Dallas, USA) and colleagues.

The researchers assessed 145 patients with primary ccRCC from the UTSW, of whom 21 had BAP1-mutated tumors, including three with mutations in both BAP1 and PBRM1, while 78 patients had tumors exclusively mutated for PBRM1.

The patients with BAP1-mutated tumors presented with more aggressive features than those with PBRM1 mutations, including higher grade, sarcomatoid and rhabdoid histology, and tumor necrosis.

The median overall survival was significantly shorter in patients with BAP1 mutations, at 4.6 years versus 10.6 years for patients with PBRM1 mutations. This difference in overall survival corresponded to a hazard ratio of 2.7, which was similar to the hazard ratio of 2.8 the team obtained in a validation cohort of 327 ccRCC patients from The Cancer Genome Atlas.

The patients from UTSW with the worst overall survival were those with both BAP1 and PBRM1 mutations; although in the minority, they survived for only a median of 2.1 years, Brugarolas and team report.

The BAP1 gene encodes a protein implicated in deubiquitination, while the PBRM1 gene encodes the polybromo-1 protein. Both are located on chromosome 3p, which is the same location as the VHL (von Hippel-Lindau) gene, mutations of which are already known to characterize ccRCC.

"We speculate that, in many instances, the development of clear-cell renal-cell carcinoma is initiated by a focal mutation in VHL, followed by a 3p deletion. 3p loss may eliminate VHL gene function and would leave cells with just one copy of BAP1 and PBRM1," the team writes in The Lancet Oncology.

"Mutation of the remaining BAP1 or PBRM1 allele may initiate tumorigenesis, resulting in tumors of different aggressiveness depending on which gene is mutated."

Discussing the findings in a related Comment, Toni Choueiri and colleagues, from Harvard Medical School in Boston, Massachusetts, USA, say: "Although the clinical utility of PBRM1 and BAP1 mutations status as biomarkers for renal-cell carcinoma might not be immediately applicable in daily clinical practice, these findings are a meaningful step."

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