A novel germline mutation in BAP1 predisposes to familial clear-cell renal cell carcinoma

Megan N. Farley, Laura S. Schmidt, Jessica L. Mester, Samuel Peña-Llopis, Andrea Pavia-Jimenez, Alana Christie, Cathy D. Vocke, Christopher J. Ricketts, James Peterson, Lindsay Middelton, Lisa Kinch, Nick Grishin, Maria J. Merino, Adam R. Metwalli, Chao Xing, Xian Jin Xie, Patricia L.M. Dahia, Charis Eng, W. Marston Linehan, James Brugarolas

Research output: Contribution to journalArticlepeer-review

131 Scopus citations


Renal cell carcinoma (RCC) clusters in some families. Familial RCC arises from mutations in several genes, including the von Hippel-Lindau (VHL) tumor suppressor, which is also mutated in sporadic RCC. However, a significant percentage of familial RCC remains unexplained. Recently, we discovered that the BRCA1-associated protein-1 (BAP1) gene is mutated in sporadic RCC. The BAP1 gene encodes a nuclear deubiquitinase and appears to be a classic two-hit tumor suppressor gene. Somatic BAP1 mutations are associated with high-grade, clear-cell RCC (ccRCC) and poor patient outcomes. To determine whether BAP1 predisposes to familial RCC, the BAP1 gene was sequenced in 83 unrelated probands with unexplained familial RCC. Interestingly, a novel variant (c.41T>A; p.L14H) was uncovered that cosegregated with the RCC phenotype. The p.L14H variant targets a highly conserved residue in the catalytic domain, which is frequently targeted by missense mutations. The family with the novel BAP1 variant was characterized by early-onset ccRCC, occasionally of high Fuhrman grade, and lacked other features that typify VHL syndrome. These findings suggest that BAP1 is an early-onset familial RCC predisposing gene. Implications: BAP1 mutations may drive tumor development in a subset of patients with inherited renal cell cancer.

Original languageEnglish (US)
Pages (from-to)1061-1071
Number of pages11
JournalMolecular Cancer Research
Issue number9
StatePublished - Sep 2013

ASJC Scopus subject areas

  • General Medicine


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