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

127 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

  • Medicine(all)


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