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 journalArticle

102 Scopus citations

Abstract

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
Volume11
Issue number9
DOIs
StatePublished - Sep 2013

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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    Farley, M. N., Schmidt, L. S., Mester, J. L., Peña-Llopis, S., Pavia-Jimenez, A., Christie, A., Vocke, C. D., Ricketts, C. J., Peterson, J., Middelton, L., Kinch, L., Grishin, N., Merino, M. J., Metwalli, A. R., Xing, C., Xie, X. J., Dahia, P. L. M., Eng, C., Linehan, W. M., & Brugarolas, J. (2013). A novel germline mutation in BAP1 predisposes to familial clear-cell renal cell carcinoma. Molecular Cancer Research, 11(9), 1061-1071. https://doi.org/10.1158/1541-7786.MCR-13-0111