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

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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

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BRCA1 Protein
Germ-Line Mutation
Renal Cell Carcinoma
Genes
Mutation
von Hippel-Lindau Disease
Missense Mutation
Tumor Suppressor Genes
Catalytic Domain
Neoplasms
Familial renal cell carcinoma
Phenotype

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology

Cite this

Farley, M. N., Schmidt, L. S., Mester, J. L., Peña-Llopis, S., Pavia-Jimenez, A., Christie, A., ... 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

A novel germline mutation in BAP1 predisposes to familial clear-cell renal cell carcinoma. / Farley, Megan N.; Schmidt, Laura S.; Mester, Jessica L.; Peña-Llopis, Samuel; Pavia-Jimenez, Andrea; Christie, Alana; Vocke, Cathy D.; Ricketts, Christopher J.; Peterson, James; Middelton, Lindsay; Kinch, Lisa; Grishin, Nick; Merino, Maria J.; Metwalli, Adam R.; Xing, Chao; Xie, Xian Jin; Dahia, Patricia L M; Eng, Charis; Linehan, W. Marston; Brugarolas, James.

In: Molecular Cancer Research, Vol. 11, No. 9, 09.2013, p. 1061-1071.

Research output: Contribution to journalArticle

Farley, MN, Schmidt, LS, Mester, JL, Peña-Llopis, S, Pavia-Jimenez, A, Christie, A, Vocke, CD, Ricketts, CJ, Peterson, J, Middelton, L, Kinch, L, Grishin, N, Merino, MJ, Metwalli, AR, Xing, C, Xie, XJ, Dahia, PLM, Eng, C, Linehan, WM & Brugarolas, J 2013, 'A novel germline mutation in BAP1 predisposes to familial clear-cell renal cell carcinoma', Molecular Cancer Research, vol. 11, no. 9, pp. 1061-1071. https://doi.org/10.1158/1541-7786.MCR-13-0111
Farley MN, Schmidt LS, Mester JL, Peña-Llopis S, Pavia-Jimenez A, Christie A et al. A novel germline mutation in BAP1 predisposes to familial clear-cell renal cell carcinoma. Molecular Cancer Research. 2013 Sep;11(9):1061-1071. https://doi.org/10.1158/1541-7786.MCR-13-0111
Farley, Megan N. ; Schmidt, Laura S. ; Mester, Jessica L. ; Peña-Llopis, Samuel ; Pavia-Jimenez, Andrea ; Christie, Alana ; Vocke, Cathy D. ; Ricketts, Christopher J. ; Peterson, James ; Middelton, Lindsay ; Kinch, Lisa ; Grishin, Nick ; Merino, Maria J. ; Metwalli, Adam R. ; Xing, Chao ; Xie, Xian Jin ; Dahia, Patricia L M ; Eng, Charis ; Linehan, W. Marston ; Brugarolas, James. / A novel germline mutation in BAP1 predisposes to familial clear-cell renal cell carcinoma. In: Molecular Cancer Research. 2013 ; Vol. 11, No. 9. pp. 1061-1071.
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AU - Christie, Alana

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