TY - JOUR
T1 - A novel germline mutation in BAP1 predisposes to familial clear-cell renal cell carcinoma
AU - Farley, Megan N.
AU - Schmidt, Laura S.
AU - Mester, Jessica L.
AU - Peña-Llopis, Samuel
AU - Pavia-Jimenez, Andrea
AU - Christie, Alana
AU - Vocke, Cathy D.
AU - Ricketts, Christopher J.
AU - Peterson, James
AU - Middelton, Lindsay
AU - Kinch, Lisa
AU - Grishin, Nick
AU - Merino, Maria J.
AU - Metwalli, Adam R.
AU - Xing, Chao
AU - Xie, Xian Jin
AU - Dahia, Patricia L M
AU - Eng, Charis
AU - Linehan, W. Marston
AU - Brugarolas, James
PY - 2013/9
Y1 - 2013/9
N2 - 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.
AB - 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.
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U2 - 10.1158/1541-7786.MCR-13-0111
DO - 10.1158/1541-7786.MCR-13-0111
M3 - Article
C2 - 23709298
AN - SCOPUS:84884497841
SN - 1541-7786
VL - 11
SP - 1061
EP - 1071
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 9
ER -