A Novel Germline Mutation in BAP1 Predisposes to Familial Clear-Cell Renal Cell Carcinoma

被引：121

作者：

Farley, Megan N. ^{[1
,2
]}

Schmidt, Laura S. ^{[8
,10
]}

Mester, Jessica L. ^{[11
,12
,13
]}

Pena-Llopis, Samuel ^{[1
,3
,4
]}

Pavia-Jimenez, Andrea ^{[1
,3
,4
]}

Christie, Alana ^{[1
]}

Vocke, Cathy D. ^{[8
]}

Ricketts, Christopher J. ^{[8
]}

Peterson, James ^{[8
]}

Middelton, Lindsay ^{[8
]}

Kinch, Lisa ^{[5
]}

Grishin, Nick ^{[5
]}

Merino, Maria J. ^{[9
]}

Metwalli, Adam R. ^{[8
]}

Xing, Chao ^{[6
]}

Xie, Xian-Jin ^{[1
]}

Dahia, Patricia L. M. ^{[7
]}

Eng, Charis ^{[11
,12
,13
,14
,15
]}

Linehan, W. Marston ^{[8
]}

Brugarolas, James ^{[1
,3
,4
]}

机构：

[1] Univ Texas SW Med Ctr Dallas, Simmons Comprehens Canc Ctr, Dallas, TX 75390 USA

[2] Univ Texas SW Med Ctr Dallas, Dept Clin Genet, Dallas, TX 75390 USA

[3] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA

[4] Univ Texas SW Med Ctr Dallas, Dept Dev Biol, Dallas, TX 75390 USA

[5] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA

[6] Univ Texas SW Med Ctr Dallas, McDermott Ctr Human Growth & Dev, Dallas, TX 75390 USA

[7] Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, Dept Med, San Antonio, TX 78229 USA

[8] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA

[9] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA

[10] SAIC Frederick Inc, Basic Sci Program, Frederick Natl Lab Canc Res, Frederick, MD USA

[11] Cleveland Clin, Genom Med Inst, Cleveland, OH USA

[12] Cleveland Clin, Lerner Res Inst, Cleveland, OH USA

[13] Cleveland Clin, Taussig Canc Inst, Cleveland, OH USA

[14] Case Western Reserve Univ, Sch Med, Dept Genet & Genome Sci, Cleveland, OH USA

[15] Case Western Reserve Univ, Sch Med, CASE Comprehens Canc Ctr, Cleveland, OH USA

来源：

MOLECULAR CANCER RESEARCH | 2013年 / 11卷 / 09期

关键词：

UBIQUITIN HYDROLASE; SOMATIC MUTATIONS; UVEAL MELANOMA; KIDNEY CANCER; PARAGANGLIOMA; MESOTHELIOMA;

D O I：

10.1158/1541-7786.MCR-13-0111

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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. (C) 2013 AACR.

引用

页码：1061 / 1071

页数：11

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