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Mol Cancer Res. 2013 Sep;11(9):1061-1071. doi: 10.1158/1541-7786.MCR-13-0111. Epub 2013 May 24.

A novel germline mutation in BAP1 predisposes to familial clear-cell renal cell carcinoma.

Author information

1
Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
2
Department of Clinical Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
3
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD 20892, USA.
4
Basic Science Program, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
5
Genomic Medicine Institute and Lerner Research Institute, Cleveland Clinic, Cleveland OH 44195, USA.
6
Taussig Cancer Institute, Cleveland Clinic, Cleveland OH, 44195, USA.
7
Deparment of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas USA.
8
Deparment of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
9
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
10
Translational Surgical Pathology, Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
11
McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, Texas, USA.
12
Cancer Therapy and Research Center, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, USA.
13
Department of Genetics and Genome Sciences and CASE Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
#
Contributed equally

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.

PMID:
23709298
PMCID:
PMC4211292
DOI:
10.1158/1541-7786.MCR-13-0111
[Indexed for MEDLINE]
Free PMC Article

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