Journal article
A novel germline mutation in BAP1 predisposes to familial clear-cell renal cell carcinoma
Molecular cancer research, Vol.11(9), pp.1061-1071
09/2013
DOI: 10.1158/1541-7786.MCR-13-0111
PMCID: PMC4211292
PMID: 23709298
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. BAP1 mutations may drive tumor development in a subset of patients with inherited renal cell cancer.
Details
- Title: Subtitle
- A novel germline mutation in BAP1 predisposes to familial clear-cell renal cell carcinoma
- Creators
- Megan N Farley - Department of Clinical Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, USALaura S Schmidt - Basic Science Program, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USAJessica L Mester - Taussig Cancer Institute, Cleveland Clinic, Cleveland OH, 44195, USASamuel Pena-Llopis - Deparment of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USAAndrea Pavia-Jimenez - Deparment of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USAAlana Christie - Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USACathy D Vocke - Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD 20892, USAChristopher J Ricketts - Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD 20892, USAJames Peterson - Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD 20892, USALindsay Middelton - Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD 20892, USALisa Kinch - Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USANick Grishin - Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USAMaria J Merino - Translational Surgical Pathology, Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892Adam R Metwalli - Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD 20892, USAChao Xing - McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, Texas, USAXian-Jin Xie - Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USAPatricia L M Dahia - Cancer Therapy and Research Center, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, USACharis Eng - Department of Genetics and Genome Sciences and CASE Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USAW Marston Linehan - Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD 20892, USAJames Brugarolas - Deparment of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Resource Type
- Journal article
- Publication Details
- Molecular cancer research, Vol.11(9), pp.1061-1071
- Publisher
- United States
- DOI
- 10.1158/1541-7786.MCR-13-0111
- PMID
- 23709298
- PMCID
- PMC4211292
- ISSN
- 1557-3125
- eISSN
- 1557-3125
- Grant note
- ZIA BC011038-05 / Intramural NIH HHS ZIA BC011028-05 / Intramural NIH HHS P30 CA142543 / NCI NIH HHS HHSN261200800001E / PHS HHS HHSN261200800001C / CCR NIH HHS HHSN261200800001E / NCI NIH HHS
- Language
- English
- Date published
- 09/2013
- Academic Unit
- Preventive and Community Dentistry; Biostatistics; Dental Research
- Record Identifier
- 9983917686902771
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