title: Genomic profiling of the genes on chromosome 3p in sporadic clear cell renal cell carcinoma.
abstract: Somatic mutations of the BRCA1 associated protein-1 (BAP1) gene, which maps to 3p21, have been found in several tumors including malignant mesothelioma, uveal melanoma, and renal cell carcinoma (RCC). The role of BAP1 inactivation in tumor development remains unclear. It has been reported that Vhl knock-out mice did not develop RCC, but Vhl knock-out mice with single allele loss of Bap1 in nephron progenitor cells developed RCC, indicating that Bap1 inactivation may be essential in murine renal tumorigenesis. To clarify the role of BAP1 in human RCC development, we performed mutation analyses, including copy number detection of BAP1 and assessment of allelic imbalance using microsatellite polymorphisms on 3p, in 45 RCC samples derived from 45 patients without VHL or BAP1 germline mutation. Additionally, we analyzed the sequences of the VHL, PBRM1, and SETD2 genes, and examined promoter methylation of VHL. Using immunostaining, we also checked for expression of BAP1 protein, which is normally located in the nuclei. None of the RCCs had biallelic deletion of BAP1, but five (11.1%) showed a biallelic mutation (four with a sequence-level mutation with monoallelic loss and one with a biallelic sequence-level mutation); these cells were negative for nuclear BAP1 staining. These patients had worse recurrence-free survival than the patients without a biallelic mutation (p=0.046). However, there were no significant differences in worse outcome by multivariate analysis combined with age, T stage, histological subtype, infiltration and vascular invasion. In 35 RCCs (77.8%), monoallelic loss of BAP1 was accompanied by VHL biallelic mutation or VHL promoter hypermethylation. In five RCCs (11.1%), we detected 3p loss-of-heterozygosity, but the copy number of BAP1 was normal. Surprisingly, nuclear staining of BAP1 was negative in 10 out of 31 tumors (32.3%) with hemizygous normal BAP1, suggesting that haploinsufficiency may relate to RCC development.
authors.affiliation: Department of Urology, Hyogo College of Medicine, Hyogo 663-8501, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Togo
authors.affiliation: Department of Genetics, Hyogo College of Medicine, Hyogo 663-8501, Japan.
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Yoshikawa
authors.affiliation: Department of Urology, Hyogo College of Medicine, Hyogo 663-8501, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Genetics, Hyogo College of Medicine, Hyogo 663-8501, Japan.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Nakano
authors.affiliation: Department of Urology, Hyogo College of Medicine, Hyogo 663-8501, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kanematsu
authors.affiliation: Division of Surgical Pathology, Department of Pathology, Hyogo College of Medicine, Hyogo 663-8501, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Zozumi
authors.affiliation: Department of Urology, Hyogo College of Medicine, Hyogo 663-8501, Japan.
authors.forename: Michio
authors.initials: M
authors.lastname: Nojima
authors.affiliation: Division of Surgical Pathology, Department of Pathology, Hyogo College of Medicine, Hyogo 663-8501, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Hirota
authors.affiliation: Department of Urology, Hyogo College of Medicine, Hyogo 663-8501, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Department of Genetics, Hyogo College of Medicine, Hyogo 663-8501, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hashimoto-Tamaoki
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057895:Haploinsufficiency; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D017422:Sequence Analysis, DNA / Q000379:methods; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000235:genetics* / Q000378:metabolism*
chemical_list: C400134:BAP1 protein, human; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase