title: Identification and characterization of Birt-Hogg-Dubé associated renal carcinoma.
abstract: The Birt-Hogg-Dubé (BHD) gene is responsible for BHD syndrome, a rare autosomal dominant disease, characterized by benign hair follicle tumours, spontaneous pneumothorax and renal neoplasms with diverse histology. To elucidate its involvement in the development of renal neoplasms, we examined a total of 100 sporadic renal tumours with various histological subtypes for BHD mutation by SSCP-sequencing analyses. We found one germline insertion mutation in the C8 hotspot of exon 11 (c.1733insC), which is known to have a strong association with renal tumour occurrence. The germline-mutated patient suffered from solitary renal cell carcinoma (RCC) but did not have any other BHD manifestations or family history. The tumour revealed heterogeneous cytomorphology, mainly a mixture of eosinophilic and focally clear cells with tubulopapillary architecture. In this tumour, both BHD alleles were inactivated by germline mutation concomitant with loss of heterozygosity, and the amount of BHD mRNA detected by real-time quantitative PCR (RQ-PCR) was very low. Renal tumour subtype/nephron segment-specific gene expression detected by RQ-PCR demonstrated that the tumour expressed relatively high amounts of alpha-methylacyl-CoA racemase (AMACR) and the KIT oncogene, but relatively low amounts of carbonic anhydrase IX (CA9), aquaporin 1 (AQP1), claudin 7 (CLDN7), parvalbumin (PVALB), chloride channel Kb (CLCNKB) and 11-beta-hydroxysteroid dehydrogenase 2 (HSD11B2), suggesting diverse mRNA signatures. Further clustering analysis of 88 renal tumours based on expression of these eight genes sub-classified the tumour as close to oncocytomas and chromophobe RCCs, which are considered distal nephron-associated tumours. These data suggest that somatic mutation of BHD is relatively rare in Japanese patients. The BHD-mutated RCC identified in this study, which exhibits heterogeneous biological features in both morphology and gene expression signatures, seems to deviate from our current understanding of renal tumour classification.
authors.affiliation: Department of Urology and Molecular Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Murakami
authors.affiliation: Department of Urology and Molecular Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: F
authors.initials: F
authors.lastname: Sano
authors.affiliation: Department of Urology and Molecular Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Urology and Molecular Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Komiya
authors.affiliation: Department of Urology and Molecular Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Baba
authors.affiliation: Department of Urology, Kanagawa Cancer Centre, Yokohama, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Osada
authors.affiliation: Department of Molecular Pathology and Oncology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Nagashima
authors.affiliation: Department of Urology, Yokohama City University Medical Centre, Yokohama, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kondo
authors.affiliation: Department of Urology and Molecular Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Nakaigawa
authors.affiliation: Department of Urology, Kanagawa Cancer Centre, Yokohama, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Miura
authors.affiliation: Department of Urology and Molecular Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kubota
authors.affiliation: Department of Urology and Molecular Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Yao
authors.affiliation: Department of Urology, Yokohama City University Medical Centre, Yokohama, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kishida
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D016000:Cluster Analysis; D004802:Eosinophilia / Q000235:genetics / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D016147:Genes, Tumor Suppressor / Q000502:physiology; D018095:Germ-Line Mutation / Q000235:genetics; D006201:Hair Diseases / Q000235:genetics / Q000473:pathology; D018859:Hair Follicle / Q000473:pathology; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D019656:Loss of Heterozygosity / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics*; D011030:Pneumothorax / Q000235:genetics / Q000473:pathology; D016133:Polymerase Chain Reaction / Q000379:methods; D018807:Polymorphism, Single-Stranded Conformational; D011506:Proteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D013577:Syndrome; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C476078:FLCN protein, human; D009363:Neoplasm Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins