title: Inactivation of BHD in sporadic renal tumors.
abstract: Studies of families with Birt-Hogg-Dubé syndrome (BHD) have recently revealed protein-truncating mutations in the BHD gene, leading to tumorigenesis of the skin and of different cell types of kidney. To additionally evaluate the role of BHD in kidney tumorigenesis, we studied 39 sporadic renal tumors of different cell types: 7 renal oncocytomas, 9 chromophobe renal cell carcinomas (RCCs), 11 papillary RCCs, and 12 clear cell RCCs. We screened for BHD mutations and identified a novel somatic mutation in exon 13: c.1939_1966delinsT in a papillary RCC. We performed loss of heterozygosity (LOH) analysis on 28 matched normal/tumor sets, of which 10 of 28 (36%) demonstrated LOH: 2 of 6 (33%) chromophobe RCCs, 5 of 6 (83%) papillary RCCs, 3 of 12 (25%) clear cell RCCs, but 0 of 4 renal oncocytomas. BHD promoter methylation status was examined by a methylation-specific PCR assay of all of the tumors. Methylation was detected in 11 of 39 (28%) sporadic renal tumors: 2 of 7 (29%) renal oncocytomas, 1 of 9 (11%) chromophobe RCCs, 4 of 11 (36%) papillary RCCs, and 4 of 12 (33%) clear cell RCCs. Five tumors with methylation also exhibited LOH. Mutation and methylation were absent in 9 kidney cancer cell lines. Our results showed that somatic BHD mutations are rare in sporadic renal tumors. The alternatives, LOH and BHD promoter methylation, are the two possible inactivating mechanisms involved. In conclusion, unlike other hereditary kidney cancer-related genes (i.e., VHL and MET), which are cell type-specific, BHD is involved in the entire spectrum of histological types of renal tumors, suggesting its major role in kidney cancer tumorigenesis.
authors.affiliation: Laboratory of Cancer Genetics, Van Andel Research Institute, 333 Bostwick Avenue N.E., Grand Rapids, MI 49503, USA.
authors.forename: Sok Kean
authors.initials: SK
authors.lastname: Khoo
authors.forename: Katherine
authors.initials: K
authors.lastname: Kahnoski
authors.forename: Jun
authors.initials: J
authors.lastname: Sugimura
authors.forename: David
authors.initials: D
authors.lastname: Petillo
authors.forename: Jindong
authors.initials: J
authors.lastname: Chen
authors.forename: Ken
authors.initials: K
authors.lastname: Shockley
authors.forename: John
authors.initials: J
authors.lastname: Ludlow
authors.forename: Robert
authors.initials: R
authors.lastname: Knapp
authors.forename: Sophie
authors.initials: S
authors.lastname: Giraud
authors.forename: Stéphane
authors.initials: S
authors.lastname: Richard
authors.forename: Magnus
authors.initials: M
authors.lastname: Nordenskjöld
authors.forename: Bin Tean
authors.initials: BT
authors.lastname: Teh
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000235:genetics; D018249:Adenoma, Oxyphilic / Q000235:genetics; D001483:Base Sequence; D002291:Carcinoma, Papillary / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics*; D019656:Loss of Heterozygosity; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
chemical_list: C476078:FLCN protein, human; D011506:Proteins; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins