title: Novel intronic germline FLCN gene mutation in a patient with multiple ipsilateral renal neoplasms.
abstract: Multiple renal tumors of diverse morphology are rare and typically seen in Birt-Hogg-Dubé syndrome. Birt-Hogg-Dubé syndrome is a rare inherited cancer syndrome caused by a germline mutation in the folliculin (FLCN) gene, but the genetic causes for histologic diversity of renal tumors in Birt-Hogg-Dubé syndrome have not been elucidated. We describe here a 64-year-old man with a novel germline mutation in the FLCN gene who presented with 3 phenotypically distinct renal tumors in the same kidney, which were histologically classified as oncocytoma (1.4 cm), oncocytic papillary carcinoma (0.5 cm), and clear cell renal carcinoma (0.8 cm). Genetic analysis of normal kidney tissue revealed a heterozygous germline FLCN mutation (intron 9, IVS9+6 C>T). Additional molecular genetic testing revealed somatic mutations and epigenetic events in genes typically associated with these specific histologic tumor types: oncocytoma harbored a second FLCN mutation (intron 12, IVS12+4 C>T), oncocytic papillary carcinoma harbored promoter methylation of FLCN, and a missense mutation in the MET gene (P246L), whereas clear cell carcinoma harbored inactivating VHL mutation (5-base pair deletion in exon 2) and VHL gene promoter methylation. In addition, chromosomal analysis of peripheral blood lymphocytes showed low level chromosome instability, not previously associated with germline mutations in the FLCN gene.
authors.affiliation: Department of Pathology, Creighton University Medical Center, Omaha, NE 68131, USA. zorangatalica@creighton.edu
authors.forename: Zoran
authors.initials: Z
authors.lastname: Gatalica
authors.forename: Stan L
authors.initials: SL
authors.lastname: Lilleberg
authors.forename: Semir
authors.initials: S
authors.lastname: Vranic
authors.forename: Eduardo
authors.initials: E
authors.lastname: Eyzaguirre
authors.forename: Eduardo
authors.initials: E
authors.lastname: Orihuela
authors.forename: Gopalrao
authors.initials: G
authors.lastname: Velagaleti
mesh_terms: D001483:Base Sequence; D004252:DNA Mutational Analysis; D005142:Eyelid Neoplasms / Q000473:pathology; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D007438:Introns / Q000235:genetics; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009378:Neoplasms, Multiple Primary / Q000235:genetics*; D010212:Papilloma / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D013577:Syndrome; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C476078:FLCN protein, human; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins