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.