FLCN-mutated oncocytic tumor in the thyroid defines a biologically distinct subset characterized by metabolic remodeling and canonical oncogenic signaling suppression [RNA-Seq]

ABSTRACT: Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant disorder caused by germline pathogenic variants in FLCN. Here, we describe an oncocytic tumor in the thyroid harboring pathogenic FLCN alterations. The tumor showed indolent clinical behavior and was composed of solid sheets of oncocytic cells with abundant granular eosinophilic cytoplasm. Mitochondrial genome sequencing demonstrated preserved mitochondrial architecture without pathogenic mitochondrial DNA alterations. In vitro functional studies demonstrated that FLCN deficiency was associated with global attenuation of canonical phosphorylation–dependent signaling pathways, activation of AMPK signaling, upregulation of GPNMB, and increased expression of the mitochondrial marker Prohibitin, consistent with a cellular stress response. RNA sequencing analyses further indicated coordinated suppression of multiple metabolic and signaling pathways. These findings suggest that an FLCN-mutated oncocytic tumor in the thyroid represents a biologically distinct subset driven primarily by compensatory mitochondrial biogenesis rather than by classical oncogenic signaling activation or primary mitochondrial genome instability.

ORGANISM(S): Homo sapiens

PROVIDER: GSE327395 | GEO | 2026/04/15

REPOSITORIES: GEO