Genetic variants implicate dual oxidase-2 in familial and sporadic nonmedullary thyroid cancer

Highly penetrant hereditary thyroid cancer manifests as familial nonmedullary thyroid cancer (FNMTC), whereas low-penetrance hereditary thyroid cancer manifests as sporadic disease and is associated with common polymorphisms, including rs965513[A]. Whole-exome sequencing of an FNMTC kindred identified a novel Y1203H germline dual oxidase-2 (DUOX2) mutation. DUOX2Y1203H is enzymatically active, with increased production of reactive oxygen species. Furthermore, patients with sporadic thyroid cancer homozygous for rs965513[A] demonstrated higher DUOX2 expression than heterozygous rs965513[A/G] or homozygous rs965513[A]- negative patients. These data suggest that dysregulated hydrogen peroxide metabolism is a common mechanism by which high- and low-penetrance genetic factors increase thyroid cancer risk.