Genetic Variants Implicate Dual Oxidase-2 (DUOX2) in Familial and Sporadic Non-Medullary Thyroid Cancer

Highly penetrant hereditary thyroid cancer manifests as familial nonmedullary thyroid cancer (FNMTC), while low-penetrance hereditary thyroid cancer manifests as sporadic disease and is associated with common polymorphisms, including rs965513. Whole-exome sequencing of an FNMTC kindred identified a novel Y1203H germline Dual Oxidase-2 (DUOX2) mutation. DUOX2Y1203H is enzymatically active and increased production of reactive oxygen species. Furthermore, sporadic thyroid cancer patients homozygous for rs965513 demonstrated higher DUOX2 expression than heterozygous or homozygous 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.