Genetic and Functional Evidence Links Germline Biallelic Inactivating Variants in WWOX to Histological Mixed‐Type Thyroid Cancer

Abstract Despite WWOX's established role as a tumor suppressor, conclusive evidence linking germline WWOX loss‐of‐function variants to oncogenesis remains scarce. Two germline homozygous WWOX missense variants (p.P252A and p.P282A) are identified in a patient with histological mixed‐type thyroid cancer. In vitro and in vivo functional assays demonstrate that both WWOX P252A and WWOX P282A mutants exhibit complete loss of tumor‐suppressive activity, failing to inhibit tumor cell growth and invasion. The WWOX P252A mutant undergo accelerated degradation via HSC70 chaperone‐mediated autophagy in the lysosome. Furthermore, both P252A and P282A variants impair the WWOX protein's critical role in DNA damage repair. A nucleotide excision repair‐related protein, POLE4, is identified to interact with WWOX, but not with the WWOX P282A mutant. Finally, low WWOX expression is found to be associated with epithelial‐mesenchymal transition and aggressive phenotype in thyroid cancer. These findings provide the first genetic and functional evidence that germline WWOX loss‐of‐function variants drive cancer pathogenesis by perturbing multiple tumor‐suppressive mechanisms.