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Genetic and Functional Evidence Links Germline Biallelic Inactivating Variants in WWOX to Histological Mixed-Type
Xiaopeng Zhang1,2, Jian Qi1,2, Jialiang Wang1
1Hefei Cancer Hospital of CAS, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences (CAS), Hefei, Anhui, 230031, China.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|October 22, 2025
Summary
Germline WWOX variants cause cancer by disrupting tumor suppression. These loss-of-function mutations impair DNA repair and promote aggressive thyroid cancer phenotypes.
Area of Science:
- Genetics
- Molecular Biology
- Oncology
Background:
- The tumor suppressor WWOX (WW domain-containing oxidoreductase) role is established, but germline loss-of-function variants linking it to cancer are not well-defined.
- Thyroid cancer is a significant health concern with complex genetic underpinnings.
Purpose of the Study:
- To investigate the oncogenic potential of germline WWOX loss-of-function variants.
- To elucidate the molecular mechanisms by which WWOX variants contribute to cancer development.
Main Methods:
- Identification and characterization of germline homozygous WWOX missense variants (p.P252A and p.P282A) in a thyroid cancer patient.
- In vitro and in vivo functional assays to assess tumor-suppressive activity, protein degradation, and DNA repair functions.
- Interaction studies with DNA repair proteins like POLE4.
Main Results:
- WWOXP252A and WWOXP282A mutants showed complete loss of tumor suppression, failing to inhibit cell growth and invasion.
- WWOXP252A underwent accelerated degradation via chaperone-mediated autophagy.
- Both variants impaired DNA damage repair, and P282A failed to interact with POLE4.
- Low WWOX expression correlated with epithelial-mesenchymal transition and aggressive thyroid cancer.
Conclusions:
- This study provides the first genetic and functional evidence that germline WWOX loss-of-function variants drive cancer pathogenesis.
- Perturbation of WWOX's tumor-suppressive functions, including DNA repair, contributes to thyroid cancer development and progression.
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