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

Sep 29, 2026

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Despite WWOX’s established role as a tumor suppressor, direct evidence connecting germline WWOX loss-of-function variants to cancer development has been limited. This study identifies two germline homozygous WWOX missense variants in a patient with histological mixed-type thyroid cancer. Functional assays show complete loss of tumor-suppressive activity, including impaired inhibition of growth, invasion, DNA damage repair, altered protein degradation pathways, and reduced WWOX expression linked to EMT and aggressive phenotype.

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Introduction

WWOX tumor suppressor role and genetic context

Evidence for WWOX loss in cancer and mechanisms

RESEARCH ARTICLE [www.advancedscience.com](www.advancedscience.com) Genetic and Functional Evidence Links Germline Biallelic Inactivating Variants in WWOX to Histological Mixed-Type Thyroid Cancer Xiaopeng Zhang, Jian Qi, Jialiang Wang, Zhipeng Wang, Yongguang Wang, Zongtao Hu, Ao Xu,* Bo Hong,* and Hongzhi Wang* 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 WWOXP252A and WWOXP282A mutants exhibit complete loss of tumor-suppressive activity, failing to inhibit tumor cell growth and invasion. The WWOXP252A mutant undergo accelerated degradation via HSC70 chaperone-mediated autophagyin 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 WWOXP282A 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. 1. Introduction The gene encoding WWOX (WW domaincontaining oxidoreductase), spanning chromosome region 16q23.1-16q23.2 and crossing 1.1 million base pairs, ranks among the largest genes in the human genome. [1] The WWOX gene is located within the FRA16D chromosomal region, a common fragile site characterized by susceptibility to chromosomal breakage, which consequently leads to frequent deletion events of the gene. [2] The WWOX gene has been implicated in the pathogenesis of multiple cancer types, with recurrent deletions in diverse malignancies including bladder, colon, esophageal, ovarian, stomach, and uterine cancers. [1] Mice harboring either homozygous or heterozygous deletion of WWOX exhibited spontaneous tumorigenesis, developing malignancies resembling human osteosarcoma, pulmonary, and X. Zhang, J. Qi, J. Wang, Z. Wang, Y. Wang, Z. Hu, B. Hong, H. Wang Hefei Cancer Hospital of CAS Institute of Health and Medical Technology Hefei Institutes of Physical Science Chinese Academy of Sciences (CAS) Hefei, Anhui 230031, China E-mail: bhong@hmﬂ.[ac.cn](ac.cn); [wanghz@hfcas.ac.cn](wanghz@hfcas.ac.cn) X. Zhang, J. Qi, Z. Wang, B. Hong, H. Wang Science Island Branch Graduate School of the University of Science and Technology of China Hefei, Anhui 230026, China A. Xu Department of Pathology The First Aﬃliated Hospital of USTC Division of Life Sciences and Medicine University of Science and Technology of China (USTC) Hefei, Anhui 230036, China E-mail: [aoxuhf@ustc.edu.cn](aoxuhf@ustc.edu.cn) The ORCID identiﬁcation number(s) for the author(s) of this article can be found under [https://doi.org/10.1002/advs.202507602](https://doi.org/10.1002/advs.202507602)[ ](https://doi.org/10.1002/advs.202507602)© 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. DOI: 10.1002/advs.202507602 mammary carcinomas. [3,4] These studies demonstrated that WWOX functions as a tumor suppressor gene. A hallmark feature of classical tumor suppressor genes such as BRCA1, BRCA2, and TP53 is their propensity to acquire loss-of-function point mutations that disrupt their tumor-suppressive activities. [5] However, point mutations in the WWOX gene associated with functional loss of its tumor suppressor activity have rarely been identiﬁed to date. Therefore, this pauci

FAQs

What germline WWOX variants were identified in the thyroid cancer case?

Two germline homozygous WWOX missense variants (p.P252A and p.P282A) were identified in a patient with histological mixed-type thyroid cancer.

How do the WWOX P252A and P282A mutants affect tumor-suppressive activity?

Both mutants show complete loss of tumor-suppressive activity, failing to inhibit tumor cell growth and invasion in functional assays.

What additional mechanisms are disrupted by these variants besides tumor suppression?

The variants impair WWOX’s role in DNA damage repair, disrupt interactions related to nucleotide excision repair (POLE4 interaction differs by variant), and are linked to reduced WWOX expression associated with EMT and aggressive thyroid cancer phenotype.

Sep 29, 2026

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