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Two germline homozygous\n                    <jats:italic>WWOX<\/jats:italic>\n                    missense variants (p.P252A and p.P282A) are identified in a patient with histological mixed\u2010type thyroid cancer. In vitro and in vivo functional assays demonstrate that both WWOX\n                    <jats:sup>P252A<\/jats:sup>\n                    and WWOX\n                    <jats:sup>P282A<\/jats:sup>\n                    mutants exhibit complete loss of tumor\u2010suppressive activity, failing to inhibit tumor cell growth and invasion. The WWOX\n                    <jats:sup>P252A<\/jats:sup>\n                    mutant undergo accelerated degradation via HSC70 chaperone\u2010mediated 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\u2010related protein, POLE4, is identified to interact with WWOX, but not with the WWOX\n                    <jats:sup>P282A<\/jats:sup>\n                    mutant. Finally, low WWOX expression is found to be associated with epithelial\u2010mesenchymal transition and aggressive phenotype in thyroid cancer. These findings provide the first genetic and functional evidence that germline\n                    <jats:italic>WWOX<\/jats:italic>\n                    loss\u2010of\u2010function variants drive cancer pathogenesis by perturbing multiple tumor\u2010suppressive mechanisms.\n                  <\/jats:p>","DOI":"10.1002\/advs.202507602","type":"journal-article","created":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T20:10:46Z","timestamp":1761163846000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Genetic and Functional Evidence Links Germline Biallelic Inactivating Variants in\n                    <i>WWOX<\/i>\n                    to Histological Mixed\u2010Type Thyroid Cancer"],"prefix":"10.1002","volume":"13","author":[{"given":"Xiaopeng","family":"Zhang","sequence":"first","affiliation":[{"name":"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"},{"name":"Science Island Branch Graduate School of the University of Science and Technology of China  Hefei Anhui 230026 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Qi","sequence":"additional","affiliation":[{"name":"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"},{"name":"Science Island Branch Graduate School of the University of Science and Technology of China  Hefei Anhui 230026 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jialiang","family":"Wang","sequence":"additional","affiliation":[{"name":"Hefei Cancer Hospital of CAS Institute of Health and Medical Technology Hefei Institutes of Physical Science Chinese Academy of Sciences (CAS)  Hefei Anhui 230031 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Chinese Academy of Sciences (CAS)  Hefei Anhui 230031 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ao","family":"Xu","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8117-5029","authenticated-orcid":false,"given":"Bo","family":"Hong","sequence":"additional","affiliation":[{"name":"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"},{"name":"Science Island Branch Graduate School of the University of Science and Technology of China  Hefei Anhui 230026 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