{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T03:04:23Z","timestamp":1793847863003,"version":"4.6.1"},"reference-count":49,"publisher":"Bioscientifica","issue":"4","license":[{"start":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T00:00:00Z","timestamp":1772236800000},"content-version":"vor","delay-in-days":380,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Germline mutations in the tumor suppressor phosphatase and tensin homolog (PTEN) cause PTEN hamartoma tumor syndrome (PHTS). PHTS is characterized by an elevated lifetime risk of differentiated thyroid cancer (DTC), 30 times higher than the general population. However, only 1 in 3 PHTS patients develop DTC, and it remains unknown whether specific PTEN variants are associated with an increased risk of DTC. PTEN antagonizes the phosphatidylinositol 3-kinase (PI3K)\u2013AKT signaling pathway, a frequently affected pathway in sporadic DTC. PTEN also acts as a guardian of the genome by interacting with other tumor suppressors. Here, we report how ionizing radiation, an environmental tumorigenic contributor, modifies the DNA damage response based on the type of germline PTEN variants. We hypothesized that certain PTEN variants associated with DTC create a pro-oncogenic molecular signature upon radiation-induced DNA damage. DTC-associated (PTENM134R) or DTC-non-associated (PTENG132D) germline PTEN mutant alleles were introduced into a human induced pluripotent cell (hiPSC) line derived from a healthy donor utilizing CRISPR-Cas9 gene editing technology. We determined radiation-induced transcriptomic changes in functional thyroid organoids induced from wild-type and both heterozygous PTEN mutant hiPSCs. Both bulk and single-cell RNA sequencing data indicated that radiation upregulated the p53 network more potently in the thyroid organoids with PTENWT\/G132D than those with PTENWT\/M134R, which could be mediated by AKT-dependent MDM2 inactivation and PTEN\u2013p53 physical interaction. Our data suggest that the lack of p53 pathway activation through PTEN\u2013p53 network interactions explains why PTENM134R is a DTC-susceptible variant.<\/jats:p>","DOI":"10.1530\/erc-24-0216","type":"journal-article","created":{"date-parts":[[2025,2,18]],"date-time":"2025-02-18T05:59:31Z","timestamp":1739858371000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-8","source":"Crossref","is-referenced-by-count":5,"title":["Divergent PTEN\u2013p53 interaction upon DNA damage in a human thyroid organoid model with germline\n                    <i>PTEN<\/i>\n                    mutations"],"prefix":"10.1530","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2680-6171","authenticated-orcid":true,"given":"Juan Andres","family":"Venegas","sequence":"first","affiliation":[{"name":"Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic 1 , , ,","place":["Cleveland, Ohio, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omer Enes","family":"Onur","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic 1 , , ,","place":["Cleveland, Ohio, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin Chung","family":"Kang","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic 1 , , ,","place":["Cleveland, Ohio, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0937-6640","authenticated-orcid":false,"given":"Masahiro","family":"Hitomi","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic 1 , , ,","place":["Cleveland, Ohio, USA"]},{"name":"Cleveland Clinic Lerner College of Medicine, Case Western Reserve University 2 , , ,","place":["Cleveland, Ohio, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charis","family":"Eng","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic 1 , , ,","place":["Cleveland, Ohio, USA"]},{"name":"Cleveland Clinic Lerner College of Medicine, Case Western Reserve University 2 , , ,","place":["Cleveland, Ohio, USA"]},{"name":"Center for Personalized Genetic Healthcare, Medical Specialties Institute, Cleveland Clinic 3 , , ,","place":["Cleveland, Ohio, USA"]},{"name":"Taussig Cancer Institute, Cleveland Clinic Foundation 4 , , ,","place":["Cleveland, Ohio, USA"]},{"name":"Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine 5 , , ,","place":["Cleveland, Ohio, USA"]},{"name":"Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine 6 , , ,","place":["Cleveland, Ohio, 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