{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T12:00:59Z","timestamp":1774008059855,"version":"3.50.1"},"reference-count":33,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T00:00:00Z","timestamp":1773446400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Papillary thyroid cancer (PTC) is the most common endocrine malignancy with especially high incidence in Middle Eastern populations. While classical hereditary syndromes explain a minority of cases, the broader germline landscape of non-syndromic PTC remains unclear. Whole-exome sequencing was performed on 245 unselected Saudi PTC patients to identify germline pathogenic or likely pathogenic variants (PVs\/LPVs) in cancer predisposition genes. Clinical and molecular characteristics, and family history were integrated to assess phenotypic correlations. Eleven patients (4.5%) harbored germline PVs\/LPVs in cancer susceptibility genes including STK11, TP53, BRCA1, BRCA2, FANCA, SLX4, RAD50, MSH6, POLD1 and NF1. Four patients (36.4%) carried PVs\/LPVs in canonical FA pathway genes; this increased to five patients (45.5%) when RAD50 was included. Two unrelated patients harbored the same STK11 variant (p.R304Q) without classical Peutz\u2013Jeghers syndrome features. A TP53 hotspot mutation (p.R175H) was identified in a patient with a personal history of gastric cancer, a malignancy associated with Li\u2013Fraumeni syndrome. Notably, the BRCA1 PV detected matches a known Saudi founder mutation in hereditary breast cancer, now observed in PTC. Most germline positive cases lacked syndromic manifestations, underscoring limitations of phenotype or family history-driven genetic testing strategies. These findings suggest that a small subset of non-syndromic PTC cases may carry germline PVs\/LPVs in cancer predisposition genes, highlighting the need for broader genetic screening frameworks. Unbiased whole-exome analysis in unselected cohorts can uncover under-recognized genetic risk and guide screening strategies to address the unique hereditary landscape of thyroid cancer in underrepresented populations.<\/jats:p>","DOI":"10.3390\/ijms27062656","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T10:10:43Z","timestamp":1773655843000},"page":"2656","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["STK11 and DNA Repair Gene Mutations Define Hereditary Subset of Middle Eastern Papillary Thyroid Cancer"],"prefix":"10.3390","volume":"27","author":[{"given":"Rong","family":"Bu","sequence":"first","affiliation":[{"name":"Genomic Analytics, Research Laboratories, Innovation and Research, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wael","family":"Haqawi","sequence":"additional","affiliation":[{"name":"Genomic Analytics, Research Laboratories, Innovation and Research, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eman A. Abdul","family":"Razzaq","sequence":"additional","affiliation":[{"name":"Translational Oncology Research, Research Laboratories, Innovation and Research, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8091-5280","authenticated-orcid":false,"given":"Saud","family":"Azam","sequence":"additional","affiliation":[{"name":"Human Cancer Genomic Research, Research Laboratories, Innovation and Research, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5634-5030","authenticated-orcid":false,"given":"Kaleem","family":"Iqbal","sequence":"additional","affiliation":[{"name":"Genomic Analytics, Research Laboratories, Innovation and Research, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zeeshan","family":"Qadri","sequence":"additional","affiliation":[{"name":"Human Cancer Genomic Research, Research Laboratories, Innovation and Research, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandeep Kumar","family":"Parvathareddy","sequence":"additional","affiliation":[{"name":"Human Cancer Genomic Research, Research Laboratories, Innovation and Research, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maha","family":"Alrasheed","sequence":"additional","affiliation":[{"name":"Human Cancer Genomic Research, Research Laboratories, Innovation and Research, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khadija","family":"Alobaisi","sequence":"additional","affiliation":[{"name":"Translational Oncology Research, Research Laboratories, Innovation and Research, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fouad","family":"Al-Dayel","sequence":"additional","affiliation":[{"name":"Anatomic Pathology Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdul Khalid","family":"Siraj","sequence":"additional","affiliation":[{"name":"Translational Oncology Research, Research Laboratories, Innovation and Research, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4126-3419","authenticated-orcid":false,"given":"Khawla S.","family":"Al-Kuraya","sequence":"additional","affiliation":[{"name":"Human Cancer Genomic Research, Research Laboratories, Innovation and Research, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/s12105-010-0236-9","article-title":"Papillary thyroid carcinoma variants","volume":"5","author":"Lloyd","year":"2011","journal-title":"Head. 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