STK11 and DNA Repair Gene Mutations Define Hereditary Subset of Middle Eastern Papillary Thyroid Cancer

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 <i>STK11</i>, <i>TP53</i>, <i>BRCA1</i>, <i>BRCA2</i>, <i>FANCA</i>, <i>SLX4</i>, <i>RAD50</i>, <i>MSH6</i>, <i>POLD1</i> and <i>NF1</i>. Four patients (36.4%) carried PVs/LPVs in canonical FA pathway genes; this increased to five patients (45.5%) when <i>RAD50</i> was included. Two unrelated patients harbored the same <i>STK11</i> variant (p.R304Q) without classical Peutz-Jeghers syndrome features. A <i>TP53</i> hotspot mutation (p.R175H) was identified in a patient with a personal history of gastric cancer, a malignancy associated with Li-Fraumeni syndrome. Notably, the <i>BRCA1</i> 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.