STK11 and DNA Repair Gene Mutations Define Hereditary Subset of Middle Eastern Papillary Thyroid Cancer.
PMID 41898519 | PMCID PMC13026885 | DOI 10.3390/ijms27062656 · International journal of molecular sciences · 2026
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-Jeghers 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-Fraumeni 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.
Validated evidence
| Type | Entity | Source evidence | Confidence | Extractor |
|---|---|---|---|---|
| gene | STK11 | “STK11 and DNA Repair Gene Mutations Define Hereditary Subset of Middle Eastern Papillary Thyroid Cancer.” | 0.98 | hgnc_dict_v1 |
| gene | TP53 | “Eleven patients (4.5%) harbored germline PVs/LPVs in cancer susceptibility genes including STK11, TP53, BRCA1, BRCA2, FANCA, SLX4, RAD50, MSH6, POLD1 and NF1.” | 0.98 | hgnc_dict_v1 |
| gene | BRCA1 | “Eleven patients (4.5%) harbored germline PVs/LPVs in cancer susceptibility genes including STK11, TP53, BRCA1, BRCA2, FANCA, SLX4, RAD50, MSH6, POLD1 and NF1.” | 0.98 | hgnc_dict_v1 |
| gene | BRCA2 | “Eleven patients (4.5%) harbored germline PVs/LPVs in cancer susceptibility genes including STK11, TP53, BRCA1, BRCA2, FANCA, SLX4, RAD50, MSH6, POLD1 and NF1.” | 0.98 | hgnc_dict_v1 |
| gene | FANCA | “Eleven patients (4.5%) harbored germline PVs/LPVs in cancer susceptibility genes including STK11, TP53, BRCA1, BRCA2, FANCA, SLX4, RAD50, MSH6, POLD1 and NF1.” | 0.98 | hgnc_dict_v1 |
| gene | SLX4 | “Eleven patients (4.5%) harbored germline PVs/LPVs in cancer susceptibility genes including STK11, TP53, BRCA1, BRCA2, FANCA, SLX4, RAD50, MSH6, POLD1 and NF1.” | 0.98 | hgnc_dict_v1 |
| gene | RAD50 | “Eleven patients (4.5%) harbored germline PVs/LPVs in cancer susceptibility genes including STK11, TP53, BRCA1, BRCA2, FANCA, SLX4, RAD50, MSH6, POLD1 and NF1.” | 0.98 | hgnc_dict_v1 |
| gene | MSH6 | “Eleven patients (4.5%) harbored germline PVs/LPVs in cancer susceptibility genes including STK11, TP53, BRCA1, BRCA2, FANCA, SLX4, RAD50, MSH6, POLD1 and NF1.” | 0.98 | hgnc_dict_v1 |
| gene | POLD1 | “Eleven patients (4.5%) harbored germline PVs/LPVs in cancer susceptibility genes including STK11, TP53, BRCA1, BRCA2, FANCA, SLX4, RAD50, MSH6, POLD1 and NF1.” | 0.98 | hgnc_dict_v1 |
| gene | NF1 | “Eleven patients (4.5%) harbored germline PVs/LPVs in cancer susceptibility genes including STK11, TP53, BRCA1, BRCA2, FANCA, SLX4, RAD50, MSH6, POLD1 and NF1.” | 0.98 | hgnc_dict_v1 |
| phenotype | thyroid cancer | “STK11 and DNA Repair Gene Mutations Define Hereditary Subset of Middle Eastern Papillary Thyroid Cancer.” | 0.98 | phenotype_alias_lexicon_v2 |
| phenotype | gastric cancer | “A TP53 hotspot mutation (p.R175H) was identified in a patient with a personal history of gastric cancer, a malignancy associated with Li-Fraumeni syndrome.” | 0.98 | phenotype_alias_lexicon_v2 |
| phenotype | breast cancer | “Notably, the BRCA1 PV detected matches a known Saudi founder mutation in hereditary breast cancer, now observed in PTC.” | 0.98 | phenotype_alias_lexicon_v2 |
| population | Saudi Arabia | “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. Notably, the BRCA1 PV detected matches a known Saudi founder mutation in hereditary breast cancer, now observed in PTC.” | 0.95 | saudi_context_rules_v1 |
| variant | p.R304Q | “Two unrelated patients harbored the same STK11 variant (p.R304Q) without classical Peutz-Jeghers syndrome features.” | 0.95 | hgvs_regex_v1 |
| variant | p.R175H | “A TP53 hotspot mutation (p.R175H) was identified in a patient with a personal history of gastric cancer, a malignancy associated with Li-Fraumeni syndrome.” | 0.95 | hgvs_regex_v1 |