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

## TL;DR

A study finds that some Middle Eastern papillary thyroid cancer cases are linked to inherited mutations in genes like STK11 and DNA repair genes, suggesting broader genetic screening is needed.

## Contribution

The study identifies germline mutations in cancer predisposition genes in non-syndromic PTC patients from Saudi Arabia, revealing under-recognized hereditary risks.

## Key findings

- 11 out of 245 Saudi PTC patients had germline pathogenic variants in cancer susceptibility genes.
- Mutations in DNA repair genes like FANCA and RAD50 were more common than expected.
- A shared STK11 variant was found in two unrelated patients without Peutz–Jeghers syndrome features.

## Abstract

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.