Molecular characterization of mismatch repair deficient tumors in young Jordanian patients

Mismatch repair deficiency (MMRD) contributes substantially to early-onset colorectal carcinoma (CRC) and pediatric malignancies in Jordan. Approximately 19% of CRCs diagnosed in adults younger than 45 years exhibit MMRD by immunohistochemistry (IHC). In pediatric tumors, MMRD accounts for 39% of high-grade gliomas (HGGs) and 44% of CRCs, likely reflecting the increased prevalence of constitutional MMRD (CMMRD) in this highly consanguineous population. However, the molecular characterization of MMRD-associated tumors in the Middle East remains limited. We analyzed 14 Jordanian patients (< 45 years) from 12 families with clinical or IHC evidence of MMRD, including four HGGs and 11 CRCs; five patients were children. Pathogenic or likely pathogenic MMR variants were identified in nine families, including one sibling pair, comprising five frameshift indels, three single nucleotide variants, and one large deletion. A variant of uncertain significance in MSH6 was identified in another sibling pair. Apparent large deletions suggestive of sequencing artifacts in six patients highlighted the need for confirmatory copy number analysis by multiplex ligation-dependent probe amplification. Tumor mutational burden ranged from 2 to 352 variants/Mb (median, 23). Microsatellite instability was low in seven tumors, likely reflecting degraded DNA from older formalin-fixed paraffin-embedded samples. Mutational signatures were concordant with the molecular findings in most cases. Notably, the only ultrahypermutated tumor harbored a canonical somatic POLE p.(Val411Leu) proofreading-domain mutation together with polymerase-associated mutational signatures, consistent with combined MMRD and polymerase proofreading deficiency. This study represents the first comprehensive molecular characterization of MMRD-associated tumors in Jordan.