From Molecular Classification to Hereditary Cancer Syndrome Identification in Endometrial Cancer

Area of Science:

• Gynecologic Oncology
• Molecular Pathology
• Cancer Genetics

Background:

• Endometrial carcinoma (EC) is a common gynecologic malignancy with increasing incidence.
• A 2013 molecular classification stratifies EC into four groups: POLE-mutated, MSI-H/dMMR, low-SCNA, and high-SCNA/p53 deficient.
• This classification aids in identifying hereditary cancer syndromes like Lynch Syndrome (LS) and polymerase proofreading-associated polyposis (PPAP).

Purpose of the Study:

• To assess the utility of routine molecular classification of EC for identifying hereditary cancer syndromes.
• To correlate molecular findings with family history and genetic testing results.
• To investigate potential overlaps between POLE mutations and mismatch repair (MMR) defects.

Main Methods:

• Routine molecular classification of 188 consecutive EC cases from 2022-2024.
• Correlation of molecular results with patient family history and constitutional genetic testing.
• Somatic mutation analysis for POLE variants and mismatch repair deficiency (dMMR).

Main Results:

• 45 ECs were dMMR, and 23 had POLE variants; 5 had both.
• Of 41 patients who accepted genetic counseling, 26 were eligible for genetic testing.
• No somatic POLE variants were found to be germline; however, Lynch Syndrome was diagnosed in 7 patients with dMMR-EC, including two with POLE-mutated EC.

Conclusions:

• Molecular classification of EC is vital for improving Lynch Syndrome identification.
• Simultaneous investigation of all molecular markers is essential to uncover overlaps between POLE mutations and MMR defects.
• This approach enhances patient stratification and clinical management strategies for EC.