Purpose: The best screening practice for Lynch syndrome (LS) in endometrial cancer (EC) remains unknown. We sought to determine whether tumor microsatellite instability (MSI) typing along with immunohistochemistry (IHC) and MLH1 methylation analysis can help identify women with LS. Patients and Methods: ECs from GOG210 patients were assessed for MSI, MLH1 methylation, and mismatch repair (MMR) protein expression. Each tumor was classified as having normal MMR, defective MMR associated with MLH1 methylation, or probable MMR mutation (ie, defective MMR but no methylation). Cancer family history and demographic and clinical features were compared for the three groups. Lynch mutation testing was performed for a subset of women. Results: Analysis of 1,002 ECs suggested possible MMR mutation in 11.8% of tumors. The number of patients with a family history suggestive of LS was highest among women whose tumors were classified as probable MMR mutation (P = .001). Lynch mutations were identified in 41% of patient cases classified as probable mutation (21 of 51 tested). One of the MSH6 Lynch mutations was identified in a patient whose tumor had intact MSH6 expression. Age at diagnosis was younger for mutation carriers than noncarriers (54.3 v 62.3 years; P < .01), with five carriers diagnosed at age > 60 years. Conclusion: Combined MSI, methylation, and IHC analysis may prove useful in Lynch screening in EC. Twenty-four percent of mutation carriers presented with ECs at age > 60 years, and one carrier had an MSI-positive tumor with no IHC defect. Restricting Lynch testing to women diagnosed at age < 60 years or to women with IHC defects could result in missing a substantial fraction of genetic disease.
Bibliographical noteFunding Information:
Supported by Grant No. P50 CA134254 from the National Institutes of Health/National Cancer Institute; by Barnes-Jewish Hospital and Siteman Cancer Center; by Ohio State University James Comprehensive Cancer Center; and by National Cancer Institute grants to Gynecologic Oncology Group (GOG) Administrative Office (No.CA27469), GOG Statistical Office (No.CA37517), NRG Oncology Group (No. 1 U10 CA180822), and GOG Tissue Bank (No. U10 CA27469, U24 CA114793, and U10 CA180868). We thank Erika Crouch, MD, and Neha Dahiya, MD (Washington University School of Medicine), for their assistance with immunohistochemistry, Tom Walsh for development of mutation testing methods, and Ms Mary McNulty for her support in biospecimen processing.