Combined Microsatellite Instability, MLH1 Methylation Analysis, and Immunohistochemistry for Lynch Syndrome Screening in Endometrial Cancers From GOG210: An NRG Oncology and Gynecologic Oncology Group Study

Paul J Goodfellow, Caroline C Billingsley, Heather A Lankes, Shamshad Ali, David E Cohn, Russell J Broaddus, Nilsa Ramirez, Colin C Pritchard, Heather Hampel, Alexis S Chassen, Luke V Simmons, Amy P Schmidt, Feng Gao, Louise A Brinton, Floor Backes, Lisa M Landrum, Melissa A Geller, Paul A DiSilvestro, Michael L Pearl, Shashikant B Lele, Matthew A Powell, Richard J Zaino, David Mutch, Paul J Goodfellow, Caroline C Billingsley, Heather A Lankes, Shamshad Ali, David E Cohn, Russell J Broaddus, Nilsa Ramirez, Colin C Pritchard, Heather Hampel, Alexis S Chassen, Luke V Simmons, Amy P Schmidt, Feng Gao, Louise A Brinton, Floor Backes, Lisa M Landrum, Melissa A Geller, Paul A DiSilvestro, Michael L Pearl, Shashikant B Lele, Matthew A Powell, Richard J Zaino, David Mutch

Abstract

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.

Trial registration: ClinicalTrials.gov NCT00340808.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

© 2015 by American Society of Clinical Oncology.

Figures

Fig 1.
Fig 1.
Two-generation pedigrees representative of familial risk group for women whose tumors classified as mismatch repair (MMR) normal, sporadic epigenetic MMR defect, or probable MMR mutation. Blue symbols indicate histologically confirmed endometrioid endometrial cancer. Gold symbols represent reported cancers. Age at diagnosis and at death (d) given when known. CRC, colorectal cancer.

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