Discordant Mutations in Paired Primary and Metastatic Endometrial Adenocarcinomas Identified by Semiconductor-Based Sequencing for Rapid Cancer Genotyping
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Updated: Mar 21, 2026
Comparative Lesions Analysis Through a Targeted Sequencing Approach
Published on: November 5, 2019
Colin P Bergstrom1, Koen De Geest2, Rebecca O'Gara3
1Department of Pathology, Oregon Health & Science University, Portland, OR, USA.
Abstract:
Although endometrial adenocarcinoma is usually treated with surgery, patients with metastatic disease have a poor prognosis. To address the need for better treatment options, molecularly targeted drug therapies are being developed. These targeted therapies rely on accurate mutational profiling of the tumor, which is most often performed on DNA from the primary tumor. Our objective was to compare mutational concordance in primary tumors with their metastases. We genotyped 11 pairs of primary and metastatic endometrial adenocarcinomas using DNA from formalin-fixed paraffin-embedded tissue blocks and semiconductor-based next-generation sequencing. Five of these cases had multiple metastases for comparison. We sequenced 37 known cancer genes that are targets for new drug therapies. A total of 62 mutations were identified in 16 of these 37 genes. The most common mutations were in PIK3CA and PTEN. Overall, there was a 53% discordance in mutations between primary tumors and their paired (33 of 62). The absence of mutations in metastases (25 of 33, 76%) compared with the primary neoplasm was more common than gain of mutations (8 of 33, 24%). There was a 15% discordance rate between paired metastases within individuals (6 of 40), which was significantly less frequent than the rate between primary tumors and their metastases (Fisher exact P value <.0001). Although the sample size is relatively small, our data suggest it may be prudent to test metastases, rather than the primary neoplasm, when using molecularly targeted drug therapies, because isolated metastases may lack mutations detected in the heterogeneous mixture of the tumor's origin.
Insights
Tumor mutations in endometrial adenocarcinoma often differ between primary tumors and metastases. Testing metastases is recommended for targeted therapy selection, as they may lack mutations found in the primary tumor.
Area of Science:
- Oncology
- Genetics
- Cancer Research
Background:
- Endometrial adenocarcinoma treatment typically involves surgery, but metastatic disease carries a poor prognosis.
- Development of molecularly targeted drug therapies offers new treatment avenues.
- Accurate mutational profiling of tumors, usually from primary sites, is crucial for these therapies.
Purpose of the Study:
- To compare the mutational concordance between primary endometrial adenocarcinomas and their corresponding metastases.
- To evaluate the reliability of primary tumor profiling for guiding targeted therapy in metastatic settings.
Main Methods:
- Genotyping of 11 primary and metastatic endometrial adenocarcinoma pairs using DNA from formalin-fixed paraffin-embedded tissues.
- Semiconductor-based next-generation sequencing of 37 known cancer genes targeted by new drug therapies.
- Analysis of mutation concordance and discordance rates, including comparison between multiple metastases within individuals.
Main Results:
- A total of 62 mutations were identified across 16 genes, with PIK3CA and PTEN being the most common.
- Significant discordance in mutations was observed between primary tumors and metastases (53%).
- Loss of mutations in metastases was more frequent (76%) than new mutations (24%); discordance between paired metastases was lower (15%).
Conclusions:
- Mutational profiles can differ substantially between primary endometrial tumors and their metastases.
- Testing metastases for mutations may be more appropriate than testing primary tumors for selecting molecularly targeted therapies.
- These findings highlight the importance of assessing metastatic tissue for personalized cancer treatment strategies.
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