Genes involved in DNA repair are mutational targets in endometrial cancers with microsatellite instability
Vessela Vassileva1, Anna Millar, Laurent Briollais
1Samuel Lunenfeld Research Institute, Toronto, Ontario, M5G 1X5 Canada.
Abstract:
Microsatellite instability (MSI) is observed in a subset of endometrial cancers (ECs) and is attributed to defects in mismatch repair. Mismatch repair deficiency allows for accumulation of mutations in the coding repeats of key target genes, which may be involved in the initiation and progression of MSI+ EC. We examined genes implicated in DNA repair pathways in 38 MSI-high (MSI-H), 10 MSI-low, 25 microsatellite stable ECs, and a selected panel of associated premalignant hyperplasias. Genetic alterations were correlated to histopathological data, including tumor grade and stage. Somatic frameshift mutations were observed in hMLH3, hMSH3, hMSH6, CHK1, and BAX genes in MSI-H endometrial hyperplasias and cancers, whereas mutations in ATR and CDC25C were observed only in MSI-H ECs. Increased mutation frequency in DNA damage response pathway genes including ATR, CHK1, and BAX demonstrated a significant trend with advancing tumor grade (P < 0.05). Our observations of the same mutations at short coding mononucleotide repeats in both premalignant lesions and tumors and association of increased frequency of mutation accumulation with advancing tumor grade suggest that these alterations may play a role in the development and progression of MSI+ EC.
Insights
Microsatellite instability (MSI) in endometrial cancer is linked to DNA repair defects. Mutations in key genes accumulate, potentially driving tumor development and progression, especially with increasing tumor grade.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Microsatellite instability (MSI) occurs in endometrial cancers (ECs) due to mismatch repair defects.
- This deficiency leads to mutations in target genes, potentially initiating and progressing MSI-positive (MSI+) EC.
Purpose of the Study:
- To investigate genetic alterations in DNA repair pathways in MSI-high, MSI-low, and microsatellite-stable ECs and associated hyperplasias.
- To correlate these genetic changes with histopathological features like tumor grade and stage.
Main Methods:
- Analysis of genes in DNA repair pathways across 38 MSI-high, 10 MSI-low, and 25 microsatellite-stable ECs.
- Examination of associated premalignant hyperplasias.
- Correlation of genetic alterations with histopathological data.
Main Results:
- Somatic frameshift mutations found in hMLH3, hMSH3, hMSH6, CHK1, and BAX in MSI-H hyperplasias and cancers.
- Mutations in ATR and CDC25C were specific to MSI-H ECs.
- Increased mutation frequency in ATR, CHK1, and BAX showed a significant trend with advancing tumor grade (P < 0.05).
Conclusions:
- Identical mutations in short coding repeats were observed in both premalignant lesions and tumors.
- The accumulation of mutations in DNA damage response genes correlates with increasing tumor grade.
- These alterations likely contribute to the development and progression of MSI+ endometrial cancer.
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