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Updated: Jun 10, 2026
Assessment of Global DNA Double-Strand End Resection using BrdU-DNA Labeling coupled with Cell Cycle Discrimination Imaging
Published on: April 28, 2021
Double strand break repair components are frequent targets of microsatellite instability in endometrial cancer
Cristina Bilbao1, Raquel Ramírez, Germán Rodríguez
1Cancer Research Institute of the Canary Islands, Las Palmas de Gran Canaria, Canary Islands, Spain. cbilbao@dbbf.ulpgc.es
Aim:
DNA double strand break (DSB) repair is a central cellular mechanism of the DNA damage response to maintain genomic stability. DSB components are frequently mutated in colorectal cancer with microsatellite instability (MSI). We investigated whether DSB repair is involved in endometrial cancer (EC) with MSI.
Methods:
Mononucleotide microsatellite tracts of 14 genes of the DSB repair system were analysed in a series of 41 EC with MSI. Among these genes, the microcephalin 1 (MCPH1/BRIT1) has never been tested as target of MSI in tumour series.
Results:
The most frequently mutated gene was DNAPKcs (n=14, 34%) followed by RAD50 (n=7, 17%), MRE11, ATR and BRCA1 (n=6, 15%), and by CtIP and MCPH1 (n=5, 12%). While DSB biallelic mutations were infrequent, a high proportion of tumours (n=30, 73%) presented mutations at some component of the DSB repair pathway, and almost half of them showed alterations at two or more components. Tumours with mutations in two or more genes were significantly associated with advanced grade (p=0.03) and vascular invasion (p=0.02) and marginally associated with advanced stage (p=0.07).
Conclusions:
Our results suggest that in EC, the DSB repair is a relatively common mutational target of MSI and might contribute to tumour progression, and also that MCHP1 may be a novel target gene of MSI.
Insights
DNA double-strand break (DSB) repair genes are frequently mutated in endometrial cancer (EC) with microsatellite instability (MSI). These mutations may contribute to tumor progression, with microcephalin 1 (MCPH1) identified as a potential novel target.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- DNA double-strand break (DSB) repair is crucial for maintaining genomic stability.
- Mutations in DSB repair genes are common in colorectal cancer with microsatellite instability (MSI).
- The role of DSB repair in endometrial cancer (EC) with MSI is not well understood.
Purpose of the Study:
- To investigate the involvement of DSB repair pathways in endometrial cancer (EC) with microsatellite instability (MSI).
- To identify specific DSB repair genes that are targets of MSI in EC.
- To explore the potential association between DSB repair gene mutations and EC progression.
Main Methods:
- Analysis of mononucleotide microsatellite tracts in 14 DSB repair genes in 41 EC samples with MSI.
- Specific focus on microcephalin 1 (MCPH1/BRIT1) as a novel target for MSI analysis.
Main Results:
- Mutations were observed in several DSB repair genes, with DNAPKcs being the most frequent (34%).
- A significant proportion of tumors (73%) exhibited mutations in at least one DSB repair component.
- Mutations in two or more DSB repair genes were associated with advanced tumor grade and vascular invasion.
Conclusions:
- DSB repair is a common mutational target in MSI-positive endometrial cancer.
- DSB repair pathway alterations may contribute to EC progression.
- MCPH1 is identified as a potential novel MSI target gene in EC.
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