Double strand break repair components are frequent targets of microsatellite instability in endometrial cancer

Abstract

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.