The MRE11/RAD50/NBS1 complex destabilization in Lynch-syndrome patients

Abstract

Lynch syndrome is an inherited disease leading to the development predominantly of colorectal cancer (CRC). The crucial cause is malfunction of DNA mismatch repair that is characterized by high level of microsatellite instability; however, new knowledge of two MSI modes (types A and B) suggests a more complex molecular basis of this syndrome. To investigate, whether the extensive alterations in individual MSI markers (type B) can indicate the potential deficiency of DNA double-strand break (DSB) repair in Lynch-syndrome-related tumours, we evaluated the MSI type and alterations in the MRE11 and RAD50 repeats that are associated with the reduced protein expression and functional impairment of the MRE11-RAD50-NBS1 (MRN) complex. Of 27 CRCs, 21 samples manifested type B in at least one MSI+ marker. From type B tumours, the genetic alterations were identified in 16 (76%) samples; seven, one and eight cases manifested mutations in MRE11, RAD50 and both genes, respectively. However, predominantly biallelic MRE11 alterations with simultaneously developed RAD50 mutations impaired the protein expressions with different intensity and location in tumour. Of six tumours presenting changes <or=6 bp (type A), in four samples identical alterations and protein expressions were observed. Moreover, in two patients with different MSI types germline insertions in the MRE11(T)(11) were found. Overall, our findings indicate the absence of significant association between type B MSI and MRE11 or RAD50 mutations in tumours of Lynch-syndrome patients, but a subset of them manifested causal mutations for MRN destabilization that could lead to the additional defect in DSB repair.