Microsatellite Instability and Aberrant Pre-mRNA Splicing: How Intimate Is It?

Cancers that belong to the microsatellite instability (MSI) class can account for up to 15% of all cancers of the digestive tract. These cancers are characterized by inactivation, through the mutation or epigenetic silencing of one or several genes from the DNA MisMatch Repair (MMR) machinery, including MLH1, MLH3, MSH2, MSH3, MSH6, PMS1, PMS2 and Exo1. The unrepaired DNA replication errors turn into mutations at several thousand sites that contain repetitive sequences, mainly mono- or dinucleotides, and some of them are related to Lynch syndrome, a predisposition condition linked to a germline mutation in one of these genes. In addition, some mutations shortening the microsatellite (MS) stretch could occur in the 3'-intronic regions, i.e., in the ATM (ATM serine/threonine kinase), MRE11 (MRE11 homolog) or the HSP110 (Heat shock protein family H) genes. In these three cases, aberrant pre-mRNA splicing was observed, and it was characterized by the occurrence of selective exon skipping in mature mRNAs. Because both the ATM and MRE11 genes, which as act as players in the MNR (MRE11/NBS1 (Nibrin)/RAD50 (RAD50 double strand break repair protein) DNA damage repair system, participate in double strand breaks (DSB) repair, their frequent splicing alterations in MSI cancers lead to impaired activity. This reveals the existence of a functional link between the MMR/DSB repair systems and the pre-mRNA splicing machinery, the diverted function of which is the consequence of mutations in the MS sequences.

Radiogenomics-based cancer prognosis in colorectal cancer.

Radiogenomics aims at investigating the relationship between imaging radiomic features and gene expression alterations. This study addressed the potential prognostic complementary value of contrast enhanced computed tomography (CE-CT) radiomic features and gene expression data in primary colorectal cancers (CRC). Sixty-four patients underwent CT scans and radiomic features were extracted from the delineated tumor volume. Gene expression analysis of a small set of genes, previously identified as relevant for CRC, was conducted on surgical samples from the same tumors. The relationships between radiomic and gene expression data was assessed using the Kruskal-Wallis test. Multiple testing was not performed, as this was a pilot study. Cox regression was used to identify variables related to overall survival (OS) and progression free survival (PFS). ABCC2 gene expression was correlated with N (p = 0.016) and M stages (p = 0.022). Expression changes of ABCC2, CD166, CDKNV1 and INHBB genes exhibited significant correlations with some radiomic features. OS was associated with Ratio 3D Surface/volume (p = 0.022) and ALDH1A1 expression (p = 0.042), whereas clinical stage (p = 0.004), ABCC2 expression (p = 0.035), and EntropyGLCM_E (p = 0.0031), were prognostic factors for PFS. Combining CE-CT radiomics with gene expression analysis and histopathological examination of primary CRC could provide higher prognostic stratification power, leading to improved patient management.