Mismatch repair-deficient
colorectal cancers (CRC) display widespread instability at
DNA microsatellite sequences (MSI). Although MSI has been reported to commonly occur at coding repeats, leading to alterations in the function of a number of genes encoding
cancer-related
proteins, nothing is known about the putative impact of this process on non-coding
microRNAs. In miRbase V15, we identified very few human
microRNA genes with mono- or di-
nucleotide repeats (n = 27). A mutational analysis of these sequences in a large series of MSI CRC cell lines and primary
tumors underscored instability in 15 of the 24
microRNA genes successfully studied at variable frequencies ranging from 2.5% to 100%. Following a maximum likelihood statistical method,
microRNA genes were separated into two groups that differed significantly in their mutation frequencies and in their tendency to represent mutations that may or may not be under selective pressures during MSI tumoral progression. The first group included 21 genes that displayed no or few mutations in CRC. The second group contained three genes, i.e., hsa-mir-1273c,
hsa-mir-1303 and hsa-mir-567, with frequent (≥ 80%) and sometimes bi-allelic mutations in MSI
tumors. For the only one expressed in colonic tissues,
hsa-mir-1303, no direct link was found between the presence or not of mono- or bi-allelic alterations and the levels of mature miR expression in MSI cell lines, as determined by sequencing and quantitative PCR respectively. Overall, our results provide evidence that
DNA repeats contained in human
miRNA genes are relatively rare and preserved from mutations due to MSI in MMR-deficient
cancer cells. Functional studies are now required to conclude whether mutated
miRNAs, and especially the miR-1303, might have a role in MSI
tumorigenesis.