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Background  Coding region microsatellite instability (MSI) results in loss of gene products and promotion of microsatellite-unstable (MSI-H) carcinogenesis. Recent studies have indicated that MSI within 3′-untranslated regions (3′UTRs) may post-transcriptionally dysregulate gene products. Within this context, we conducted a broad mutational survey of 42 short 3′UTR microsatellites (MSs) in 45 MSI-H colorectal tumors and their corresponding normal colonic mucosae.    Methodology/Principal Findings  In order to estimate the overall susceptibility of MSs to MSI in MSI-H tumors, the observed MSI frequency of each MS was correlated with its length, interspecies sequence conservation level, and distance from some genetic elements (i.e., stop codon, polyA signal, and microRNA binding sites). All MSs were stable in normal colonic mucosae. The MSI frequency at each MS in MSI-H tumors was independent of sequence conservation level and distance from other genetic elements. In contrast, MS length correlated significantly with MSI frequency in MSI-H tumors (r = 0.86, p = 7.2×10 −13 ). 3′UTR MSs demonstrated MSI frequencies in MSI-H tumors higher than the 99% upper limit predicted by MS length for  RB1-inducible coiled-coil 1 ( RB1CC1 , mutation frequency 68.4%),  NUAK family SNF1-like kinase 1 ( NUAK1 , 31.0%), and  Rtf1, Paf1/RNA polymerase II complex component, homolog  ( RTF1 , 25.0%). An  in silico  prediction of RNA structure alterations was conducted for these MSI events to gauge their likelihood of affecting post-transcriptional regulation.  RB1CC1  mutant was predicted to lose a microRNA-accessible loop structure at a putative binding site for the tumor-suppressive microRNA, miR-138. In contrast, the predicted 3′UTR structural change was minimal for  NUAK1-  and  RTF1  mutants. Notably, real-time quantitative RT-PCR analysis revealed significant  RB1CC1  mRNA overexpression  vs.  normal colonic mucosae in MSI-H cancers manifesting  RB1CC1  3′UTR MSI (9.0-fold; p = 3.6×10 −4 ).    Conclusions  This mutational survey of well-characterized short 3′UTR MSs confirms that MSI incidence in MSI-H colorectal tumors correlates with MS length, but not with sequence conservation level or distance from other genetic elements. This study also identifies  RB1CC1  as a novel target of frequent mutation and aberrant upregulation in MSI-H colorectal tumors. The predicted loss of a microRNA-accessible structure in mutant  RB1CC1  RNA fits the hypothesis that 3′UTR MSI involves in aberrant  RB1CC1  posttranscriptional upregulation. Further direct assessments are indicated to investigate this possibility.

Screening for Microsatellite Instability Identifies Frequent 3′-Untranslated Region Mutation of the RB1-Inducible Coiled-Coil 1 Gene in Colon Tumors