Characterizing Microsatellite Instability and Chromosome Instability in Interval Colorectal Cancers

There are a substantial portion of colorectal cancers (CRCs), termed interval CRCs (I-CRCs), that are diagnosed shortly after a negative colonoscopy (i.e., no detectable polyps or CRC) and before recommended follow-up screening. The underlying cause(s) accounting for I-CRCs remain poorly understood, but may involve aberrant biology that drives genome instability. Genetic defects inducing genome instability are pathogenic events that lead to the development and progression of traditional sporadic (Sp-) CRCs. Classically, there are two genome instability pathways that give rise to virtually all Sp-CRCs, chromosome instability (CIN; ~85% of Sp-CRCs) and microsatellite instability (MSI; ~15% of Sp-CRCs); however, the contribution MSI and CIN have in I-CRCs is only beginning to emerge. To date, no study has simultaneously evaluated both MSI and CIN within an I-CRC cohort, and thus we sought to determine and compare the prevalence of MSI and/or CIN within population-based I-CRC and matched Sp-CRC cohorts. MSI status was established using a clinically validated, immunohistochemical approach that assessed the presence or absence of four proteins (MLH1, MSH2, MSH6 and PMS2) implicated in MSI. By combining the MSI results of the current study with those of our previous CIN study, we provide unprecedented insight into the prevalence of MSI and/or CIN between and within Sp- and I-CRCs. Our data show that MSI+ tumors are 1.5-times more prevalent within I-CRCs than Sp-CRCs in a population-based setting and further show that CIN+/MSI+ I-CRCs occur at similar frequency as CIN+/MSI+ Sp-CRCs.