A substantial proportion of colorectal cancers (CRCs) are interval CRCs (I-CRCs; i.e., CRCs diagnosed soon after a colonoscopy). Chromosomal instability (CIN) is defined as an increase in the rate of which whole chromosomes/large chromosomal fragments are gained or lost and is observed in 85% of non-hereditary CRCs. The contribution of CIN to the etiology of I-CRCs remains unknown. We established a fluorescence in situ hybridization (FISH) approach to characterize CIN by enumerating specific chromosomes and determined the prevalence of numerical CIN in a population-based cohort of I-CRCs and control (sporadic) CRCs. Using the population-based Manitoba Health administrative databases and Manitoba Cancer Registry, we identified an age, sex, and colonic site of CRC matched cohort of I-CRCs and controls and retrieved their archived paraffin-embedded tumor samples. FISH chromosome enumeration probes specifically recognizing the pericentric regions of chromosomes 8, 11, and 17 were first used on cell lines and then CRC tissue microarrays to detect aneusomy, which was then used to calculate a CIN score (CS). The 15th percentile CS for control CRC was used to define CIN phenotype. Mean CSs were similar in the control CRCs and I-CRCs; 82% of I-CRCs exhibited a CIN phenotype, which was similar to that in the control CRCs. This study suggests that CIN is the most prevalent contributor to genomic instability in I-CRCs. Further studies should evaluate CIN and microsatellite instability (MSI) in the same cohort of I-CRCs to corroborate our findings and to further assess concomitant contribution of CIN and MSI to I-CRCs.

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.