Chromosome instability (CIN), characterized by structural or numerical chromosomal alterations, may drive cancer development and progression. CIN is associated with poor prognosis and drug resistance in cancers. However, the mechanisms that underlie CIN in cancer remain unclear. Besides gene mutations, deletion of a tumor suppressor gene can induce CIN. Our previous study demonstrated that the Migration and Invasion Inhibitory Protein (MIIP) gene, located on chromosome 1p36, is a tumor-suppressor gene in glioma. In fact, 1p36 deletion has been associated with a large spectrum of human cancers, such as colorectal cancer (CRC) and neuroblastoma. Our preliminary analyses of The Cancer Genome Atlas (TCGA) data revealed the correlations between MIIP deletion and CIN and metastasis in CRC. Our studies using the Zinc Finger Nuclease technology further demonstrated that deletion of only MIIP in HCT116 CRC cells led to CIN.