A large number of structural variations including deletion, inversion, and trans-location are often found in the cancer genome, but delineating their effect in gene regulation during cancer development and progression has been challenging because they are mostly non-coding. We postulate that structural variations may disorganize higher-order chromatin structure, resulting in abnormal gene regulation through the alteration of the relationship between cis-regulatory elements and their target genes. To test our hypothesis, we generate genome-wide chromatin contact maps with 40 colorectal cancer patients’ samples and reveal extensively disorganized higher-order chromatin structure largely explained by structural variations. These changes frequently rewire or disrupt super-enhancer and target gene relationships, which is correlated with either activation of proto-oncogenes or inhibition of tumor-suppressor genes. Unexpectedly, we reveal chromosome-wide disorganized higher-order chromatin structure that may represent a massive chromosomal rearrangement in cancer genome, associating with widespread abnormal gene expression changes without coding sequence mutations. Our study highlights the effect of non-coding structural variations on cancer-specific gene expression. In this talk, I will discuss how investigating 3D genome organization provides a new mechanistic insight to understand abnormal gene regulation mechanisms underlying cancer development and progression.