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Type 2 diabetes mellitus (T2DM) has an increased risk of cancer. In the present study, the relationship between T2DM and 13 types of cancer was analyzed and key methylation genes were searched. First, DNA methylation and mRNA expression were obtained data for T2DM and 13 types of cancer from The Cancer Genome Atlas and Gene Expression Omnibus. The t-test was used to screen the differentially methylated expression overlapping genes (DE-MGs) in T2DM and cancer on both methylation and expression levels. DE-MGs are weighted based on the methylation and projected into the human protein interaction network. The correlation between T2DM and each type of cancer was analyzed, and key genes were identified. The results showed that 293 DE-MGs were related to T2DM and 3307 were related to cancer. The network found that T2DM is more related to colorectal cancer (CRC) compare with the other 12 types of cancer. A total of 5 from 8 candidate genes were associated with CRC. A total of 28 clinical patients were used to validate these 5 genes. A CRC tissue sample was collected from each patient, as well as a paracancerous sample that served as a control. A total of 56 tissue samples were divided into 4 groups: control group, T2DM group, CRC group and T2DM with CRC group (combination group). Compared with the control group, the methylation level of adenylate cyclase 5 (ADCY5), neuregulin 1 and ELAV-like RNA-binding protein 4 in the combination group was significantly upregulated, and the mRNA level was significantly downregulated. Furthermore, based on the methylation level of ADCY5, the correlation coefficient between the combination group and the T2DM group was greater than that of the CRC group. In conclusion, T2DM is most likely to be associated with CRC among 13 common types of cancer based on methylation characteristics. An upregulated methylation of ADCY5 in T2DM may have a higher risk of CRC. [ABSTRACT FROM AUTHOR]