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C-reactive protein (CRP) is an established marker of inflammation with pattern-recognition receptor-like activities. Despite the close association of the serum level of CRP with the risk and prognosis of several types of cancer, it remains elusive whether CRP contributes directly to tumorigenesis or just represents a bystander marker. We have recently identified recurrent mutations at the SNP position -286 (rs3091244) in the promoter of CRP gene in several tumor types, instead suggesting that locally produced CRP is a potential driver of tumorigenesis. However, it is unknown whether the -286 site is the sole SNP position of CRP gene targeted for mutation and whether there is any association between CRP SNP mutations and other frequently mutated genes in tumors. Herein, we have examined the genotypes of three common CRP non-coding SNPs (rs7553007, rs1205, rs3093077) in tumor/normal sample pairs of 5 cancer types (n = 141). No recurrent somatic mutations are found at these SNP positions, indicating that the -286 SNP mutations are preferentially selected during the development of cancer. Further analysis reveals that the -286 SNP mutations of CRP tend to co-occur with mutated APC particularly in rectal cancer (p = 0.04; n = 67). By contrast, mutations of CRP and p53 or K-ras appear to be unrelated. There results thus underscore the functional importance of the -286 mutation of CRP in tumorigenesis and imply an interaction between CRP and Wnt signaling pathway.