Background Serum
tumor markers are ubiquitously used in the clinic for
cancer screening. However, the mechanisms accounting for the elevated levels of the serum
tumor markers remain to be explored. Methods We performed a pan-
cancer analysis of serum
alpha-fetoprotein (AFP),
carcinoembryonic antigen (CEA) and
prostate-specific antigen (PSA). The relation between concentration of serum
tumor markers and the expression of their coding genes was assessed. Then the expression of AFP and its genomic background in
hepatocellular carcinoma (
liver cancer) was studied. Results High expression of AFP
mRNA was found mainly in
liver cancer. In
gastric cancer,
breast cancer and
lung cancer, high AFP
mRNA expression was also discovered occasionally. In
liver cancer patients, serum AFP levels correlated significantly with AFP
mRNA expression in
cancer tissues (r = 0.72, p = 1.6e-45). Whole transcriptome analysis revealed that serum AFP levels clearly separated
liver cancer into two classes with distinct expression profiles according to PCA analysis. Gene co-expression analysis revealed that AFP expression was connected to a module enriched with genes accounting for cell cycle and cell proliferation regulation. In addition, high AFP expression was associated with the molecular classification of
liver cancer, including iCluster (Chi-square: 16.86, P = 0.0002). Methylation analysis revealed de-methylation of AFP promoter occurred in some
liver cancer tissues, which was significantly related to AFP
mRNA expression. Survival analysis indicated high serum AFP levels was prognostic of poorer survival of the
liver cancer patients (Log-rank test: p = 0.046). This was confirmed by an independent dataset in which
liver cancer patients with high serum AFP also had poorer survival (Log-rank test: p = 0.024). Conclusion High expression of AFP defined a subtype of
liver cancer with distinct gene expression profiles and clinical features. De-methylation of
cytosine from CpG di-
nucleotides in AFP promoter may be the cause of AFP re-expression in adult human
liver cancer tissue.