Colorectal cancer susceptibility loci as predictive markers of rectal cancer prognosis after surgery

Background: Colorectal cancer (CRC) is among the leading causes of cancer death. Rectal cancers account for one third of CRC cases. The role and significance of colorectal cancer risk loci in rectal cancer progression has not been investigated. Methods: We generated and explored a dataset from 230 rectal cancer patients by expression microarray of cancer samples and matched controls, and SNP arrays of lymphocytes. Results: 8q24 (upstream of MYC) and 18q21 (in the intron of SMAD7), two of the loci most strongly linked with colorectal cancer risk, as well as 20q13 (in the intron of LAMA5), are tightly associated with the prognosis of rectal cancer patients. For SNPs on 18q21 (rs12953717 and rs4464148) and 20q13 (rs4925386), alleles that correlate with higher risk for the development of colorectal cancer are associated with shorter disease free survival. However, for rs6983267 on 8q24, the low risk allele is associated with a higher risk for recurrence and metastasis after surgery, and importantly, is strongly correlated with the resistance of colorectal cancer cell lines to chemoradiotherapy. We also found that although MYC expression is dramatically increased in cancer, patients with higher levels of MYC have a better prognosis. The expression of SMAD7 is weakly correlated with disease free time. Notably, the presence of the 8q24 and 18q21 SNP alleles is not correlated with a change of expression of MYC and SMAD7. rs4464148), and probably rs6983267 and rs4925386, are linked with overall survival time of patients. Conclusions: SNPs at three colorectal cancer risk loci detect subpopulations of rectal cancer patients with poor prognosis. rs6983267 probably affects prognosis through interfering with the resistance of cancer cells to chemoradiotherapy. Key words colorectal cancer, rectal cancer, SNP, MYC, prognosis, chemoradiotherapy, radiation resistance, rs6983267, rs12953717, rs4464148, rs4925386