Further reinforcing the role of the immune system, individual SNP analyses reveal that the MHC class II locus contains three variants (rs9267673, rs2647073, and rs3997872) strongly associated with HCC. MHC class II molecules present antigen to CD4+ (helper) T cells.31 The three SNPs may be associated with altered MHC class II proteins that result in an ineffective T-cell response. Interestingly, rs2647073 lies 3.4 kb from rs660895, an SNP recently identified as a risk factor for the autoimmune liver disease biliary cirrhosis.32 Analysis of SNP allele distributions in pathways further reinforces this observation. In multiple SNP analysis, Trametinib “antigen processing

and presentation” emerged as the pathway with the strongest association with HCC. Among the SNPs in this pathway, multiple variants at the HLA-DQB2 locus were observed to be associated with CNVs at the TCR loci. Analysis of copy number variation at TCR gene complexes supports the findings from the SNP analyses. Healthy individuals, on average, have lower copy number at the T-cell receptor loci TRA@ and TRG@ than do persons with HCC (Fig. 1). T-cell maturation involves TCR gene rearrangements that eliminate large portions of the T-cell receptor loci. Thus,

successful T-cell receptor rearrangements appear to occur less frequently in cancer patients. Because TCR CNV is absent in DNA MK-2206 purchase samples derived from liver tissue or immortalized B cells, the observed findings are attributable to somatic events occurring in T lymphocytes. CNV patterns at TRA@ suggest that rearrangement events generate functional alpha chain more frequently than delta chain. Low copy number segments observed in individual samples frequently encompass the TCR delta constant region, but rarely include the TCR alpha constant region (Fig. 2). Support for the idea that altered ID-8 T-cell activation contributes directly to carcinogenesis in the liver, rather than simply being a systemic reaction to cancer, comes from the strong association we see between

CNV at the T-cell receptor loci and liver cirrhosis, a risk factor for and precursor to HCC (Table 2). Two of the three MHC class II locus SNPs whose genotypes correlate with HCC, rs9267673 and rs2647073, also exhibited strong association with LC (Table 3; Supporting Table S4). Although the role of the immune system in constitutional susceptibility to HCC is new, the involvement of the immune system in HCC carcinogenesis has been previously suggested in clinical studies and research involving model organisms. Increased activity of helper T cells, which promote inflammation, is associated with HCC.33 Conversely, activation and proliferation of cytotoxic T lymphocytes is suppressed in individuals with HCC.34, 35 Further, chronic inflammation has been implicated in the development of liver cancer in both animal models and in humans.