The results, summarized in buy R788 Table 5, show that “antigen processing and presentation” is the pathway most strongly associated with HCC in combined Stage 1 and Stage 2 data, with an unadjusted P of 1 × 10−11. We next examined the relationship between SNPs in antigen processing loci and CNV at the T-cell receptor loci. We found that multiple SNPs at the HLA-DQB2 locus were associated with CNVs at the TCR loci. Allelic variants of rs9276427, rs28420297, rs9276429, and rs9276490 are correlated with CNVs at TCR-gamma, all with P below 5 × 10−4. We performed a multidimensional genomic analysis of HCC and LC, examining

the association of CNVs, individual SNPs, and genetic pathways to liver disease. Our GWAS, the first to focus on HCC, reveals that both constitutional genetic variations and somatic genomic events behave as risk factors for HCC. HCC is frequently preceded by cirrhosis. Because only a subset of LC patients develop HCC, it is of great interest to identify factors that affect the transition

from LC to cancer. We identified two SNPs whose allele frequencies differ significantly between HCC and LC (Table 4). The first is located in 2q14.1, ≈175 kb from the nearest gene. The second variant lies within an intron of TPTE2, which encodes a homolog of the PTEN tumor suppressor protein.19 Our study is the first to suggest TPTE2 is involved in carcinogenesis. Our analysis of HCC patients and healthy individuals identified six loci where selleckchem inherited CNV is strongly associated with HCC (Table 1). Several of these have functions plausibly related to the etiology of HCC. SPRK2 encodes a product reported to phosphorylate the HBV core protein.20 Work by Zheng et al.21 suggests that SRPK2 can inhibit HBV replication. Two loci where CNV is associated with liver cancer may play roles in tumorigenesis.

TMPO encodes a protein that regulates the subnuclear localization of Rb. Knockdown of TMPO in fibroblasts disrupts cell cycle progression22, 23; elevated expression of the gene product has been observed in a variety selleck inhibitor of primary tumors.24 Consistent with its apparent role in promoting tumor formation, low TMPO copy number is associated with reduced HCC risk. In contrast to TMPO, increased copy number in a small region of 1p36.33 is associated with reduced HCC risk. Deletions at 1p36 have been reported in a wide variety of cancers.25-28 Although the 1p36.33 CNV region contains no known or predicted genes, the region does show homology to the mitochondrial genome.29 We are undertaking further analyses to determine whether the observed 1p36.33 CNV reflects variation in mitochondrial or chromosomal DNA. The most striking outcome of our analysis of SNPs and CNVs is that germline variation may modulate somatic immune events that drive HCC susceptibility.