Notably, the major regions of copy number gains were observed to reside within 1q and 8q, accounting for 48.2% (464/963) Cell Cycle inhibitor of all gains, whereas the major regions of losses were found within 4q and
8p, accounting for 51.3% (143/278) of all copy number losses. The most frequently amplified region observed was 8q24.21-24.22, which occurred in 53.4% of samples and targets the known oncogenes MYC, DDEF1, and MLZE. Additionally, two other recurrent amplified regions at chromosome 8q were found to be 8q21.13, which targets hairy/enhancer-of-split related with YRPW motif 1 (HEY1), and 8q24.3, which contains several genes, including SCRIB and BOP1 (Table 1). Consistent with previous studies, we found peaks of amplified regions targeting MET on 7q31.2,15 TERT on 5p15.33,16 and SRC on 20q11.2317 as well as an interstitial 11q13.2-13.3 amplification spanning CCND1.18 Other amplifications included 1q21.2-q21.3, which spans MCL1 and LASS2, in addition to ARNT, which is a previously reported target of this genomic amplification.19 The most commonly deleted loci included DLC1 at 8p23.1-8p22 and a previously unreported tripartite motif-containing 35 (TRIM35) deletion at 8p21.2-8p21.1. Several other frequent deletions were also observed, including a deletion targeting SERPINA5 at 14q31.1-32.13 and a larger 17p13.3-13.1 deletion spanning PER1, ENO3, and TP53 (Table
SB431542 price MCE 1). To discover candidate cancer genes in regions of CNAs, we performed an integrated analysis of CNAs and gene expression data. First, we profiled genome-wide gene expression for 49 paired HCC and nontumor tissues and a total of 1,409 differentially expressed genes (DEGs) were obtained. Subsequently, the list of genes located in the 1,241 aberrant regions was matched with the DEG list. The results showed
that a set of 362 genes were differentially expressed in the aberrant regions, with 228 exhibiting increased expression in the amplified regions and 134 showing decreased expression in the deleted regions (Fig. 2A; Supporting Table 1). To further define the cellular processes and pathways in which these 362 DEGs are involved, we performed gene ontology (GO) enrichment analysis. Overall, the 362 genes were enriched for cancer-dominant functions, such as DNA replication / messenger RNA (mRNA) processing, cell cycle/cell proliferation, protein transport/protein folding, and cell adhesion/cell motility (Supporting Fig. 1). Additionally, to determine the regulatory relationships of these genes and the key players in HCC neoplastic processes, we performed a network analysis to generate an interaction network containing relevant biological information for the 362 genes. The resulting network shows a high degree of connectivity that further supported the existence of biologically related functions (Fig. 2B).