Clinical implication of recurrent copy number alterations in hepatocellular carcinoma and putative oncogenes in recurrent gains on 1q

Abstract

To elucidate the pathogenesis of hepatocellular carcinoma (HCC) and develop useful prognosis predictors, it is necessary to identify biologically relevant genomic alterations in HCC. In our study, we defined recurrently altered regions (RARs) common to many cases of HCCs, which may contain tumor-related genes, using whole-genome array-CGH and explored their associations with the clinicopathologic features. Gene set enrichment analysis was performed to investigate functional implication of RARs. On an average, 23.1% of the total probes were altered per case. Mean numbers of altered probes are significantly higher in high-grade, bigger and microvascular invasion (MVI) positive tumors. In total, 32 RARs (14 gains and 18 losses) were defined and 4 most frequent RARs are gains in 1q21.1-q32.1 (64.5%), 1q32.1-q44 (59.2%), 8q11.21-q24.3 (48.7%) and a loss in 17p13.3-p12 (51.3%). Through focusing on RARs, we identified genes and functional pathways likely to be involved in hepatocarcinogenesis. Among genes in the recurrently gained regions on 1q, expression of KIF14 and TPM3 was significantly increased, suggesting their oncogenic potential in HCC. Some RARs showed the significant associations with the clinical features. Especially, the recurrent loss in 9p24.2-p21.1 and gain in 8q11.21-q24.3 are associated with the high tumor grade and MVI, respectively. Functional analysis showed that cytokine receptor binding and defense response to virus pathways are significantly enriched in high grade-related RARs. Taken together, our results and the strategy of analysis will help to elucidate pathogenesis of HCC and to develop biomarkers for predicting behaviors of HCC.

Ectopic Overexpression of COTE1 Promotes Cellular Invasion of Hepatocellular Carcinoma

“…Chromosomal abnormalities may lead to the inactivation of tumor suppressor genes (TSGs) or activation of oncogenes via amplification (Kim et al, 2008). According to previous study, high incidence of C1q copy number gain was found in HCC (60 to 80%) (Nathalie et al, 2001).…”

Genomic losses at 5q13.2 and 8p23.1 in dysplastic hepatocytes are common events in hepatitis B virus-related hepatocellular carcinoma

“…Chromosomal abnormalities in HCC have been well-documented, and comparative genomic hybridization (CGH) has identified a consistent pattern of chromosomal losses and gains associated with the development and progression of HCC (3,4). Furthermore, a number of studies have demonstrated characteristic chromosomal abnormalities in HCC by CGH and fluorescence in situ hybridization (FISH) (3)(4)(5).…”

“…Furthermore, a number of studies have demonstrated characteristic chromosomal abnormalities in HCC by CGH and fluorescence in situ hybridization (FISH) (3)(4)(5). The most significant changes are partial or entire gains of chromosome arms 1q, 8q and 2q, and losses of 1p and 1q, 4q, 8p, 13q, 16q and 17p.…”

Comparative proteomic analysis of ductal and lobular invasive breast carcinoma

“…TPM3 had a 2.07-fold higher expression in IDC. Several studies have reported increased or decreased expression of different tropomyosin isoforms in a number of human solid tumors (Pawlak et al, 2004;Kim et al, 2008), even though the functional significance of the differential expression is unclear. Franzen et al (1996) initially suggested that the absence of tropomyosin in tumor cells might reduce the stability of actin microfilaments because of a higher susceptibility to depolymerization.…”