**8. Integrative and comparative analyses of HCC for identification of novel therapeutic targets and biomarker discovery**

It has been shown that CNAs have clear impact on expression levels in a variety of tumors [9, 13, 15]. The presence of such CNAs and LOH may contribute to cancer formation [9-11]. Integrating the gene expression with the CNA data reveals the chromosomal regions with concordantly altered genomic and transcriptional status in tumors [12, 52, 104]. The pattern of genomic modifications in a tumor represents a structural fingerprint that may include the transcriptional control mechanisms and locally impact gene expression levels [10, 12]. Therefore, focusing on differentially-expressed genes with concomitant altered DNA copy number may identify novel early HCC markers of malignant transformation, progression and survival [17].

The studies using integrative analysis of genomic aberrations with the expression profiling demonstrated the usefulness of this approach to identify the likely drivers of cancer [105] and helped better understand the processes affected by the drivers/passenger factors and led to obtain novel insights into pathobiology of HCC [17, 54, 105].

In this context, we performed cross-species and integrative genomic analysis to identify potential biomarker genes for early HCC [54]. In this study, we first developed a rat model of early HCC as well as liver regeneration post-hepatectomy and compared them to normal liver using a microarray approach. We then performed a cross-species comparative analysis coupled with CNAs of early human HCCs to identify the critical regulatory modules conserved across species. We identified 35 gene signature conserved across species, with more than 50% mapping to human CNA regions associated with HCC [54]. Combining cross-species comparative and/or functional genomics approaches from human and animal models of HCC along with genomic DNA copy number alterations enhances the ability to identify robust predictive markers for HCC [13, 36, 52-54].
