Classification of Human Hepatocellular Carcinoma

应用全球方法分析包括人类疾病在内的复杂生物现象可能是有用的，这一概念在后基因组领域得到了相当大的支持。例如，几项独立研究表明，以前未被识别的不同亚型癌症可以通过检查临床或实验肿瘤样本的全基因组转录谱来识别。事实上，从肿瘤细胞系和原发肿瘤的微阵列分析中获得的表达谱已被用于几种人类癌症的分类，包括黑色素瘤、乳腺癌、白血病和淋巴瘤。同样，通过比较基因组杂交（CGH）对肿瘤疾病中染色体改变的全局分析提供了整个基因组中DNA序列的增加和减少的位置鉴定。在我们实验室最近的一项研究中，对19个HCC细胞系进行了CGH分析，发现了一种独特的基因组失衡模式，除了揭示了DNA获得和损失的新复发区域外，还证实了CGH先前在原发性HCC肿瘤中发现的基因组改变。这些结果表明，源自人类HCC的细胞系基本上保留了原发肿瘤的基因组改变。

The notion that application of global approaches to the analysis of complex biological phenomena including human diseases may be useful has gained considerable strength in the postgenome area. For example, several independent studies have illustrated that previously unrecognized distinct subtypes of cancers could be identified by examining the genome-wide transcriptional profiles of clinical or experimental tumor samples. In fact, expression profiles obtained from microarray analysis of both tumor cell lines and primary tumors have been used to classify several human cancers including melanoma, breast cancer, leukemias and lymphomas. Similarly, global analysis of chromosomal alterations in neoplastic diseases by comparative genomic hybridization (CGH) has provided positional identifications of gains and losses of DNA sequences in the entire genome. In a recent study from our laboratory using CGH analysis of 19 HCC cell lines, a distinct pattern of genomic imbalance was defined that, in addition to revealing novel recurrent regions of DNA gains and losses, also confirmed genomic alterations previously identified by CGH in primary HCC tumors. These results suggest that cell lines derived from human HCC essentially retain the genomic alterations of the primary tumors. We are currently using the cDNA microarray technique to define global expression profiles in liver tumors from both human and mouse. Our long-term goal is to use the expression profiles to construct a molecular classification of human and mouse liver tumors. In our initial approach we have used the HCC cell lines, previously characterized by CGH, to conduct a systematic characterization of global gene expression by cDNA microarray. Two questions were addressed: (1) are HCC cell lines useful in defining expression modules that can be utilized to define interactive pathways critical in development of liver tumors; and (2) is the structural genomic alterations retained in the HCC cell lines reflected in the expression patterns of the transcriptome. Current results have revealed two distinct subtypes of hepatocellular carcinoma (HCC) that are distinguished from each other by the differential expression of hundreds of different genes. Remarkably, expression of a-fetoprotein was highly correlated with the molecular subtypes of HCC. Sets of co-expressed known and unknown genes that are specific for the subtypes of HCC were also identified. Comparison of gene expression patterns for each chromosome revealed region-wide expression bias within HCC, reflecting chromosomal aberrations in cell lines. These results not only identified unrecognized subtypes of HCC, but also provided potential molecular markers for each subtype that can be useful for diagnostic and/or therapeutic purposes.