Classification of Human Hepatocellular Carcinoma

人类肝细胞癌的分类

• 批准号: 6557497
• 负责人: SNORRI S THORGEIRSSON
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6557497
• 关键词: alpha fetoprotein; animal genetic material tag; carcinogenesis; cell line; chromosome aberrations; comparative genomic hybridization; complementary DNA; gene expression; hepatocellular carcinoma; human genetic material tag; microarray technology; neoplastic growth; tissue /cell culture

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.

在后基因组领域，将全球方法应用于分析包括人类疾病在内的复杂生物现象可能是有用的，这一概念已经获得了相当大的力量。例如，几项独立的研究表明，通过检查临床或实验肿瘤样本的全基因组转录谱，可以识别出以前未被识别的不同癌症亚型。事实上，从肿瘤细胞系和原发性肿瘤的微阵列分析获得的表达谱已用于对几种人类癌症进行分类，包括黑素瘤、乳腺癌、白血病和淋巴瘤。类似地，通过比较基因组杂交（CGH）对肿瘤疾病中的染色体改变的全局分析提供了整个基因组中DNA序列的获得和丢失的位置鉴定。在我们实验室最近的一项研究中，使用CGH分析19个HCC细胞系，定义了一种独特的基因组不平衡模式，除了揭示DNA获得和丢失的新复发区域外，还证实了先前通过CGH在原发性HCC肿瘤中鉴定的基因组改变。这些结果表明，来源于人HCC的细胞系基本上保留了原发性肿瘤的基因组改变。 我们目前正在使用的cDNA微阵列技术，以确定全球表达谱在肝肿瘤从人类和小鼠。我们的长期目标是利用表达谱构建人类和小鼠肝脏肿瘤的分子分类。在我们最初的方法中，我们使用了肝癌细胞系，以前的特点是CGH，进行系统的表征的全球基因表达的cDNA微阵列。讨论了两个问题：（1）是可用于定义表达模块的HCC细胞系，所述表达模块可用于定义在肝肿瘤发展中至关重要的相互作用途径;和（2）是在转录组的表达模式中反映的保留在HCC细胞系中的结构基因组改变。目前的研究结果已经揭示了两种不同的肝细胞癌（HCC）亚型，它们通过数百种不同基因的差异表达而彼此区分。值得注意的是，甲胎蛋白的表达与HCC的分子亚型高度相关。还鉴定了对HCC亚型特异的共表达的已知和未知基因的集合。每个染色体的基因表达模式的比较揭示了HCC内的区域表达偏差，反映了细胞系中的染色体畸变。这些结果不仅确定了未识别的HCC亚型，而且为每个亚型提供了潜在的分子标记物，可用于诊断和/或治疗目的。