Jou Yuh-Shan, Lee Chih-Shia, Chang Ya-Hui, Hsiao Chin-Fu, Chen Chian-Feng, Chao Chuan-Chuan, Wu Lawrence S H, Yeh Shiou-Hwei, Chen Ding-Shinn, Chen Pei-Jer
Division of Molecular and Genomic Medicines, National Health Research Institute, Taipei, Taiwan.
Cancer Res. 2004 May 1;64(9):3030-6. doi: 10.1158/0008-5472.can-03-2320.
Systematic scan and statistical analysis of loss of heterozygosity (LOH) has been widely used to define chromosomal aberrations in various cancers for cloning of tumor suppressor genes and for development of prognostic markers. However, the establishment of novel strategies is needed, so that the nonrandom but heterogeneous chromosomal aberration data could provide significant insights into our understanding of molecular pathogenesis of cancers. After comprehensive allelotyping of recurrent allelic losses with 441 highly informative microsatellite markers and overlapping LOH regions on human hepatocellular carcinoma (HCC) chromosomes, 33 minimal deleted regions (MDRs) were revealed. Five and 15 of the 33 MDRs have physical intervals in less than 5 and 10 Mb, respectively, with the smallest MDR9p1 of 2.2 Mb located at 9p21.3-p21.2. Statistical and Kaplan-Meier survival analysis revealed a significant association between the loss of MDR15q1 (15q21.1-q22.2) and the HCC patient survival (adjusted P = 0.033). After cluster analysis of 33 MDRs that represented LOH profiles of each HCC tissue based on clinicopathological features and p53 mutations, two major genetic pathways, low-stage and advanced-stage HCC, were uncovered based on high concordance of MDR clusters. We propose that the definition of genome-wide MDRs on the cancer genome not only narrows down the location of existing tumor suppressor genes to facilitate positional candidate cloning and develop potential prognostic markers after statistical association of MDRs with clinicopathological features but also dissects genetic interactions and pathways of chromosomal aberrations in tumorigenesis.
杂合性缺失（LOH）的系统扫描和统计分析已被广泛用于确定各种癌症中的染色体畸变，以克隆肿瘤抑制基因并开发预后标志物。然而，需要建立新的策略，以便非随机但异质性的染色体畸变数据能够为我们理解癌症的分子发病机制提供重要见解。在用441个高信息量微卫星标记对复发性等位基因缺失进行全面的等位基因分型以及对人肝细胞癌（HCC）染色体上的重叠LOH区域进行分析后，发现了33个最小缺失区域（MDR）。33个MDR中的5个和15个分别具有小于5 Mb和10 Mb的物理间隔，最小的MDR9p1为2.2 Mb，位于9p21.3 - p21.2。统计分析和Kaplan-Meier生存分析显示，MDR15q1（15q21.1 - q22.2）的缺失与HCC患者的生存之间存在显著关联（校正P = 0.033）。在基于临床病理特征和p53突变对代表每个HCC组织LOH谱的33个MDR进行聚类分析后，基于MDR簇的高度一致性，发现了两个主要的遗传途径，即低分期和高分期HCC。我们提出，在癌症基因组上定义全基因组MDRs不仅可以缩小现有肿瘤抑制基因的定位，以便在将MDRs与临床病理特征进行统计关联后促进定位候选克隆并开发潜在的预后标志物，还可以剖析肿瘤发生过程中染色体畸变的遗传相互作用和途径。
