Molecular karyotyping of human hepatocellular carcinoma using single-nucleotide polymorphism arrays
Molecular karyotyping of human hepatocellular carcinoma using single-nucleotide polymorphism arrays
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DOI：
10.1038/sj.onc.1209537
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发表时间：
2006-09-01
期刊：
影响因子：
8
通讯作者：
Aburatani, H.
中科院分区：
文献类型：
--
作者：
Midorikawa, Y.;Yamamoto, S.;Aburatani, H.
癌基因的扩增和抑癌基因的失活在人类癌症的发病机制中至关重要。为了确定与肝癌发生相关的染色体改变，我们对36例肝细胞癌（HCC）进行了等位基因剂量分析。使用基因组不平衡图（GIM）算法分析来自高密度单核苷酸多态性阵列的数据，该算法同时检测DNA拷贝数改变和杂合性丢失（洛）事件。基因组不平衡图谱分析确定了等位基因不平衡区域，包括单亲二体性，并预测了杂合子癌细胞群的共存。我们观察到1q、5p、5q、6p、7q、8q、17 q和20 q的增加和1p、4q、6q、8p、10 q、13 q、16 p、16 q和17 p的洛缺失与肝癌显著相关。在含有印记基因簇的6q24 - 25上，我们观察到由于未甲基化等位基因的丢失，PLAGL 1表达水平降低。最后，我们将拷贝数数据与基因表达强度相结合，发现基因组剂量与基因表达的改变相关。这些观察结果表明，高分辨率GIM分析可以准确地确定等位基因不平衡的基因组区域的定位，并且当与表观遗传信息整合时，阐明了HCC中肿瘤抑制基因失活的机制基础。
Genomic amplification of oncogenes and inactivation of suppressor genes are critical in the pathogenesis of human cancer. To identify chromosomal alterations associated with hepatocarcinogenesis, we performed allelic gene dosage analysis on 36 hepatocellular carcinomas (HCCs). Data from high-density single-nucleotide polymorphism arrays were analysed using the Genome Imbalance Map (GIM) algorithm, which simultaneously detects DNA copy number alterations and loss of heterozygosity (LOH) events. Genome Imbalance Map analysis identified allelic imbalance regions, including uniparental disomy, and predicted the coexistence of a heterozygous population of cancer cells. We observed that gains of 1q, 5p, 5q, 6p, 7q, 8q, 17q and 20q, and LOH of 1p, 4q, 6q, 8p, 10q, 13q, 16p, 16q and 17p were significantly associated with HCC. On 6q24-25, which contains imprinting gene clusters, we observed reduced levels of PLAGL1 expression owing to loss of the unmethylated allele. Finally, we integrated the copy number data with gene expression intensity, and found that genome dosage is correlated with alteration in gene expression. These observations indicated that high-resolution GIM analysis can accurately determine the localizations of genomic regions with allelic imbalance, and when integrated with epigenetic information, a mechanistic basis for inactivation of a tumor suppressor gene in HCC was elucidated.