Frequent occurrence of uniparental disomy in colorectal cancer
Frequent occurrence of uniparental disomy in colorectal cancer
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DOI：
10.1093/carcin/bgl086
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发表时间：
2007-01-01
期刊：
影响因子：
4.7
通讯作者：
Orntoft, Torben Falck
中科院分区：
文献类型：
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作者：
Andersen, Claus Lindbjerg;Wiuf, Carsten;Orntoft, Torben Falck
我们使用SNP阵列来识别和表征与结直肠癌（CRC）相关的基因组改变。通过Affymetrix映射10K SNP阵列研究了来自15个腺苷瘤的激光微解剖癌细胞。对从SNP阵列中提取的数据的分析揭示了多个区域，具有拷贝数改变和杂合性损失（LOH）。在染色体13、14和15上鉴定出新的LOH区域。对LOH和拷贝数数据的组合分析揭示了基因组结构，这些结构无法鉴定出无法鉴定出仅分析任何数据类型的基因组结构。确定的LOH区域的一半没有显示出拷贝数减少的证据，表明存在单亲结构。这些结构的分布是非随机的，主要涉及8q，13q和20q。这一发现得到了对一组基于阵列的转录谱的分析，该分析由17种正常粘膜和66个腺癌样品组成。转录分析显示，在完整拷贝数的区域中表达不变的表达水平，包括具有单亲疾病的区域，以及代表事实损失的LOH区域的表达水平降低（包括5Q，8P和17p）。分析还表明，拷贝数增加（包括7p和20q）区域的基因主要上调。对SNP数据的进一步分析显示，已确定的改变的子集与TP53失活（包括8Q增益和17p损失）和淋巴结转移状态（增益为7Q和13Q）。证明已确定的变化的另一个子集表示代表肿瘤内的异质性。总之，我们证明了CRC中的单亲疾病经常存在，并确定与TP53失活和淋巴结状态有关的基因组改变。
We used SNP arrays to identify and characterize genomic alterations associated with colorectal cancer (CRC). Laser microdissected cancer cells from 15 adenocarinomas were investigated by Affymetrix Mapping 10K SNP arrays. Analysis of the data extracted from the SNP arrays revealed multiple regions with copy number alterations and loss of heterozygosity (LOH). Novel LOH areas were identified at chromosomes 13, 14 and 15. Combined analysis of the LOH and copy number data revealed genomic structures that could not have been identified analyzing either data type alone. Half of the identified LOH regions showed no evidence of a reduced copy number, indicating the presence of uniparental structures. The distribution of these structures was non-random, primarily involving 8q, 13q and 20q. This finding was supported by analysis of an independent set of array-based transcriptional profiles, consisting of 17 normal mucosa and 66 adenocarcinoma samples. The transcriptional analysis revealed an unchanged expression level in areas with intact copy number, including regions with uniparental disomy, and a reduced expression level in the LOH regions representing factual losses (including 5q, 8p and 17p). The analysis also showed that genes in regions with increased copy number (including 7p and 20q) were predominantly upregulated. Further analyses of the SNP data revealed a subset of the identified alterations to be specifically associated with TP53 inactivation (including 8q gain and 17p loss) and lymph node metastasis status (gain of 7q and 13q). Another subset of the identified alterations was shown to represent intratumor heterogeneity. In conclusion, we demonstrate that uniparental disomy is frequent in CRC, and identify genomic alterations associated with TP53 inactivation and lymph node status.