Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway.
Mol Cancer. 2010 May 6;9:100. doi: 10.1186/1476-4598-9-100.
BACKGROUND: Estimates suggest that up to 30% of colorectal cancers (CRC) may develop due to an increased genetic risk. The mean age at diagnosis for CRC is about 70 years. Time of disease onset 20 years younger than the mean age is assumed to be indicative of genetic susceptibility. We have compared high resolution tumor genome copy number variation (CNV) (Roche NimbleGen, 385 000 oligo CGH array) in microsatellite stable (MSS) tumors from two age groups, including 23 young at onset patients without known hereditary syndromes and with a median age of 44 years (range: 28-53) and 17 elderly patients with median age 79 years (range: 69-87). Our aim was to identify differences in the tumor genomes between these groups and pinpoint potential susceptibility loci. Integration analysis of CNV and genome wide mRNA expression data, available for the same tumors, was performed to identify a restricted candidate gene list. RESULTS: The total fraction of the genome with aberrant copy number, the overall genomic profile and the TP53 mutation spectrum were similar between the two age groups. However, both the number of chromosomal aberrations and the number of breakpoints differed significantly between the groups. Gains of 2q35, 10q21.3-22.1, 10q22.3 and 19q13.2-13.31 and losses from 1p31.3, 1q21.1, 2q21.2, 4p16.1-q28.3, 10p11.1 and 19p12, positions that in total contain more than 500 genes, were found significantly more often in the early onset group as compared to the late onset group. Integration analysis revealed a covariation of DNA copy number at these sites and mRNA expression for 107 of the genes. Seven of these genes, CLC, EIF4E, LTBP4, PLA2G12A, PPAT, RG9MTD2, and ZNF574, had significantly different mRNA expression comparing median expression levels across the transcriptome between the two groups. CONCLUSIONS: Ten genomic loci, containing more than 500 protein coding genes, are identified as more often altered in tumors from early onset versus late onset CRC. Integration of genome and transcriptome data identifies seven novel candidate genes with the potential to identify an increased risk for CRC.
背景：据估计，高达 30%的结直肠癌（CRC）可能是由于遗传风险增加而导致的。CRC 的平均诊断年龄约为 70 岁。发病时间比平均年龄早 20 年被认为是遗传易感性的指标。我们比较了两个年龄组的微卫星稳定（MSS）肿瘤中高分辨率肿瘤基因组拷贝数变异（CNV）（罗氏 NimbleGen，385000 个寡核苷酸 CGH 阵列），包括 23 名无已知遗传性综合征且中位年龄为 44 岁（范围：28-53）的年轻发病患者和 17 名中位年龄为 79 岁（范围：69-87）的老年患者。我们的目的是确定这两组肿瘤基因组之间的差异，并确定潜在的易感基因座。对相同肿瘤的 CNV 和全基因组 mRNA 表达数据进行了整合分析，以确定受限的候选基因列表。 结果：两组之间总基因组中异常拷贝数的比例、整体基因组图谱和 TP53 突变谱相似。然而，两组之间的染色体异常数量和断点数量存在显著差异。2q35、10q21.3-22.1、10q22.3 和 19q13.2-13.31 的增益和 1p31.3、1q21.1、2q21.2、4p16.1-q28.3、10p11.1 和 19p12 的缺失，这些位置总共包含超过 500 个基因，在早发组中比晚发组更频繁地发现。整合分析显示，这些位点的 DNA 拷贝数与 mRNA 表达存在共变，其中 107 个基因。在比较两组之间整个转录组的中位数表达水平时，这些基因中的 7 个，CLC、EIF4E、LTBP4、PLA2G12A、PPAT、RG9MTD2 和 ZNF574，其 mRNA 表达水平有显著差异。 结论：确定了 10 个基因组位点，其中包含超过 500 个蛋白质编码基因，这些基因在早发性与晚发性 CRC 肿瘤中更常发生改变。基因组和转录组数据的整合确定了七个新的候选基因，它们有可能识别 CRC 的风险增加。
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