Distinct high resolution genome profiles of early onset and late onset colorectal cancer integrated with gene expression data identify candidate susceptibility loci.
Distinct high resolution genome profiles of early onset and late onset colorectal cancer integrated with gene expression data identify candidate susceptibility loci.
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DOI：
10.1186/1476-4598-9-100
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发表时间：
2010-05-06
期刊：
影响因子：
37.3
通讯作者：
Lothe RA
中科院分区：
文献类型：
--
作者：
Berg M;Agesen TH;Thiis-Evensen E;INFAC-study group;Merok MA;Teixeira MR;Vatn MH;Nesbakken A;Skotheim RI;Lothe RA
据估计，高达30%的结直肠癌（CRC）可能是由于遗传风险增加而发生的。诊断CRC的平均年龄约为70岁。发病时间比平均年龄小20岁被认为是遗传易感性的指标。我们比较了来自两个年龄组的微卫星稳定（MSS）肿瘤的高分辨率肿瘤基因组拷贝数变异（CNV）（Roche NimbleGen，385 000寡核苷酸CGH阵列），包括23例年轻发病患者，无已知的遗传综合征，中位年龄为44岁（范围：28-53）和17例老年患者，中位年龄为79岁（范围：69-87）。我们的目的是确定这些群体之间肿瘤基因组的差异，并查明潜在的易感基因位点。对相同肿瘤的CNV和全基因组mRNA表达数据进行整合分析，以鉴定限制性候选基因列表。两个年龄组之间的基因组的异常拷贝数的总分数，总体基因组谱和TP 53突变谱是相似的。然而，染色体畸变的数量和断裂点的数量在两组之间存在显著差异。2 q35、10q21.3-22.1、10q22.3和19q13.2-13.31的增加和1p31.3、1q21.1、2q21.2、4p16.1-q28.3、10p11.1和19 p12的丢失，这些位置总共包含超过500个基因，在早发性组中比晚发性组明显更常见。整合分析显示，在这些网站和mRNA表达的107个基因的DNA拷贝数的协变。这些基因中的七个，CLC、EIF 4 E、LTBP 4、PLA 2G 12 A、PPAT、RG 9 MTD 2和ZNF 574，具有显著不同的mRNA表达，比较两组之间转录组的中值表达水平。10个基因组基因座，包含超过500个蛋白质编码基因，被确定为在早发性与晚发性CRC的肿瘤中更经常改变。基因组和转录组数据的整合确定了7个新的候选基因，这些基因有可能确定CRC风险增加。
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. 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. 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.
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