Exome sequencing of a colorectal cancer family reveals shared mutation pattern and predisposition circuitry along tumor pathways.
Exome sequencing of a colorectal cancer family reveals shared mutation pattern and predisposition circuitry along tumor pathways.
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DOI：
10.3389/fgene.2015.00288
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发表时间：
2015
影响因子：
3.7
通讯作者：
Ibrahim ME
中科院分区：
文献类型：
--
作者：
Suleiman SH;Koko ME;Nasir WH;Elfateh O;Elgizouli UK;Abdallah MO;Alfarouk KO;Hussain A;Faisal S;Ibrahim FM;Romano M;Sultan A;Banks L;Newport M;Baralle F;Elhassan AM;Mohamed HS;Ibrahim ME
癌症和癌症多表型的分子基础尚未完全了解。下一代测序有望对遗传相互作用在塑造癌症复杂性中的作用有新的见解。为了概述家族性结直肠癌病例和对照之间突变模式的差异，我们分析了来自扩展的结直肠癌谱系的癌组织和对照样品的全外显子组，提供了非洲人群中癌症外显子组测序的第一批数据集之一，背景是通常具有过量变体的大有效大小。肿瘤显示与Lynch综合征一致的hMSH 2功能丧失SNV。然而，在肿瘤组织中携带插入-缺失的基因组揭示了显著的GO富集，这是在对照样品中未观察到的特征，表明有序的插入-缺失对这种类型的癌症中的肿瘤发生至关重要。网络分析确定了多个中心基因。ELAVL 1/HuR表现出显著的中心性，特别是与携带非同义SNV的基因相互作用，从而加强了癌症途径中靶向诱变的主张。对这种突变模式的一种可能的解释是DNA/RNA编辑，这里通过显著偏离预期值（p值5e-6）的核苷酸转换-颠换比率来表明。NFKB 1也与ELAVL 1一起显示出显著的中心性沿着，考虑到致癌病毒与这些蛋白质之间的已知相互作用，引起了对病毒病因学的怀疑。
The molecular basis of cancer and cancer multiple phenotypes are not yet fully understood. Next Generation Sequencing promises new insight into the role of genetic interactions in shaping the complexity of cancer. Aiming to outline the differences in mutation patterns between familial colorectal cancer cases and controls we analyzed whole exomes of cancer tissues and control samples from an extended colorectal cancer pedigree, providing one of the first data sets of exome sequencing of cancer in an African population against a background of large effective size typically with excess of variants. Tumors showed hMSH2 loss of function SNV consistent with Lynch syndrome. Sets of genes harboring insertions–deletions in tumor tissues revealed, however, significant GO enrichment, a feature that was not seen in control samples, suggesting that ordered insertions–deletions are central to tumorigenesis in this type of cancer. Network analysis identified multiple hub genes of centrality. ELAVL1/HuR showed remarkable centrality, interacting specially with genes harboring non-synonymous SNVs thus reinforcing the proposition of targeted mutagenesis in cancer pathways. A likely explanation to such mutation pattern is DNA/RNA editing, suggested here by nucleotide transition-to-transversion ratio that significantly departed from expected values (p-value 5e-6). NFKB1 also showed significant centrality along with ELAVL1, raising the suspicion of viral etiology given the known interaction between oncogenic viruses and these proteins.