Somatic Alterations in the Melanoma Genome: A High-Resolution Array-Based Comparative Genomic Hybridization Study
Somatic Alterations in the Melanoma Genome: A High-Resolution Array-Based Comparative Genomic Hybridization Study
复制标题
DOI：
10.1002/gcc.20785
复制
发表时间：
2010-08-01
影响因子：
3.7
通讯作者：
Kumar, Rajiv
中科院分区：
文献类型：
--
作者：
Gast, Andreas;Scherer, Dominique;Kumar, Rajiv
我们进行了DNA微阵列为基础的比较基因组杂交，以确定特定的黑色素瘤基因组在60人细胞系转移的黑色素瘤和44个相应的外周血单核细胞的体细胞改变。我们的数据显示了肿瘤基因组特有的总体但非随机的体细胞变化。虽然CDKN 2A（78%）和PTEN（70%）位点是单等位基因和双等位基因缺失的主要靶点，但扩增影响了BRAF（53%）和NRAS（12%）以及EGFR（52%）、MITF（40%）、NOTCH 2（35%）、CCND 1（18%）、MDM 2（18%）、CCNE 1（10%）和CDK 4（8%）的位点。扩增的基因座携带额外的基因，其中许多可能在黑色素瘤中发挥作用。拷贝数变化的不同模式表明，CDKN 2A的改变往往在BRAF和NRAS基因突变的细胞系中更集中; PTEN基因座主要与BRAF突变一起靶向。在没有BRAF-NRAS突变的细胞系中，CCND 1、CDK 4和其他基因座的扩增显著增加，染色体臂13 q和16 q的丢失也是如此。我们的数据表明涉及不同的遗传途径，这些遗传途径通过致癌BRAF和NRAS突变驱动，并辅以CDKN 2A和PTEN基因的畸变，或涉及致癌基因组位点的扩增和13 q和16 q的丢失。还出现的是，每个肿瘤除了受到主要和最常见的体细胞遗传改变的影响外，还获得了额外的遗传改变，这些遗传改变在确定对目前正在追求的小分子抑制剂的反应中可能是至关重要的。(C)2010 Wiley-Liss，Inc.
We performed DNA microarray-based comparative genomic hybridization to identify somatic alterations specific to melanoma genome in 60 human cell lines from metastasized melanoma and from 44 corresponding peripheral blood mononuclear cells. Our data showed gross but nonrandom somatic changes specific to the tumor genome. Although the CDKN2A (78%) and PTEN (70%) loci were the major targets of mono-allelic and bi-allelic deletions, amplifications affected loci with BRAF (53%) and NRAS (12%) as well as EGFR (52%), MITF (40%), NOTCH2 (35%), CCND1 (18%), MDM2 (18%), CCNE1 (10%), and CDK4 (8%). The amplified loci carried additional genes, many of which could potentially play a role in melanoma. Distinct patterns of copy number changes showed that alterations in CDKN2A tended to be more clustered in cell lines with mutations in the BRAF and NRAS genes; the PTEN locus was targeted mainly in conjunction with BRAF mutations. Amplification of CCND1, CDK4, and other loci was significantly increased in cell lines without BRAF-NRAS mutations and so was the loss of chromosome arms 13q and 16q. Our data suggest involvement of distinct genetic pathways that are driven either through oncogenic BRAF and NRAS mutations complemented by aberrations in the CDKN2A and PTEN genes or involve amplification of oncogenic genomic loci and loss of 13q and 16q. It also emerges that each tumor besides being affected by major and most common somatic genetic alterations also acquires additional genetic alterations that could be crucial in determining response to small molecular inhibitors that are being currently pursued. (C) 2010 Wiley-Liss, Inc.