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使用高密度单核苷酸多态性阵列对黑色素瘤进行全基因组杂合性缺失和拷贝数分析。

Genome-wide loss of heterozygosity and copy number analysis in melanoma using high-density single-nucleotide polymorphism arrays.

作者信息

Stark Mitchell, Hayward Nicholas

机构信息

Oncogenomics Laboratory, Queensland Institute of Medical Research, Herston, Queensland, Australia.

出版信息

Cancer Res. 2007 Mar 15;67(6):2632-42. doi: 10.1158/0008-5472.CAN-06-4152.

Abstract

Although a number of genes related to melanoma development have been identified through candidate gene screening approaches, few studies have attempted to conduct such analyses on a genome-wide scale. Here we use Illumina 317K whole-genome single-nucleotide polymorphism arrays to define a comprehensive allelotype of melanoma based on loss of heterozygosity (LOH) and copy number changes in a panel of 76 melanoma cell lines. In keeping with previous reports, we found frequent LOH on chromosome arms 9p (72%), 10p (55%), 10q (55%), 9q (49%), 6q (43%), 11q (43%), and 17p (41%). Tumor suppressor genes (TSGs) can be identified through homozygous deletion (HD). We detected 174 HDs, the most common of which targeted CDKN2A (n = 33). The second highest frequency of HD occurred in PTEN (n = 8), another well known melanoma TSG. HDs were also common for PTPRD (n = 7) and HDAC4 (n = 3), TSGs recently found to be mutated or deleted in other cancer types. Analysis of other HDs and regions of LOH that we have identified might lead to the characterization of further melanoma TSGs. We noted 197 regional amplifications, including some centered on the melanoma oncogenes MITF (n = 9), NRAS (n = 3), BRAF (n = 3), and CCND1 (n = 3). Other amplifications potentially target novel oncogenes important in the development of a subset of melanomas. The numerous focal amplifications and HDs we have documented here are the first step toward identifying a comprehensive catalog of genes involved in melanoma development, some of which may be useful prognostic markers or targets for therapies to treat this disease.

摘要

尽管通过候选基因筛选方法已经鉴定出一些与黑色素瘤发生相关的基因,但很少有研究尝试在全基因组范围内进行此类分析。在这里,我们使用Illumina 317K全基因组单核苷酸多态性阵列,基于76个黑色素瘤细胞系的杂合性缺失(LOH)和拷贝数变化来定义黑色素瘤的综合等位基因型。与之前的报道一致,我们发现9号染色体短臂(72%)、10号染色体短臂(55%)、10号染色体长臂(55%)、9号染色体长臂(49%)、6号染色体长臂(43%)、11号染色体长臂(43%)和17号染色体短臂(41%)上频繁出现LOH。肿瘤抑制基因(TSG)可通过纯合缺失(HD)来鉴定。我们检测到174个HD,其中最常见的靶向CDKN2A(n = 33)。HD出现频率第二高的是PTEN(n = 8),它是另一个著名的黑色素瘤TSG。PTPRD(n = 7)和HDAC4(n = 3)的HD也很常见,这两个TSG最近在其他癌症类型中被发现发生了突变或缺失。对我们所鉴定的其他HD和LOH区域的分析可能会导致进一步鉴定黑色素瘤TSG。我们注意到197个区域扩增,包括一些以黑色素瘤癌基因MITF(n = 9)、NRAS(n = 3)、BRAF(n = 3)和CCND1(n = 3)为中心的扩增。其他扩增可能靶向在一部分黑色素瘤发生过程中重要的新癌基因。我们在此记录的众多局灶性扩增和HD是朝着鉴定参与黑色素瘤发生的基因综合目录迈出的第一步,其中一些基因可能是有用的预后标志物或治疗该疾病的治疗靶点。

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