Integrative genomic analysis of aneuploidy in uveal melanoma
Integrative genomic analysis of aneuploidy in uveal melanoma
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DOI：
10.1158/1078-0432.ccr-07-1825
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发表时间：
2008-01-01
影响因子：
11.5
通讯作者：
Harbour, J. William
中科院分区：
文献类型：
--
作者：
Ehlers, Justis P.;Worley, Lori;Harbour, J. William
目的：非整倍体是癌症的一个标志，与肿瘤的转移和不良的临床预后密切相关。然而，导致非整倍体的机制及其在肿瘤进展中的作用仍然知之甚少。许多实体肿瘤中广泛而复杂的核型异常可能阻碍对与病理相关的染色体改变的识别。葡萄膜黑色素瘤是研究非整倍体很有吸引力的实体瘤，因为它是一种相对同质的癌症，转移率高，非特异性染色体不稳定性低。实验设计：采用比较基因组杂交和基因表达谱分析49例原发性葡萄膜黑色素瘤的非整倍体模式。对336个已发表病例的细胞遗传学研究结果进行了回顾。结果：根据染色体3和6p的状态，确定了三种预后有意义的肿瘤亚型。染色体改变的离散模式在这三个亚组中以非随机的时间序列累积。不良的临床结果与早期的染色体改变有关，而不是与整体的非整倍体有关。与非整倍体相关的基因表达特征丰富了参与细胞周期调节、中心体功能和DNA损伤修复的基因。其中一个基因是抑癌基因PTEN，它是一种基因组完整性守护者，随着非整倍体的增加而下调(P=0.003)。结论：非整倍体与预后不良的关系可能是由特定的、与病理相关的染色体改变决定的，而不是由整体的非整倍体决定的。这种改变可以使用整合基因组方法来识别，并可能为新的治疗方法提供见解。
Purpose: Aneuploidy is a hallmark of cancer and is closely linked to metastasis and poor clinical outcome. Yet, the mechanisms leading to aneuploidy and its role in tumor progression remain poorly understood. The extensive and complex karyotypic abnormalities seen in many solid tumors could hinder the identification of pathogenetically relevant chromosomal alterations. Uveal melanoma is an attractive solid tumor for studying aneuploidy because it is a relatively homogeneous cancer that is highly metastatic and has low nonspecific chromosomal instability.Experimental Design: Comparative genomic hybridization and gene expression profiling were used to analyze patterns of aneuploidy in 49 primary uveal melanomas. This analysis was supplemented by a review of cytogenetic findings in 336 published cases.Results: Three prognostically significant tumor subgroups were identified based on the status of chromosomes 3 and 6p. Discrete patterns of chromosomal alterations accumulated in these three subgroups in a nonrandom temporal sequence. Poor clinical outcome was associated with early chromosomal alterations rather than overall aneuploidy. A gene expression signature associated with aneuploidy was enriched for genes involved in cell cycle regulation, centrosome function, and DNA damage repair. One of these genes was PTEN, a tumor suppressor and genomic integrity guardian, which was down-regulated in association with increasing aneuploidy (P = 0.003).Conclusions: The relationship between aneuploidy and poor prognosis may be determined by specific, pathogenetically relevant chromosomal alterations, rather than overall aneuploidy. Such alterations can be identified using integrative genomic methods and may provide insights for novel therapeutic approaches.