Fragile sites and cancer genes on the short arm of chromosome 8.
Fragile sites and cancer genes on the short arm of chromosome 8.
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8 号染色体短臂上的脆弱位点和癌症基因。
DOI：
10.1016/s1470-2045(04)01377-4
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发表时间：
2004
期刊：
影响因子：
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通讯作者：
Popescu,NicholasC
中科院分区：
文献类型：
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作者：
Popescu,NicholasC
在 2003 年 10 月出版的《柳叶刀肿瘤学》中，Birnbaum 及其同事 1 概述了 8 号染色体短臂 (p) 的解剖结构——在许多类型的癌症中发现的一个基因组区域，非常容易被缺失。为了解释 8p 的脆弱性，作者假设了脆弱位点与癌症基因改变之间的关系。 1 癌症中经常缺失的染色体区域被认为是肿瘤抑制基因的位点，其缺失会导致细胞增殖不受限制。虽然8p是一个相对较小的染色体臂，但它富含抑癌基因。 1 此类基因的失活或异常表达可能是由于基因组缺失、启动子高甲基化或基因突变造成的。事实上，启动子高甲基化似乎与人类癌症相关，其频率与肿瘤抑制基因突变破坏相关的频率相似。 2 此外，因启动子高甲基化而失调或沉默的抑制基因通常位于肿瘤组织中经常缺失的基因组区域。 8p 的断裂倾向与最不稳定的脆弱位点（例如 FRA3B、FRA16 和 FRA7B）的断裂倾向相似。 3, 4 脆弱位点在癌症中的作用直到最近才开始受到关注，因为人们发现染色体易位、原癌基因扩增、抑癌基因缺失、致癌病毒整合以及化学致癌物诱导基因组损伤经常发生在这些独特位点。 3 事实上，人们很容易推测各种类型癌症中 8p 缺失的易感性与脆弱位点的断裂有关。 Birnbaum 及其同事发现，乳腺癌和胰腺肿瘤中 8p12 处的染色体断裂会破坏 NRG1。 1 基于这一观察，他们推测，除了 FRA8B（先前在 8p22 处鉴定的阿菲迪霉素诱导的常见脆弱位点）之外，4 号染色体 8p 还在 NRG1 基因座处或附近包含一个不常见的脆弱位点，此外，该位点的断裂导致了 NRG1 的破坏，并可能解释了邻近癌基因的扩增。 NRG1 晚上 8 点 11 分至 12 点。 1 不幸的是，Birnbaum 和合著者在提出假设时似乎没有意识到 1988 年在 8p11–q11 上发现的常见阿非迪霉素诱导的脆弱位点。 5 最近，在评估阿非迪霉素诱导的常见脆弱位点分布的个体间变异时，发现 8p11–q11 在 20 多个核型正常的成年个体中表达。 6 FRA8B 是一个对阿菲迪霉素敏感的常见脆弱位点，由 Richards 放置在 8p22，4 作为 Birnbaum 等人脆弱假说的锚点。然而，FRA8B 的正确定位是 8q22·1。 6 一些癌症相关基因，包括 DLC1 和 FEZ17, 8，在各种类型的癌症中充当合法的肿瘤抑制基因，位于 8p 区域。尽管不太可能，但在 8p22-21 处识别出一个脆弱位点可能解释了该区域癌症相关基因的高频率缺失。
In the October 2003 issue of The Lancet Oncology, Birnbaum and colleagues1 presented an overview of the anatomy of the short arm (p) of chromosome 8—a genomic region identified in many types of cancer to be notoriously susceptible to deletion. To provide an explanation for the fragility of 8p, the authors hypothesised a relation between fragile sites and cancer-gene alterations. 1 Chromosomal regions frequently deleted in cancer are thought to be the loci for tumour suppressor genes, whose loss results in unrestricted cell proliferation. Although 8p is a relatively small chromosome arm, it is rich in tumour suppressor genes. 1 Inactivation or aberrant expression of such genes may result from genomic deletion, promoter hypermethylation, or gene mutation. Indeed, promoter hypermethylation appears to be associated with human cancer at a frequency similar to that associated with the disruption of tumour suppressor genes by mutation. 2 Furthermore, suppressor genes that are deregulated or silenced by promoter hypermethylation are often located in genomic regions frequently deleted in neoplastic tissue. The propensity for breakage of 8p is similar to that seen for the most unstable fragile sites, such as FRA3B, FRA16, and FRA7B. 3, 4 The role of fragile sites in cancer only recently started to receive attention when it was discovered that chromosome translocations, amplification of proto-oncogenes, deletion of tumour suppressor genes, integration of oncogenic viruses, and induction of genomic damage by chemical carcinogens frequently occur at these unique sites. 3 Indeed, it is tempting to speculate that the susceptibility of 8p to deletion in various types of cancer is related to breakage at fragile sites. Birnbaum and colleagues have found that chromosome breaks at 8p12 disrupt NRG1 in breast and pancreatic tumours. 1 On the basis of this observation they postulated that, in addition to FRA8B (an aphidicolin-induced common fragile site previously identified at 8p22), 4 chromosome 8p also contains a noncommon fragile site at, or near, the locus of NRG1, and furthermore breakage at this site is responsible for the disruption of NRG1 and might explain the amplification of an oncogene proximal to NRG1 at 8p11–12. 1 Unfortunately, while formulating their hypothesis, Birnbaum and co-authors appear to have been unaware of a common aphidicolininduced fragile site at 8p11–q11 identified in 1988. 5 Recently, in an evaluation of the interindividual variation in distribution of aphidicolininduced common fragile sites, 8p11–q11 was found to be among those expressed in more than 20 karyotypically normal adult individuals. 6 FRA8B, an aphidicolin-sensitive common fragile site placed at 8p22 by Richards, 4 served as the anchor point in Birnbaum et al’s fragile hypothesis. The correct localisation of the FRA8B, however, is 8q22· 1. 6 Several cancerrelated genes, including DLC1 and FEZ17, 8 that act as legitimate tumour suppressor genes in various types of cancer, are located in the region of 8p. Although unlikely, the identification of a fragile site at 8p22–21 might explain the high frequency of deletion of cancer-related genes in this region.