Przybytkowski Ewa, Girouard Sonia, Allard Brigitte, Lamarre Louis, Basik Mark
Department of Surgery, Centre Hospitalier de l'Université de Montréal-Hôtel-Dieu, 3840 rue St. Urbain, Montreal, Quebec, Canada H2W 1T8.
Cancer Res. 2003 Aug 1;63(15):4588-93.
Genomic instability is thought to underlie tumor progression in solid tumors, such as breast cancer. Although evidence that the hereditary breast cancer genes, BRCA1 and BRCA2, are involved in DNA repair suggests that genomic instability plays an important role in hereditary breast tumorigenesis, genomic instability remains poorly characterized in sporadic breast cancers. Using a DNA fingerprinting technique, inter-(simple sequence repeat) PCR (inter-SSR PCR), the degree of genomic instability was quantified in 47 sporadic breast cancers compared with matched adjacent normal breast tissues. Almost all sporadic breast cancers show significant genomic instability by inter-SSR PCR. The distribution of this instability is bimodal; 57% of the tumors show fewer changes, whereas 43% show striking genomic alterations. Further analysis of two inter-SSR PCR tumor-normal differences revealed a genomic amplification and probable deletion. Thus, inter-SSR PCR can detect chromosomal breakage-related genomic alterations in most sporadic breast cancers. Genomic instability as detected by inter-SSR PCR is not correlated with aneuploidy, suggesting that this technique preferentially detects intrachromosomal alterations. Chromosomal instability in breast cancer can therefore be subdivided into at least two groups: (a) intrachromosomal and (b) gross chromosomal. Allelic imbalance at markers at the 13q13 and retinoblastoma loci (13q) and not at 17q loci was significantly associated with high levels of intrachromosomal instability, suggesting genes at 13q13 and retinoblastoma loci are either selectively targeted or involved in the genesis of genomic instability in sporadic breast cancers.
基因组不稳定被认为是实体瘤（如乳腺癌）肿瘤进展的基础。尽管有证据表明遗传性乳腺癌基因BRCA1和BRCA2参与DNA修复，这提示基因组不稳定在遗传性乳腺肿瘤发生中起重要作用，但在散发性乳腺癌中，基因组不稳定仍未得到充分表征。使用一种DNA指纹技术，即简单序列重复区间PCR（inter-SSR PCR），对47例散发性乳腺癌及其配对的相邻正常乳腺组织的基因组不稳定程度进行了量化。几乎所有散发性乳腺癌通过inter-SSR PCR都显示出显著的基因组不稳定。这种不稳定的分布是双峰的；57%的肿瘤显示变化较少，而43%显示出明显的基因组改变。对两个inter-SSR PCR肿瘤-正常差异的进一步分析揭示了一个基因组扩增和可能的缺失。因此，inter-SSR PCR可以检测大多数散发性乳腺癌中与染色体断裂相关的基因组改变。通过inter-SSR PCR检测到的基因组不稳定与非整倍体无关，这表明该技术优先检测染色体内的改变。因此，乳腺癌中的染色体不稳定可至少分为两组：（a）染色体内的和（b）染色体总体的。13q13和视网膜母细胞瘤基因座（13q）而非17q基因座处标记的等位基因失衡与高水平的染色体内不稳定显著相关，这表明13q13和视网膜母细胞瘤基因座处的基因要么被选择性靶向，要么参与散发性乳腺癌基因组不稳定的发生。
