Candidate tumor-suppressor genes on chromosome arm 8p in early-onset and high-grade breast cancers
Candidate tumor-suppressor genes on chromosome arm 8p in early-onset and high-grade breast cancers
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DOI：
10.1038/sj.onc.1207740
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发表时间：
2004-07-22
期刊：
影响因子：
8
通讯作者：
Venter, DJ
中科院分区：
文献类型：
--
作者：
Armes, JE;Hammet, F;Venter, DJ
染色体臂8p的遗传物质丢失在乳腺癌中很常见，这表明该区域是一个或多个肿瘤抑制基因(TSG)的位置。比较基因组杂交分析显示，与绝经后患者相比，绝经前乳腺癌和高级别乳腺癌中8P缺失更常见，无论绝经状态如何。随后，在临床肿瘤样本的扩展队列中，对定位于染色体8p的基因进行了高分辨率的基因表达谱分析，表明乳腺癌临床病理类型有类似的二分法。其中一些基因在早发、晚发、高级别癌症与低级别、晚发癌症中显示出不同程度的下调。在代表乳腺肿瘤和正常组织样本的组织芯片上，通过原位技术对三个这样的基因进行了进一步的分析。编码中心体蛋白的PCM1和编码MAPK磷酸酶的DUSP4/MKP-2在癌症中都显示出频繁的基因和蛋白缺失。相反，在没有SFRP1基因拷贝数减少的情况下，有过多的病例显示表达缺失，SFRP1编码Wnt家族配体的显性负性受体。这些候选TSG可能构成乳腺癌发生过程中染色体臂8P缺失的一些分子驱动因素。
Loss of genetic material from chromosome arm 8p occurs commonly in breast carcinomas, suggesting that this region is the site of one or more tumor-suppressor genes (TSGs). Comparative genomic hybridization analysis showed that 8p loss is more common in breast cancers from pre-menopausal compared with post-menopausal patients, as well as in high-grade breast cancers, regardless of the menopausal status. Subsequent high-resolution gene expression profiling of genes mapped to chromosome arm 8p, on an extended cohort of clinical tumor samples, indicated a similar dichotomy of breast cancer clinicopathologic types. Some of these genes showed differential downregulation in early-onset and later-onset, high-grade cancers compared with lower-grade, later-onset cancers. Three such genes were analysed further by in situ technologies, performed on tissue microarrays representing breast tumor and normal tissue samples. PCM1, which encodes a centrosomal protein, and DUSP4/MKP-2, which encodes a MAP kinase phosphatase, both showed frequent gene and protein loss in carcinomas. In contrast, there was an excess of cases showing loss of expression in the absence of reduced gene copy number of SFRP1, which encodes a dominant-negative receptor for Wnt-family ligands. These candidate TSGs may constitute some of the molecular drivers of chromosome arm 8p loss in breast carcinogenesis.