Institute of Pathology, University of Münster, Germany.
J Pathol. 2011 Aug;224(4):517-28. doi: 10.1002/path.2938. Epub 2011 Jun 27.
A whole chromosome arm loss of 16q belongs to the most frequent and earliest chromosomal alterations in invasive and in situ breast cancers of all common subtypes. Besides E-cadherin, several putative tumour suppressor genes residing on 16q in breast cancer have been investigated. However, the significance of these findings has remained unclear. Thus, other mechanisms leading to gene loss of function (eg haploinsufficiency, or distortion of multiple regulative subnetworks) remain to be tested as a hypothesis. To define the effect on gene expression of whole-arm loss of chromosome 16q in invasive breast cancer, we performed global gene expression analysis on a series of 18 genetically extensively characterized invasive ductal breast carcinomas and verified the results by quantitative real-time PCR (qRT-PCR). The distribution of the differential genes across the genome and their expression status was studied. A second approach by qRT-PCR in an independent series of 30 breast carcinomas helped to narrow down the observed effect. Whole-arm chromosome 16q losses, irrespective of other chromosomal changes, are associated with decreased expression of a number of candidate genes located on 16q (eg CDA08, CGI-128, SNTB2, NQO1, SF3B3, KIAA0174, ATBF1, GABARAPL2, KARS, GCSH, MBTPS1 and ZDHHC7) in breast carcinomas with a low degree of genetic instability. qRT-PCR provided evidence to suggest that the expression of these genes was reduced in a gene dosage-dependent manner. The differential expression of the candidate genes according to the chromosomal 16q-status vanished in genetically advanced breast cancer cases and changed ER status. These results corroborate previous reports about the importance of whole-arm loss of chromosome 16q in breast carcinogenesis and give evidence for the first time that haploinsufficiency, in the sense of a gene dosage effect, might be an important contributing factor in the early steps of breast carcinogenesis.
整条 16q 染色体臂的缺失属于所有常见亚型浸润性和原位乳腺癌中最常见和最早的染色体改变之一。除了 E-钙黏蛋白，在乳腺癌中位于 16q 的几个假定的肿瘤抑制基因已经被研究过。然而，这些发现的意义仍不清楚。因此，其他导致基因功能丧失（例如杂合性缺失，或多个调节子网络的扭曲）的机制仍有待作为假设进行测试。为了确定整条 16 号染色体臂缺失对浸润性乳腺癌基因表达的影响，我们对 18 例遗传上广泛特征的浸润性导管乳腺癌进行了全基因组基因表达分析，并通过定量实时 PCR（qRT-PCR）验证了结果。研究了差异基因在基因组中的分布及其表达状态。qRT-PCR 在独立的 30 例乳腺癌系列中的第二种方法有助于缩小观察到的影响。无论其他染色体变化如何，整条 16q 染色体的缺失与位于 16q 上的一些候选基因（例如 CDA08、CGI-128、SNTB2、NQO1、SF3B3、KIAA0174、ATBF1、GABARAPL2、KARS、GCSH、MBTPS1 和 ZDHHC7）的表达降低有关在遗传不稳定性低的乳腺癌中。qRT-PCR 提供的证据表明，这些基因的表达呈剂量依赖性降低。根据染色体 16q 状态，候选基因的差异表达在遗传上先进的乳腺癌病例中消失，并改变了 ER 状态。这些结果证实了以前关于整条 16q 染色体缺失在乳腺癌发生中的重要性的报告，并首次证明了杂合性缺失（即基因剂量效应）可能是乳腺癌发生早期的一个重要因素。
