Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
Genes Chromosomes Cancer. 2012 Dec;51(12):1067-78. doi: 10.1002/gcc.21991. Epub 2012 Aug 9.
Only a minority of intraductal carcinomas of the breast give rise to stromally invasive disease. We microdissected 206 paraffin blocks representing 116 different cases of low-grade ductal carcinoma in situ (DCIS). Fifty-five were pure DCIS (PD) cases without progression to invasive carcinoma. Sixty-one cases had a small invasive component. DNA was extracted from microdissected sections and hybridized to high-density bacterial artificial chromosome arrays. Array comparative genomic hybridization analysis of 118 hybridized DNA samples yielded data on 69 samples that were suitable for further statistical analysis. This cohort included 20 pure DCIS cases, 25 mixed DCIS (MD), and 24 mixed invasive carcinoma samples. PD cases had a higher frequency of DNA copy number changes than MD cases, and the latter had similar DNA profiles compared to paired invasive carcinomas. Copy number changes on 13 chromosomal arms occurred at different rates in PD versus MD lesions. Eight of 19 candidate genes residing at those loci were confirmed to have differential copy number changes by quantitative PCR. NCOR2/SMRT and NR4A1 (both on 12q), DYNLRB2 (16q), CELSR1, UPK3A, and ST13 (all on 22q) were more frequently amplified in PD. Moreover, NCOR2, NR4A1, and DYNLRB2 showed more frequent copy number losses in MD. GRAP2 (22q) was more often amplified in MD, whereas TAF1C (16q) was more commonly deleted in PD. A multigene model comprising these candidate genes discriminated between PD and MD lesions with high accuracy. These findings suggest that the propensity to invade the stroma may be encoded in the genome of intraductal carcinomas.
仅有少数乳腺导管内癌会发展为间质浸润性病变。我们对 206 个石蜡块进行了微切割，代表了 116 个不同的低级别导管原位癌（DCIS）病例。其中 55 个为无浸润性癌进展的纯 DCIS（PD）病例。61 个病例有小的浸润性成分。从微切割的切片中提取 DNA，并与高密度细菌人工染色体阵列杂交。对 118 个杂交 DNA 样本的阵列比较基因组杂交分析产生了 69 个适合进一步统计分析的样本数据。该队列包括 20 个纯 DCIS 病例、25 个混合 DCIS（MD）和 24 个混合浸润性癌样本。PD 病例的 DNA 拷贝数变化频率高于 MD 病例，而后者的 DNA 图谱与配对的浸润性癌相似。PD 与 MD 病变中 13 条染色体臂上的拷贝数变化以不同的速率发生。位于这些位点的 19 个候选基因中的 8 个通过定量 PCR 证实存在差异拷贝数变化。NCOR2/SMRT 和 NR4A1（均位于 12q）、DYNLRB2（16q）、CELSR1、UPK3A 和 ST13（均位于 22q）在 PD 中扩增更为频繁。此外，NCOR2、NR4A1 和 DYNLRB2 在 MD 中更频繁地出现拷贝数缺失。GRAP2（22q）在 MD 中扩增更为频繁，而 TAF1C（16q）在 PD 中更为常见缺失。由这些候选基因组成的多基因模型可以准确地区分 PD 和 MD 病变。这些发现表明，侵袭间质的倾向可能编码在导管内癌的基因组中。
