Single-Cell Genetic Analysis of Ductal Carcinoma in Situ and Invasive Breast Cancer Reveals Enormous Tumor Heterogeneity yet Conserved Genomic Imbalances and Gain of MYC during Progression
Single-Cell Genetic Analysis of Ductal Carcinoma in Situ and Invasive Breast Cancer Reveals Enormous Tumor Heterogeneity yet Conserved Genomic Imbalances and Gain of MYC during Progression
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DOI：
10.1016/j.ajpath.2012.07.012
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发表时间：
2012-11-01
影响因子：
6
通讯作者：
Ried, Thomas
中科院分区：
文献类型：
--
作者：
Heselmeyer-Haddad, Kerstin;Garcia, Lissa Y. Berroa;Ried, Thomas
导管原位癌（DCIS）是乳腺浸润性导管癌（IDC）的前兆病变。为了了解这一过程中基因组改变的动态，我们使用了四种多色荧光原位杂交探针板，包括癌基因COX2、MYC、HER2、CCND1和ZNF217以及肿瘤抑制基因DBC2、CDH1和TP53，以单细胞分析为基础，观察13例同步DCIS和IDC的拷贝数变化。DCIS的染色体不稳定程度低于IDC。尽管DCIS和IDC存在巨大的细胞间异质性，但我们观察到的信号模式与基因组失衡的非随机分布一致。CDH1最常丢失，MYC的增加出现在DCIS向IDC的进展过程中。13个DCISs中有4个在IDCs中表现出相同的克隆失衡。6个案例显示了一个转换，在其中4个案例中，IDC获得了MYC的增益。在一种情况下，MC中的主要克隆是DCIS中的几个克隆之一，而在另一种情况下，DCIS中的主要克隆成为IDC中的两个主要克隆之一。尽管存在相当大的染色体不稳定性，但在大多数情况下，从DCIS到IDC的演变是由基因组失衡的复发模式决定的，与生物连续体一致。（中华病理学杂志，2012,18:1807-1822;http://dx.doi.org/10.1016/j.ajpath.2012.07.012）
Ductal carcinoma in situ (DCIS) is a precursor lesion of invasive ductal carcinoma (IDC) of the breast. To understand the dynamics of genomic alterations in this progression, we used four multicolor fluorescence in situ hybridization probe panels consisting of the oncogenes COX2, MYC, HER2, CCND1, and ZNF217 and the tumor suppressor genes DBC2, CDH1, and TP53 to visualize copy number changes in 13 cases of synchronous DCIS and IDC based on single-cell analyses. The DCIS had a lower degree of chromosomal instability than the IDC. Despite enormous intercellular heterogeneity in DCIS and IDC, we observed signal patterns consistent with a nonrandom distribution of genomic imbalances. CDH1 was most commonly lost, and gain of MYC emerged during progression from DCIS to IDC. Four of 13 DCISs showed identical clonal imbalances in the IDCs. Six cases revealed a switch, and in four of those, the IDC had acquired a gain of MYC. In one case, the major clone in the MC was one of several clones in the DCIS, and in another case, the major clone in the DCIS became one of the two major clones in the IDC. Despite considerable chromosomal instability, in most cases the evolution from DCIS to IDC is determined by recurrent patterns of genomic imbalances, consistent with a biological continuum. (Am J Pathol 2012, 181: 1807-1822; http://dx.doi.org/10.1016/j.ajpath.2012.07.012)