Combined total genome loss of heterozygosity scan of breast cancer stroma and epithelium reveals multiplicity of stromal targets
Combined total genome loss of heterozygosity scan of breast cancer stroma and epithelium reveals multiplicity of stromal targets
复制标题
DOI：
10.1158/0008-5472.can-04-2866
复制
发表时间：
2004-10-15
期刊：
影响因子：
11.2
通讯作者：
Eng, C
中科院分区：
文献类型：
--
作者：
Fukino, K;Lei, S;Eng, C
最近的乳腺癌研究强调了癌上皮和肿瘤间质之间相互作用的重要性。近年来，实体瘤的研究重点已从癌上皮细胞的突变转移到癌组织的组织紊乱。然而，这种微环境的遗传基础仍有待澄清。为了开始解决这个问题，对134例散发性浸润性乳腺癌的上皮和间质DNA进行了全基因组杂合性缺失(LOH)扫描。除了在间质中检测到比在上皮中更频繁的LOH外，我们还发现强有力的证据表明，在每条染色体的特定区域，LOH频率显著升高。我们检测了57个标记，相对于各自染色体上的背景LOH频率，这些标记优先丢失在间质(n=38)或上皮(n=19)中。这种间质细胞LOH的多样性，从而导致遗传物质的丢失，为患者之间对侵袭腺癌细胞的宿主间质反应提供了一种可能的机制。这与一个模型是一致的，在该模型中，最初的随机LOH在上皮和间质中同样发生，但随后的克隆性选择是由各种因素驱动的，这些因素似乎在恶性上皮细胞和周围间质细胞中明显不同。间质中的基因改变不能模仿上皮细胞中的基因变化，但它们可能在癌症的发生和肿瘤进展中发挥不同的、平行的作用，可能是通过改变乳腺癌特有的某些特征。
Recent breast cancer studies have highlighted the importance of interactions between cancer epithelium and tumor stroma. Recently, the focus of solid tumor investigations has shifted from mutations in carcinomatous epithelium to disturbances of tissue organization in cancer. The genetic basis of this microenvironment, however, remains to be clarified. To begin to resolve this problem, a total genome loss of heterozygosity (LOH) scan was done on epithelial and stromal DNA from 134 sporadic invasive breast carcinomas. In addition to detecting more frequent LOH at three loci in stroma than in epithelium, we found strong evidence that LOH frequencies were significantly elevated in specific regions of each chromosome. We detected 57 markers, which were preferentially lost either in stroma (n = 38) or epithelium (n = 19), relative to the background LOH frequencies on their respective chromosomes. This multiplicity of stromal cell LOH, and hence loss of genetic material, provides a possible mechanism for interpatient variation in host-stromal response to invading adenocarcinoma cells. This is consistent with a model in which initial, random LOH occurs equally among epithelium and stroma, but subsequent clonal selection is driven by factors, which appear to be distinctly different between malignant epithelial and surrounding stromal cells. Genetic alterations in stroma did not mimic those in epithelium, but they could play a different and parallel role in carcinogenesis and tumor progression, probably by modifying some features specific to breast cancer.