Ductal carcinoma in situ and the emergence of diversity during breast cancer evolution
Ductal carcinoma in situ and the emergence of diversity during breast cancer evolution
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DOI：
10.1158/1078-0432.ccr-07-1127
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发表时间：
2008-01-15
影响因子：
11.5
通讯作者：
Medina, Dan
中科院分区：
文献类型：
--
作者：
Allred, D. Craig;Wu, Yun;Medina, Dan
目的：人类浸润性乳腺癌(IBC)表现出巨大的组织学和生物学多样性。这项研究全面评估了导管原位癌(DCIS)的多样性，导管原位癌是IBC的直接先兆。实验设计：通过免疫组织化学方法评估一系列单纯DCIS(n=200)和同期系列IBC(n=200)中常规组织学分级和标准预后生物标志物的差异程度。通过DNA微阵列对DCIS的一个子集(n=25)进行评估，以确定是否存在管腔、基底型和erbB2固有亚型。通过免疫组织化学方法独立评估多个区域的组织学(核)级别和几个生物标志物，以确定固有亚型，从而确定单个DCIS(n=120)的多样性程度。结果：DCIS表现出广泛的常规组织学分级和标准生物标志物的分布，从高分化到低分化，与IBCs几乎相同。微阵列在DCIS和IBCs中显示相同的固有亚型。然而，更高分辨率的分析表明，多个组织学分级、生物标记物表型和固有亚型通常共存于同一DOS内，这些不同的区域可能竞争优势。病例的多样性与P53基因突变高度相关(P=0.0007)。结论：这些结果支持低分化DCI是通过随机获得遗传缺陷而演变为高分化DCI的假说，从而导致细胞特征日益异常。这种多样性被导致遗传不稳定的缺陷(例如，P53突变)放大，并且改变以一种独立于侵袭进展的方式传播到IBC。
Purpose: Human invasive breast cancers (IBC) show enormous histologic and biological diversity. This study comprehensively evaluated diversity in ductal carcinoma in situ (DCIS), the immediate precursors of IBCs.Experimental Design: The extent of diversity for conventional histologic grade and standard prognostic biomarkers assessed by immunohistochemistry was evaluated in a series of pure DCIS (n = 200) compared with a contemporaneous series of IBCs (n = 200). A subset of the DCIS (n = 25) was evaluated by DNA microarrays for the presence of luminal, basal, and erbB2 intrinsic subtypes. The extent of diversity within individual cases of DCIS (n = 120) was determined by assessing multiple regions independently for histologic (nuclear) grade and several biomarkers by immunohistochemistry, which approximate microarrays in determining intrinsic subtypes.Results: DCIS showed a broad distribution of conventional histologic grades and standard biomarkers ranging from well to poorly differentiated, nearly identical to IBCs. Microarrays showed the same intrinsic subtypes in DCIS as in IBCs. However, higher resolution analysis showed that multiple histologic grades, biomarker phenotypes, and intrinsic subtypes often coexist within the same DOS, and these diverse regions probably compete for dominance. Diversity within cases of DCIS was highly correlated with mutated p53 (P = 0.0007).Conclusions: These results support the hypothesis that poorly differentiated DCIS gradually evolve from well-differentiated DCIS by randomly acquiring genetic defects resulting in increasingly abnormal cellular features. This diversity is amplified by defects resulting in genetic instability (e.g., p53 mutation), and the alterations are propagated to IBC in a manner independent of progression to invasion.