Max Planck Institute for Molecular Genetics, Ihnestrasse 73, Berlin, Germany.
Genes Chromosomes Cancer. 2010 May;49(5):463-70. doi: 10.1002/gcc.20756.
Lobular intraepithelial neoplasia Grade 3 (LIN3) is a recently recognized variant of intraepithelial lobular neoplasia (LIN) of the breast composed of either uniform, generally small cells with massive lobular distension, pleomorphic cells, signet-ring cells, or any cell type with necrosis. In contrast to classic forms of LIN, there is no consensus on therapeutic strategies for LIN3. In part this is due to the paucity of molecular data that could assist in defining the relationship of LIN3 to classic LIN and carcinomas. In this study we have employed array comparative genomic hybridization to determine the patterns of chromosomal aberrations in nine LIN3 lesions. By comparison to array CGH data of 13 classic LIN lesions, we demonstrate that classic LIN and LIN3 share several recurrent changes, in particular gains of 1q and losses of 16q. Both aberrations are known to appear early in tumorigenesis and to be associated with good prognosis. However, apart from this overlap, there were a number of karyotypic features that were observed exclusively in LIN3. Clearly, this lesion was characterized by a significantly higher number of DNA copy number changes (9 vs. 31 on average), a considerable complexity of chromosomal rearrangements with more than 16 breakpoints in one chromosome and overlapping high copy amplifications encompassing a number of known oncogenes. Our data suggest that, at the genetic level, LIN3 represents a highly advanced lesion with considerable resemblance to carcinomas and, therefore, might represent the transition state from an intraepithelial neoplasm to breast carcinoma.
三级小叶上皮内瘤变（LIN3）是最近被认识到的乳腺小叶上皮内瘤变（LIN）的一种变异型，由形态一致的小细胞、广泛的小叶扩张、多形性细胞、印戒细胞或任何伴有坏死的细胞类型组成。与经典的 LIN 形式不同，对于 LIN3 的治疗策略还没有共识。部分原因是缺乏可以帮助确定 LIN3 与经典 LIN 和癌之间关系的分子数据。在这项研究中，我们使用 arrayCGH 来确定 9 例 LIN3 病变中的染色体畸变模式。通过与 13 例经典 LIN 病变的 arrayCGH 数据比较，我们证明经典 LIN 和 LIN3 存在几种共同的反复出现的改变，特别是 1q 的获得和 16q 的缺失。这两种畸变都出现在肿瘤发生的早期，与良好的预后相关。然而，除了这些重叠之外，还有一些核型特征仅在 LIN3 中观察到。显然，该病变的特点是 DNA 拷贝数变化显著增加（9 次与平均 31 次），染色体重排非常复杂，一个染色体上有超过 16 个断点，并且重叠的高拷贝扩增包含多个已知的癌基因。我们的数据表明，在遗传水平上，LIN3 代表了一种高度进展的病变，与癌非常相似，因此可能代表了从上皮内肿瘤向乳腺癌的过渡状态。
