Hypermethylation in histologically distinct classes of breast cancer
Hypermethylation in histologically distinct classes of breast cancer
复制标题
DOI：
10.1158/1078-0432.ccr-04-0667
复制
发表时间：
2004-09-15
影响因子：
11.5
通讯作者：
Gabrielson, E
中科院分区：
文献类型：
--
作者：
Bae, YK;Brown, A;Gabrielson, E
目的：已知许多不同的基因在乳腺癌中被异常高甲基化失活，但这些表观遗传学改变在多大程度上是未知的;根据特定的乳腺癌表型而不同。我们试图确定是否与乳腺癌的生物学特性的超甲基化或基因超甲基化的定义配置文件的程度。实验设计：我们评估了12个不同的基因在一系列的109个浸润性乳腺肿瘤的甲基化状态，代表导管，小叶，和粘液组织学亚型使用甲基化特异性PCR。甲基化的频率在公认的组织学分类和多变量技术之间进行比较。（潜在类别分析、因子分析、递归分割和层次聚类）被用于寻找个体基因的甲基化模式，所述个体基因区分公认的乳腺癌组织学类型或在分子水平上定义乳腺癌表型。研究的所有109例病例都有多个基因的异常甲基化（每个病例3到10个基因），表明基因超甲基化在乳腺癌中普遍存在。小叶癌和粘液癌通常具有相对较低水平的染色体变化，其高甲基化的总体频率高于导管癌（小叶癌和粘液癌中为49%，导管癌中为40%），但所有三种组织学类型的甲基化频率均呈相对单峰分布。研究的单个基因中只有一个BRCA 1具有可变的甲基化频率，其显著依赖于肿瘤生长的组织学模式，粘液癌中的甲基化频率高于导管癌或小叶癌。虽然观察到了组织学特异性基因甲基化的一些趋势，但甲基化模式不能根据组织学类型对乳腺癌进行明确分类。虽然更全面的超甲基化图谱可能对乳腺癌分类和了解这种疾病的生物学有用，不同形式乳腺癌的超甲基化模式似乎不如乳腺癌和不同组织癌症之间的差异明显，起源.此外，所有三种组织学类型的甲基化频率的相对单峰分布不支持乳腺癌存在不同的CpG岛甲基化表型。
Purpose: A number of different genes are known to be inactivated by aberrant hypermethylation in breast cancer, but it is still unknown to what extent these epigenetic alterations; differ according to specific breast cancer phenotypes. We sought to determine whether the extent of hypermethylation or defined profiles of gene hypermethylation are associated with biological characteristics of breast cancers.Experimental Design: We evaluated methylation status of 12 different genes in a series of 109 invasive breast tumors, representing the ductal, lobular, and mucinous histologic subtypes using methylation-specific PCR. Frequencies of methylation were compared across the recognized histologic classes, and multivariate techniques (latent class analysis, factor analysis, recursive partitioning, and hierarchical clustering) were used to seek patterns of methylation for individual genes that distinguish recognized histologic types of breast cancer or define breast cancer phenotypes on a molecular level.Results: All 109 cases studied have aberrant methylation of multiple genes (3 to 10 genes per case), demonstrating that gene hypermethylation is pervasive in breast cancer. Lobular cancers and mucinous cancers, which often have relatively low levels of chromosomal changes, have higher overall frequencies of hypermethylation than ductal cancers (49% in lobular and mucinous versus 40% in ductal), but there is a relatively unimodal distribution of methylation frequency for all three histologic types. Only one of the individual genes studied, BRCA1, has a variable frequency of methylation that is significantly dependent on histologic pattern of tumor growth, with a higher frequency of methylation in mucinous cancers than ductal or lobular cancers. Although some trends of histology-specific gene methylation were seen, methylation patterns could not definitively classify breast cancers according to histologic type.Conclusions: Although a more comprehensive hypermethylation profile could potentially be useful for breast cancer classification and understanding the biology of this disease, it appears that the hypermethylation patterns across various forms of breast cancer are less distinct than those between breast cancer and cancers of different tissue origins. Furthermore, the relatively unimodal distribution of methylation frequency for all three histologic types does not support there being a distinct CpG island methylator phenotype for breast cancer.