Integrated genomic and epigenomic analysis of breast cancer brain metastasis.
Integrated genomic and epigenomic analysis of breast cancer brain metastasis.
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DOI：
10.1371/journal.pone.0085448
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Tran NL
中科院分区：
文献类型：
--
作者：
Salhia B;Kiefer J;Ross JT;Metapally R;Martinez RA;Johnson KN;DiPerna DM;Paquette KM;Jung S;Nasser S;Wallstrom G;Tembe W;Baker A;Carpten J;Resau J;Ryken T;Sibenaller Z;Petricoin EF;Liotta LA;Ramanathan RK;Berens ME;Tran NL
大脑是乳腺癌患者转移性疾病的常见部位，治疗选择很少且结果不佳。我们研究的目的是确定乳腺癌脑转移的常见和罕见事件。我们进行了深度基因组分析，整合了一组乳脑转移瘤的基因拷贝数、基因表达和 DNA 甲基化数据集。我们在 1q、5p、8q、11q 和 20q 中发现了频繁的大染色体增益，以及涉及 8p、17p、21p 和 Xq 的频繁的广泛缺失。经常扩增和过表达的基因包括 ATAD2、BRAF、DERL1、DNMTRB 和 NEK2A。 ATM、CRYAB 和 HSPB2 基因通常被删除和表达不足。知识挖掘揭示了细胞周期和 G2/M 转换途径的富集，其中包括 AURKA、AURKB 和 FOXM1。使用 PAM50 乳腺癌内在分类器，Luminal B、Her2+/ER 阴性和基底样肿瘤被确定为我们的脑转移队列中最常见的乳腺癌亚型。虽然乳腺癌脑转移的总体甲基化水平升高，但基底样脑转移与甲基化水平显着降低相关。将 DNA 甲基化数据与基因表达整合，揭示了由于 PENK、EDN3 和 ITGAM 的过度甲基化和下调而导致的细胞迁移和粘附缺陷。 KRT8 的低甲基化和上调可能会影响粘附和渗透性。乳脑转移的基因组和表观基因组分析提供了对该疾病背后的体细胞事件的深入了解，这有可能成为未来治疗策略的基础。
The brain is a common site of metastatic disease in patients with breast cancer, which has few therapeutic options and dismal outcomes. The purpose of our study was to identify common and rare events that underlie breast cancer brain metastasis. We performed deep genomic profiling, which integrated gene copy number, gene expression and DNA methylation datasets on a collection of breast brain metastases. We identified frequent large chromosomal gains in 1q, 5p, 8q, 11q, and 20q and frequent broad-level deletions involving 8p, 17p, 21p and Xq. Frequently amplified and overexpressed genes included ATAD2, BRAF, DERL1, DNMTRB and NEK2A. The ATM, CRYAB and HSPB2 genes were commonly deleted and underexpressed. Knowledge mining revealed enrichment in cell cycle and G2/M transition pathways, which contained AURKA, AURKB and FOXM1. Using the PAM50 breast cancer intrinsic classifier, Luminal B, Her2+/ER negative, and basal-like tumors were identified as the most commonly represented breast cancer subtypes in our brain metastasis cohort. While overall methylation levels were increased in breast cancer brain metastasis, basal-like brain metastases were associated with significantly lower levels of methylation. Integrating DNA methylation data with gene expression revealed defects in cell migration and adhesion due to hypermethylation and downregulation of PENK, EDN3, and ITGAM. Hypomethylation and upregulation of KRT8 likely affects adhesion and permeability. Genomic and epigenomic profiling of breast brain metastasis has provided insight into the somatic events underlying this disease, which have potential in forming the basis of future therapeutic strategies.
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