Comprehensive molecular portraits of human breast tumours

摘要

来自“癌症基因组图谱”联合体的这篇文章描述了对825个人的原发性乳腺癌所做的一项多层面分析。研究人员进行了外显子组测序、版本数变化分析、DNA甲基化分析、信使RNA阵列分析、微RNA测序及蛋白质组分析，并将分析结果综合起来，以了解乳腺癌的异质性。在所有乳腺癌中，只有三个基因以超过10％的频率发生突变，它们分别是丁P53、PIK3CA和GATA3。研究人员还识别出很多“与亚型相关rn的”、新颖的突变以及有特定信号通道特征的两个乳腺癌亚类。这些分析还表明，在临床上可观察到的弹性及异质性很多都出现在乳腺癌主要亚型内，而不是出现在它们之间。%We analysed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays. Our ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at >10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GAT A3, PIK3CA and MAP3K1 with the luminal A subtype. We identified two novel protein-expression-defined subgroups, possibly produced by stromal/microenvironmental elements, and integrated analyses identified specific signalling pathways dominant in each molecular subtype including a HER2/phosphorylated HER2/EGFR/phosphorylated EGFR signature within the HER2-enriched expression subtype. Comparison of basal-like breast tumours with high-grade serous ovarian tumours showed many molecular commonalities, indicating a related aetiology and similar therapeutic opportunities. The biological finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biological subtypes of breast cancer.