ABSTRACT
This study undertook complex analysis of over 800 breast cancers using a range of different molecular techniques. These looked at DNA, RNA, microRNA, protein expression and epigenetic changes (DNA methylation). The aim was to understand the underlying molecular changes that differentiate the four major breast cancer subtypes. These are the oestrogen receptor (ER)-positive high- and low-proliferation subgroups (luminal A and B), HER2-amplified and triple-negative type. Data from the different types of analysis were correlated and analysed together to increase the depth of analysis. The paper confirmed the existence of four main breast cancer classes when combining data from the five platforms, each of which showed significant molecular heterogeneity. They were able to identify somatic (acquired or non-inherited) mutations in three genes (TP53, PIK3CA and GATA3) that 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 GATA3, PIK3CA and MAP3K1 with the luminal A subtype. They also 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 (ability to change phenotype and adapt, for example to become endocrine- or chemo-resistant) and heterogeneity occur within, and not across, these major biological subtypes of breast cancer. This is important in understanding how cancers develop and evolve, which has implications for understanding and treating recurrence and for the identification of new treatment targets.
