The breast cancer genome and the complexity of different subgroups: What does it all mean?

Abstract

Recent progress in understanding breast cancer has come from identifying the various different molecular subgroups that exist within this heterogeneous disease. The authors in this Nature paper studied the genomic and transcriptional alterations that exist in two large series of breast cancers from UK and Canada tumour banks that had prolonged clinical follow-up, using one set as a discovery cohort (n=997) which was then tested in a second independent validation cohort (n=995).1 Their unsupervised analysis of DNA-RNA profiles in the breast cancer genome specifically looked at copy number alterations (CNAs) which are a frequent acquisition in somatic breast cancers, in addition to loss of gene expression transcripts that may indicate gene deletions, somatic mutations or gene silencing by methylation. Using this approach, the authors identified ten subgroups with different and distinct clinical outcomes which were then validated in the second cohort. They discovered at least two novel subgroups. One was a high risk ER+ group with amplification of the 11q 13/14 cis-activating region which may contain some known amplicons that code for driver genes such as CCND1, as well as others such as EMSY, PAK1 and RSF1. Another subgroup with an excellent prognosis was marked by a paucity of CNAs, but had a strong immune/inflammatory signature with trans-acting deletion hotspots associated with a lymphocytic infiltrate and mature T lymphocytes with rearranged TCR loci. Yet another group of the so-called basal cancers harboured chromosome 5 deletions that were associated with alterations in the transcriptional control of cell cycle regulation and genomic/chromosomal instability that promote aneuploidy. © 2013 Royal College of Physicians of Edinburgh.