METABRIC

The elucidation of breast cancer subgroups and their molecular drivers
requires integrated views of the genome and transcriptome from
representative numbers of patients. We present an integrated analysis of
copy number and gene expression in a discovery and validation
set of 997 and 995 primary breast tumours, respectively, with long-term
clinical follow-up. Inherited variants (CNVs, SNPs) and acquired somatic
copy number aberrations (CNAs) were associated with expression in 40% of
genes, although the landscape was dominated by cis and trans-acting CNAs. By
delineating expression outlier genes driven in cis by CNAs, we identified
putative cancer genes, including deletions in PPP2R2A, MTAP, and MAP2K4.
Unsupervised analysis of paired DNA/RNA profiles revealed novel subgroups
with distinct clinical outcomes, which reproduced in the validation cohort.
These include a high-risk, ER-positive 11q13/14 cis-acting subgroup and a
favourable prognosis subgroup devoid of CNAs. Trans-acting aberration
0152hotspots were found to modulate subgroup-specific gene networks, including
a TCR deletion-mediated adaptive immune response in the 0152CNA-devoid
sub-group and a Basal-specific chromosome 5 deletion-driven mitotic network.
Our results provide a novel molecular stratification of the breast cancer
population, derived from the impact of somatic copy number aberrations on
the transcriptome.EGA study EGAS00000000083