A study analyzing 2,000 breast tumors reveals new subgroups and molecular features. The research, published in Nature, integrates genomic and transcriptomic data from 997 and 995 primary breast tumors, with long-term clinical follow-up. The study identifies inherited and acquired genetic variations that influence gene expression, with cis- and trans-acting copy number aberrations (CNAs) dominating the expression landscape. The analysis reveals novel subgroups with distinct clinical outcomes, including a high-risk subgroup with 11q13/14 cis-acting alterations and a favorable prognosis subgroup without CNAs. Trans-acting aberration hotspots modulate subgroup-specific gene networks, such as an adaptive immune response in the CNA-devoid subgroup and a mitotic network in basal-like tumors. The study highlights the impact of somatic CNAs on the transcriptome, providing a molecular stratification of breast cancer. Key findings include deletions in PPP2R2A, MTAP, and MAP2K4, which may drive cancer progression. The research also identifies trans-acting modules, such as T-cell receptor (TCR) deletions associated with adaptive immune responses and chromosome 5 deletions linked to cell cycle regulation. The study demonstrates that integrating genomic and transcriptomic data can reveal distinct subgroups with different clinical outcomes, offering new insights into breast cancer biology and potential therapeutic targets. The findings suggest that genomic copy number loss at TCR loci drives an immune response module, and that 5q deletions modulate genomic and chromosomal instability. The study underscores the importance of considering both cis- and trans-acting genetic variations in understanding breast cancer heterogeneity and developing targeted therapies.A study analyzing 2,000 breast tumors reveals new subgroups and molecular features. The research, published in Nature, integrates genomic and transcriptomic data from 997 and 995 primary breast tumors, with long-term clinical follow-up. The study identifies inherited and acquired genetic variations that influence gene expression, with cis- and trans-acting copy number aberrations (CNAs) dominating the expression landscape. The analysis reveals novel subgroups with distinct clinical outcomes, including a high-risk subgroup with 11q13/14 cis-acting alterations and a favorable prognosis subgroup without CNAs. Trans-acting aberration hotspots modulate subgroup-specific gene networks, such as an adaptive immune response in the CNA-devoid subgroup and a mitotic network in basal-like tumors. The study highlights the impact of somatic CNAs on the transcriptome, providing a molecular stratification of breast cancer. Key findings include deletions in PPP2R2A, MTAP, and MAP2K4, which may drive cancer progression. The research also identifies trans-acting modules, such as T-cell receptor (TCR) deletions associated with adaptive immune responses and chromosome 5 deletions linked to cell cycle regulation. The study demonstrates that integrating genomic and transcriptomic data can reveal distinct subgroups with different clinical outcomes, offering new insights into breast cancer biology and potential therapeutic targets. The findings suggest that genomic copy number loss at TCR loci drives an immune response module, and that 5q deletions modulate genomic and chromosomal instability. The study underscores the importance of considering both cis- and trans-acting genetic variations in understanding breast cancer heterogeneity and developing targeted therapies.