Novel subgroups of breast cancer
Genomic and transcriptomic architecture of breast tumours
- Date : 15 May 2012
- Topic : Breast cancer
Breast cancer can be reclassified into ten separate “diseases” based on its genetic characteristics, according to a new molecular study. Analysis of the DNA and RNA from almost 2000 tumours identified ten genetically different subtypes of breast cancer with different survival outcomes. The information could be used to better predict the outcomes of the disease, as well as offer tailored treatment to patients.
The elucidation of breast cancer subgroups and their molecular drivers requires integrated views of the genome and transcriptome from representative numbers of patients. A group of researchers led by Professor Carlos Caldas, senior group leader at Cancer Research UK's Cambridge Research Institute, and Professor Samuel Aparicio, based at the BC Cancer Agency in Vancouver, presented in the April 18 issue of Nature an integrated analysis of copy number and gene expression in a discovery and validation set of nearly 2000 primary breast tumours, with long-term clinical follow-up.
Discovery of novel tumour subgroups with distinct clinical outcomes
The team used tissue samples from women diagnosed with breast cancer between five and ten years ago. The samples came from tumour banks in the UK and Canada. They mapped three types of genetic mutations in the tumours: copy number variants, single nucleotide polymorphisms, and acquired somatic copy number aberrations.
This allowed the team to divide a subset of 997 tumours into ten groups of genetically similar breast cancers. They then repeated this on a separate group of 995 tumours to confirm their initial results. By delineating expression outlier genes, they identified putative cancer genes, including deletions in PPP2R2A, MTAP and MAP2K4.
Unsupervised analysis of paired DNA–RNA profiles revealed novel tumour subgroups with distinct clinical outcomes, which reproduced in the validation cohort. These include a high-risk, oestrogen receptor-positive 11q13/14 cis-acting subgroup and a favourable prognosis subgroup devoid of copy number aberrations. Trans-acting aberration hotspots were found to modulate subgroup-specific gene networks, including a TCR deletion-mediated adaptive immune response in copy number aberrations-devoid subgroup and a basal-specific chromosome 5 deletion-associated mitotic network.
Impact of the study findings
These results provide a novel molecular stratification of the breast cancer population, derived from the impact of somatic copy number aberrations on the transcriptome. The real power in the study came from the large numbers used and consequently the researchers have been able to detect new subgroups in breast cancer bringing the number from five up to at least ten. Each disease has its own molecular fingerprint that might be used to help diagnosis and treatment.
To date, breast cancer has been classified either by looking at the cells it originates from, or what treatments it might respond to (by testing for oestrogen and progesterone receptors, for example). Essentially the researchers have moved from knowing what a breast tumour looks like under a microscope to pinpointing its molecular anatomy.
The size of this study is unprecedented and provides insights into the disease such as the role of immune response, which will stimulate other avenues of research. The study has resulted in a comprehensive map of breast cancer genes, some of which were already known. But it has also discovered several completely new genes that had not been associated with breast cancer before. These genes provide potential targets for novel breast cancer treatments.
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