As cells divide and multiply, mutations accumulate naturally: the team found that, as these mutations accumulate in a cell, the changes drive divergence of the cancer into different subgroups or clones. The scientists showed that emergence of different clones was universal in the breast cancers they examined.

They also showed that one sub-clone becomes the dominant population of cancer cells. This dominant sub-clone accounts for more than 50 per cent of tumour cells in all of the breast cancers analysed, and it is only when this sub-clone has grown sufficiently populous that the tumour becomes clinically detectable. It differs from the other clones present in a tumour by many hundreds to thousands of mutations, indicating that this final stage in a cancer’s emergence may take quite some time.

“We undertook a deep excavation of the tumour DNA,” says Dr Serena Nik-Zainal, “revealing for the first time the fine structure of breast cancer genomes. We took all this data and integrated it to build an evolutionary tree of the cancers.

“This method allowed us to determine when divergence occurs, what processes are involved in the different stages of cancer evolution and the proportion of each sub-clone present in the tumours.”

The team found that some mutational processes act throughout the evolution of the cancer and some processes are present only quite late in the development of the cancer once divergence has occurred.

For example, four of the cancers had many extra copies of the gene that is the target of the Herceptin drug. The team found that the first few extra copies of the gene were gained very early in the development of the breast cancer, but it took the cancer a much longer period of time than expected to accumulate all of the extra 20-30 copies.

“Current cancer treatments do not take sub-clonal diversity into account and often target only the dominant sub-clone,” explains Professor Mike Stratton. “This leaves the possibility that one of the minor sub-clones will then replicate and become dominant, leading to re-occurrence of the tumour.

“Understanding sub-clonal diversity in breast cancer is a pivotal part of treating this destructive cancer in the most efficient way. This study forms the basis to identify sub-clones both minor and dominant.”

These findings have significant implications for our understanding of how breast cancers develop over the decades prior to diagnosis. The next step for this research is to sequence more genomes and cancer types, and also to refine current methods.

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Publication Details
Nik-Zainal et al “The Life History of 21 Breast Cancers?
Published in Cell on 25 May 2012. DOI: 10.1016/j.cell.2012.04.023

Nik-Zainal et al “Mutational Processes Molding the Genomes of 21 Breast Cancers?
Published in Cell on 25 May 2012. DOI: 10.1016/j.cell.2012.04.024

Funding
A full list of funding agencies can be found in the papers

Participating Centres
A full list of participating centres can be found in the papers.

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