17 May 2012

Deciphering the life history of 21 breast cancers

Whole genome sequencing used to determine the emergence of mutations over time

As the breast cells accumulate many thousands of mutations, the developing cancer starts to diverge into families of genetically related cells. By the time the cancer is diagnosed, one of these families has become the dominant population in the tumour.

As the breast cells accumulate many thousands of mutations, the developing cancer starts to diverge into families of genetically related cells. By the time the cancer is diagnosed, one of these families has become the dominant population in the tumour. [Genome Research Limited]

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In a study published online by Cell on 17 May 2012, researchers have deciphered the life history imprinted on the genome of 21 breast cancers.

The team, led by researchers from the Wellcome trust Sanger Institute, found that mutational processes evolve across the lifespan of a breast tumour, with distinctive patterns of mutation emerging late in the process, contributing to a large amount of variation. As the breast cells accumulate many thousands of mutations, the developing cancer starts to diverge into families of genetically related cells. By the time the cancer is diagnosed, one of these families has become the dominant population in the tumour.

Each time a cell mutates, it leaves a distinctive stamp inscribed in its genome. Each mutational process leaves distinctive marks on the genome of a cancer. As these changes accumulate one on top of one another, archaeological layers of mutations build up, leaving a record that can be deciphered to allow a glimpse of the cancer's life history.

"We wanted to see if we could decipher this history encrypted in the genome of each of the cancers," explains Dr Peter Campbell, Head of Cancer Genetics and Genomics at the Wellcome Trust Sanger Institute. "All cancers are made up of a collection of families of cells. Whole genome sequences reveal the genetic record of their emergence over time and allow us to trace the divergence of a cell to form the different families."

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, 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. "

Dr Serena Nik-Zainal

"We undertook a deep excavation of the tumour DNA," says Dr Serena Nik-Zainal, first author on the studies, from the Wellcome Trust Sanger Institute, "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, co-author and Director of the Wellcome Trust Sanger Institute. "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.

Notes to Editors

Publication details

  • The life history of 21 breast cancers.

    Nik-Zainal S, Van Loo P, Wedge DC, Alexandrov LB, Greenman CD, Lau KW, Raine K, Jones D, Marshall J, Ramakrishna M, Shlien A, Cooke SL, Hinton J, Menzies A, Stebbings LA, Leroy C, Jia M, Rance R, Mudie LJ, Gamble SJ, Stephens PJ, McLaren S, Tarpey PS, Papaemmanuil E, Davies HR, Varela I, McBride DJ, Bignell GR, Leung K, Butler AP, Teague JW, Martin S, Jönsson G, Mariani O, Boyault S, Miron P, Fatima A, Langerød A, Aparicio SA, Tutt A, Sieuwerts AM, Borg Å, Thomas G, Salomon AV, Richardson AL, Børresen-Dale AL, Futreal PA, Stratton MR, Campbell PJ and Breast Cancer Working Group of the International Cancer Genome Consortium

    Cell 2012;149;5;994-1007

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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