17 May 2012

Untangling the development of breast cancer

Researchers announce the first comprehensive genome studies of the evolution of 21 breast cancers

Video resource: Breast Cancer: A Deeper Understanding

In two back-to-back reports published online on 17 May in Cell, researchers have sequenced the genomes of 21 breast cancers and analysed the mutations that emerged during the tumours' development. The results of each paper are explored in more detail in the accompanying press releases on mutation processes and on evolution in breast cancers (please use the links to the right).

Led by researchers from the Wellcome Trust Sanger Institute, the team created a catalogue of all the mutations in the genomes of the 21 cancer genomes and identified the mutational processes that lead to breast cancer. They found that these mutations accumulate in breast cells over many years, initially rather slowly, but picking up more and more momentum as the genetic damage builds up.

By the time the breast cancers are large enough to be diagnosed, they are made up of a number of genetically related families of cells, with one such family always dominating the cancer.

All cancers are caused by mutations, called somatic mutations, acquired throughout a person's lifetime in the DNA of initially normal cells. Little is known about the processes that underlie the development of many somatic mutation patters. These studies delve more deeply into the evolution of breast cancers, discovering a number of new mutation processes that can cause many thousands of mutations in a tumour, and drive its development.

Nearly 50,000 people are diagnosed with breast cancer each year in the UK, and more than 12,000 die. Breast cancer is the most common cause of all deaths in women aged over 40 and is the second biggest cause of death from cancer for women in the UK, after lung cancer.

" Whole genome sequencing from cancers is not a new concept, but this is the first time that we’ve been able to delve fully into breast cancer genomes in such a thorough way. "

Dr Peter Campbell

"To be able to deal with breast cancer in the most effective way, we need to understand fully the processes that cause it," explains Dr Peter Campbell, Head of Cancer Genetics and Genomics from the Wellcome Trust Sanger Institute. "Whole genome sequencing from cancers is not a new concept, but this is the first time that we've been able to delve fully into breast cancer genomes in such a thorough way. This has given us a full panoramic view of the cancer genome and has allowed us to identify mutational patterns rather than individual mutations in specific genes."

To determine the processes that underlie breast cancer, the team catalogued all the mutations that had arisen in the 21 breast cancers. One of the processes they found was characterized by pockets of massively mutated regions in the genome. This sudden 'downpour' of mutations is frequently seen in breast cancers. The team called this phenomenon, which has never been seen before, kataegis after the Greek for thunderstorm.

The team found that different mutational processes act at different times in the lifespan of a breast tumour. Some mutational processes act throughout the evolution of the cancer and some processes only emerge late on in the development of the cancer. One particular mutational signature was indicative of a form of inherited breast cancer, and is linked to an inability to correctly repair breaks in DNA.

Video resource: Breast cancer, delving deeper

"These findings have implications for our understanding of how breast cancers develop over the decades before diagnosis in adults and might help to find possible targets for improved diagnosis or therapeutic intervention in the future," says Professor Mike Stratton, lead author and Director of the Wellcome Trust Sanger Institute. "Harnessing the power of whole genome sequencing, we were able to access the entire genome rather than focusing on mutations in specific regions."

Similar analyses will be undertaken in 1000s of cancer genomes, under the full programme of the International Cancer Genome Consortium, and the team expect many more mutational processes will be defined along the way.

"We are used to thinking about Darwinian evolution of species by natural selection taking place over centuries and millennia. But in cancer and infectious disease similar processes can be observed over much shorter periods," says Sir Mark Walport, Director of the Wellcome Trust. "These studies, which follow from the human genome project, are untangling the evolutionary processes that eventually lead to breast cancer, in a way that would have been impossible only a few years ago.

"We are starting to see the landscape of mutation that characterises this disease in something approaching its full complexity for the first time. As this work continues, we can hope to understand how breast cancer develops and thus how it might be treated more effectively."

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

  • Mutational processes molding the genomes of 21 breast cancers.

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

    Cell 2012;149;5;979-93


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.

Breakthrough Breast Cancer

Breakthrough Breast Cancer is dedicated to improving and saving lives through finding the causes of breast cancer, enabling early detection, ensuring precise diagnosis, discovering new and better treatments and improving medical services. Breakthrough Breast Cancer funds groundbreaking research, campaign for better services and treatments and raise awareness of the signs and symptoms of breast cancer. Through this work the charity believes passionately that breast cancer can be beaten and the fear of the disease removed for good.


The Wellcome Trust Sanger Institute

The Wellcome Trust Sanger Institute is one of the world's leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease.


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