17 May 2012

Mutational processes behind breast cancer

Researchers develop mutation catalogue to discover the processes behind 21 breast cancers

Video resource: What is Kataegis?

In a study published in Cell online on 17 May, researchers catalogue all the mutations in the genomes of 21 breast cancers and use the information to identify the mutational processes responsible for the development of these tumours.

All cancers are due to mutations - changes in DNA that occur in cells of the body during the course of a person's lifetime. Chemicals in tobacco smoke damage DNA in lung cells, causing mutations that lead to lung cancer. Similarly, sunlight damages DNA in skin cells causing mutations that lead to skin cancer. However, we have very limited knowledge of the mechanisms generating mutations in most other cancer types.

A total of almost 200,000 mutations in the genomes of the 21 breast cancers was found by the team, led by researchers from the Wellcome Trust Sanger Institute. By examining the mutations from each cancer, they could discern different patterns of mutation, which appear to represent traces of past mutational mechanisms that have acted on the genomes of individual cells during the life of the patient. These traces are like archaeological imprints left in the DNA of the cancer cell by mutational processes which could have been active many years before the cancer came to attention. Previously, there was little, if any, knowledge about most of these processes and the 21 breast cancer samples seem to have been assaulted by different combinations of them.

"What emerges is a really complex landscape of mutation, where each cancer seems to have been generated by a different combination of mutation processes," says Professor Mike Stratton, lead author and Director of the Wellcome Trust Sanger Institute.

" In our analyses, we have excavated these cancer genomes, in a similar manner to an archaeological dig, and uncovered patterns of mutation that had never been seen before. "

Professor Mike Stratton

"In our analyses, we have excavated these cancer genomes, in a similar manner to an archaeological dig, and uncovered patterns of mutation that had never been seen before. We do not know for sure what the underlying biological mechanisms causing these mutation patterns are. However, we suspect certain processes in normal cells that generate mutations have been overactive and simply caused too many mutations, hence leading to cancer. We do not think that these mutation patterns are due to external exposures like tobacco smoke or sunlight, which are known to cause mutations and cancer, but more likely are due to defective internal cellular machinery. However, further work needs to be conducted to confirm this view.

One of the novel mutation mechanisms is a remarkable process that leads to large numbers of mutations in small regions of the genome. The authors call this 'kataegis' (from the Greek for thunderstorm): although never described before, kataegis was remarkably common occurring, to some extent, in the genomes of 13 of the 21 breast cancers. The dense bursts of mutations in each patch of kataegis are likely to have occurred at one point in time rather than accumulated in a step-wise fashion over the lifetime of the cancer.

"In kataegis, a large number substitution mutations occur very close together in the genome," says Dr Serena Nik-Zainal, first author from the Wellcome Trust Sanger Institute. "They show a distinguishing mutational motif and frequently co-occur with large-scale rearrangements: it is a unique mutational pattern.

"We expect that this phenomenon is not restricted to breast cancer and might operate in other cancers. Current sequencing technologies allow us to make these discoveries which were hidden from us before."

Rainfall plot of kataegis. x axis reflecting genomic position and y axis is the intermutation distance.

Rainfall plot of kataegis. x axis reflecting genomic position and y axis is the intermutation distance. [DOI: 10.1016/j.cell.2012.04.024]

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The pattern of mutations in kataegis is highly distinctive, and the team speculate that there is a relationship between kataegis and a protein family, APOBEC. Members of this family can induce similar mutational changes in experimental systems and are thought to play a role in defence against viruses.

The mutational processes identified by the researchers allowed them to distinguish cancers from women with known BRCA1 and BRCA2 mutations from other, more common or sporadic, breast cancers. The team speculate that these distinguishing mutational patterns might be present in other types of cancer and could help to predict response to treatments such as PARP inhibitors to which BRCA1/BRCA2 cancers are particularly sensitive.

"Our results highlight the power of whole cancer genome sequencing in our quest to understand the fundamental processes that lead to the development and spread of breast cancer," says Dr Peter Campbell, Head of Cancer Genetics and Genomics at the Wellcome Trust Sanger Institute. "To understand these processes more comprehensively - to build the full picture we need of the processes behind breast cancer genetics - we will need many hundred samples of breast cancer genomes sequenced and catalogued."

Notes to Editors

Publication details

  • 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

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.

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.

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