Mutational processes behind 21 breast cancers:

The team found almost 200,000 mutations in the genomes of the 21 breast cancers. 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.

“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. “

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.

Life history of 21 breast cancers:

“We wanted to see if we could decipher this history encrypted in the genome of each of the cancers,” explains Dr Peter Campbell. “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.”