Scientists have produced a comprehensive catalogue of DNA signatures of mutations that cause the most common cancers in humans, and identified some of the biological processes involved.
They believe their findings will greatly increase understanding of cancer and make a major contribution to preventing and treating the disease.
Cancer happens when mutations in the DNA of cells disrupt normal growth and functioning causing them to form tumors. And while many triggers of genetic mutation are understood – chemicals in tobacco smoke, for example, can cause lung cancer, and ultraviolet radiation can lead to skin cancer – scientists do not know much about the biology of how such exposure actually produces the genetic damage.
Now a large international group of researchers has studied nearly 5 million mutations in over 7,000 cancers and traced 20 DNA-damaging processes that explain nearly all the mutations in 30 of the most common cancers.
In many cases they also pinpointed the underlying biological process responsible.
This work represents the first comprehensive catalogue of genetic mutational processes behind tumor development.
For each mutation, the catalogue shows the genetic trademark or signature it imprints in a cell’s DNA.
First author Ludmil Alexandrov, of the Wellcome Trust Sanger Institute in the UK, and colleagues, report their findings in an August 14th online issue of Nature.
The researchers discovered some interesting features of the cancer-driving mutations:
- All of the cancers they studied had two or more DNA signatures, showing that processes link up to cause the mutations.
- Different cancers are driven by different numbers of mutational processes: ovarian cancer is the result of two, while liver cancer is the result of six.
- Some of the signatures feature in more than one type of cancer, while others only feature in one.
- Of the 30 most common types of cancer, 25 have signatures caused by mutation processes related to aging.
- A signature that results from flaws in DNA-repairing tools caused by mutations in BRCA1, a gene already known to be involved in breast cancer, was found not only in breast cancer but also in ovarian and pancreatic cancers.
The team also found that enzymes called APOBECs which are already known to mutate DNA, were involved in over half the cancer types.
APOBEC enzymes are normally active during viral infections, where they attack viruses by damaging their DNA. Now it seems they also cause collateral damage to host cell DNA.
The researchers had only recently discovered that breast cancer shows a surprising mutation pattern where small regions of the genome are swamped with mutations, a process called kataegis.
In this latest study they found kataegis features in most cancers, and suggest its trigger may involve APOBEC enzymes.
Alexandrov told the press:
“We have identified the majority of the mutational signatures that explain the genetic development and history of cancers in patients.
We are now beginning to understand the complicated biological processes that occur over time and leave these residual mutational signatures on cancer genomes.”
Written by Catharine Paddock PhD