Cancer 'signatures' offer hope for treatment and prevention
Thursday, Aug 15, 2013, 04:33 AM | Source: The Conversation
By Melissa Southey
Cancer 'signatures' offer hope for treatment and preventionMelissa Southey, University of Melbourne
Research published in the journal Nature overnight describes the mutations that make cancer cells grow faster than ordinary cells. These "mutational signatures" don't just open up avenues for better cancer treatment, they also provide information that could help us refine cancer prevention efforts.
The hallmark of a cancer cell is its unregulated growth. The mechanism that allows these cells to escape normal cellular growth regulation involves the introduction of mutations into the DNA of the cancer cell, which is known as the cancer genome. This mechanism of genetic change is called a somatic mutation.
Somatic mutations are genetic mutations that are not inherited but arise in cells during life. In some cancers, a substantial proportion of somatic mutations are known to be caused by "exposures", such as tobacco smoking in lung cancer. But the process that causes these somatic mutations in most cancers is not well understood.
As technology has developed over the last many decades, we have gradually started to understand the nature and diversity of somatic mutations that arise during a lifetime, including those that are significant enough to cause and promote cancer development.
Technical advances in the preparation and visualisation of chromosomes during the 1950s and 1960s provided evidence that most cancers were associated with changes in chromosomes (tightly curled strips of DNA within the nucleus of cells).
A noteworthy example was the identification of the Philadelphia chromosome (a defective chromosome 22, named after the city in which it was discovered) associated with chronic myeloid leukemia.
Over the last 50 years, researchers have gained a better understanding of the Philadelphia chromosome, and chronic myeloid leukemia has been successfully treated with imatinib mesylate (commonly known as Gleevec). This drug targets the specific genetic abnormality found in chronic myeloid leukemia.
The success of this kind of targeted therapy in treating chronic myeloid leukemia stimulated the research community and pharmaceutical industry to pursue similar opportunities to advance cancer treatment and founded the current era of personalised medicine.
Working models of cancer development supported by limited, but increasing amounts of information about somatic mutations have developed extensively during the last few decades.
In 1980, Bert Vogelstein proposed that cancer was caused by sequential mutations in specific genes. This idea was supported by genetic information he had collected from colorectal cancers and applied an insightful evolutionary perspective to cancer development that remains robust today.
He suggested that somatic mutations gave some cells a growth advantage over cells without the mutation. And when these types of mutations accumulated in a cell, it was eventually able to escape normal cellular regulation (the hallmark of cancer cells).
Another enormous advance in genetic technology has now facilitated the research published in Nature to provide a significant and extensive analysis of the somatic mutations that arise in cancer cells.
This new genetic technology is known as massively parallel sequencing, and it can affordably sequence whole cancer genomes in a matter of days. It has revolutionised genetic analyses that had previously relied upon much more laborious and expensive technology such as Sanger sequencing (developed by Frederick Sanger in the 1970s).
This technology has also spawned new approaches to data analysis and, in the new report, the researchers have developed methods to describe mutational signatures (groups of somatic mutations that are found together in cancer cells).
What we've learnt
These advances enabled the analysis of 7,042 cancers (including 30 different cancer types), and the identification of 4,938,362 somatic mutations. They revealed more than 20 distinct mutational signatures, illustrating substantially more diversity in the somatic mutation process underlying the development and progression of cancer than has ever been described before.
Many aspects of the new findings are fascinating. Some cancer types carry very few somatic mutations (some childhood cancers, for instance), while others have an extensive collection of somatic mutations (such as those related to prolonged exposure to substances such as tobacco smoke). This can be attributed to a lifetime's collection of somatic mutations, or the rate of somatic mutation accumulation.
Most cancer genomes that were sequenced contained more than one mutational signature. And some of these were found in the majority of cancer genomes while others were much more specific to the type of cancer.
The authors suggest that each mutational signature is the imprint left on the cancer genome by the somatic mutational process, and that it is likely that more mutational signatures will be identified with further improvements in genetic technology and related analytical methods.
These data will greatly advance our ability to identify cancers with the same or similar origins. It has enormous implications for diversifying the current suite of drugs available for gene-targeted cancer treatment. But, perhaps more significantly, it offers the opportunity to expand strategies for cancer prevention.