The way cancer mutations accumulate in the genome depends on both the 3D structure of the chromosome and the factor that is causing the mutation, shows research from the University of Texas MD Anderson Cancer Center.
The scientists believe this information could help to guide treatment better, as well as inform investigators searching for cancer causing mutations.
“DNA is not randomly organized within the nucleus, and we found that this structure is strongly correlated with how cancer cells accumulate mutations,” said Kadir Akdemir, Ph.D., a postdoctoral researcher at the MD Anderson Cancer Center and lead author on the paper describing the research, which was published in the journal Nature Medicine.
“We know there are certain processes causing mutations in cancer cells, but we don’t always understand the underlying causes. These findings should give us a clue as to how cancer accumulates mutations, and perhaps we can target and kill cancer cells by leveraging the mutations they accumulate.”
All DNA in the nucleus of our cells is organized into chromatin, which forms the structure of the chromosomes. Within chromatin there is a complex substructure organized to make gene expression easier. Genes that are often translated into proteins are grouped into more easily accessible ‘active domains’, whereas those that are needed less frequently are located in ‘inactive domains’ that are less easy to access.
In this study, the team investigated whether cancer-causing mutations in non-germline cells are more commonly found in active or inactive domains of the chromatin. To do this they studied the genome sequence of 3000 sets of samples taken from cancerous and non-cancerous tissue around the human body. Overall, they analyzed more than 60 million mutations in 42 types of cancer.
Notably, cancer-related mutations seem to occur much more frequently in inactive as opposed to active sites in the chromatin. This was particularly evident on the inactive X chromosome in women, which accumulates significant numbers of mutations in female specific cancers such as ovarian and uterine cancer. Tissue samples taken from women also had a higher number of mutations than those taken from men in a few other cancers such as chronic lymphocytic leukemia and some brain cancers, largely due to excessive mutational build up on the inactive X chromosome.
The researchers also found a difference in where mutations accumulate based on the cause of the mutation. Those caused by external factors such as UV light from the sun or exposure to tobacco smoke were more likely to cause mutations in inactive domains, whereas mutations caused by internal issues such as malfunctioning DNA damage repair were more commonly seen in active domains.
Mutations in inactive areas of the genome are able to hide better from certain types of cancer therapies. For instance, immunotherapy response is known to be better when there are higher numbers of detectable mutations in the tumor, which is likely to be due to a higher production of neoantigens by the cancerous tissue.
Akdemir and colleagues believe that reactivating or opening up of these ‘inactive’ areas could help cancer therapies be more effective. For example, inactivation of the enzyme EZH2, which normally acts to silence genes and repress transcription, could increase neoantigen production and make a number of different cancers more vulnerable to immunotherapy. In women, opening up some of the inactive X chromosome could have the same effect in female cancers that have a high number of mutations on the inactive X.
Although this study advances the understanding of how cancer mutations accumulate in the genome, which may lead to better cancer therapies in the future, the authors acknowledge that more work is needed to better understand why these mutations accumulate as they do.
For example, “further investigations into the mutation distribution patterns along chromatin domains could help in identifying the biases generated by different mutational process over time,” they suggest.
“A more thorough understanding of the 3D genome architecture in human cancers will advance our understanding of mutational processes and DNA repair activity—ultimately painting a more informative, nuanced picture of this disease,” they conclude.
