Study Finds Cancer Mutations Accumulate in Distinct Regions

Findings published in Nature Genetics suggested that mutations found in cancers do not accumulate randomly and are found instead in distinct patterns that vary based on the 3-dimensional organization of the genome in the cell as well as the underlying factors causing the mutations.¹

Mutations caused by external factors, such as ultraviolet light or tobacco smoke, were found to lead to mutations in different regions rather than internal factors, such as defects in DNA damage repair or proofreading machinery. According to researchers, these results will be important for understanding what factors may be driving mutations in a given cancer and may also possibly point to new therapeutic targets.

“DNA is not randomly organized within the nucleus, and we found that this structure is strongly correlated with how cancer cells accumulate mutations,” lead author Kadir Akdemir, PhD, instructor of Genomic Medicine at The University of Texas MD Anderson Cancer Center, said in a press release.² “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.”

In order to better understand the interplay between spatial genome organization and specific mutational processes, researchers studied 3000 tumor-normal-pair whole-genome datasets from 42 different human cancer types.

Overall, the analyses indicated that the change in somatic mutational load in cancer genomes is co-localized with topologically-associating-domain boundaries. The researchers also suggested that domain boundaries constitute a better proxy to track mutational load change compared with replication timing measurements.

Further, the collective findings demonstrated that different mutational processes lead to distinct somatic mutation distributions where certain processes generate mutations in active domains, and others generate mutations in inactive domains.

“Interestingly, we found that different causes of mutations resulted in distinct accumulation patterns within the cell,” senior author Andy Futreal, PhD, chair of Genomic Medicine at The University of Texas MD Anderson Cancer Center, said in the release. “Extrinsic factors were associated with an enrichment of mutations in inactive domains, whereas intrinsic factors were correlated with enriched mutations in active domains. This provides us an important foundation going forward to understand the root of cancer mutations when we don’t otherwise know the cause.”

Akdemir also explained that knowing the causes and distributions of cancer-related mutations may open up potential therapeutic options, such as targeted therapies against a specific signaling pathway or combinations with immunotherapy. Moving forward, the researchers indicated they hope to investigate strategies such as that utilized in this study in future studies to determine their feasibility as treatment options.

Reference:

1. Akdemir KC, Le VT, Kim JM, et al. Somatic mutation distributions in cancer genomes vary with three-dimensional chromatin structure. Nature Genetics. doi: 10.1038/s41588-020-0708-0

2. Study finds cancer mutations accumulate in distinct regions based on structure of genome and mutational causes [news release]. Published October 5, 2020. Accessed October 6, 2020. https://www.mdanderson.org/newsroom/study-finds-cancer-mutations-accumulate-in-distinct-regions-based-on-structure-of-genome-and-mutational-causes.h00-159385890.html