Researchers Uncover Link Between Human Genome Topology and Cancer Mutations

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Researchers Uncover Link Between Human Genome Topology and Cancer Mutations

Researchers Uncover Link Between Human Genome Topology and Cancer Mutations.

Scientists at the University of California, San Diego, have revealed a connection between the topography of the human genome and mutations in human cancers. They’ve discovered that certain regions of the genome exhibit distinct features, becoming hotspots for mutation accumulation.

These findings, recently published in the journal “Cell Reports,” underscore the potential impact of the three-dimensional structure of the human genome on the development of various cancers.

Researchers Uncover Link Between Human Genome Topology and Cancer Mutations

Just as different terrains on Earth foster diverse ecosystems, certain topographic features within the genome seem to provide an environment conducive to the proliferation of specific mutations.

“While the human genome is often pictorially represented as the iconic DNA double helix composed of the four letters A, C, G, and T, it is far more than that,” explains senior author of the study, Ludmil Alexandrov, Professor of Bioengineering and Cellular and Molecular Medicine at the University of California, San Diego. “Much like Earth possesses varied landscapes, the genome possesses a rich topography of distinct structures, shapes, and features.”

For instance, the genome comprises tightly wound sections of DNA as well as loosely coiled ones. Some parts take on a circular form. The genome also exhibits various features, such as one called replication timing, where certain regions of the genome are replicated early during cell division while others are replicated much later.

Alexandrov’s team conducted a comprehensive study on how this genomic topography influences the occurrence of cancer mutations in the human genome. Similar to how different terrains on Earth give rise to different ecosystems, certain topographical features in the genome appear to create an environment conducive to the growth of specific mutations.

“When studying cancer genomes, we often assume that mutations accumulate randomly throughout the genome. However, that’s not the case because different parts of the genome have different characteristics,” says Burçak Otlu, the first author of the research report and former postdoctoral researcher in Alexandrov’s lab. “Through topological analysis, we found that certain mutations in cancer preferentially accumulate in specific regions of the genome.”

Researchers examined all known genomic topographic features and looked for connections with specific mutation patterns, or mutation features, across all human cancers. They analyzed the impact of 516 topographic features from 5,120 whole-genome sequenced tumors representing 40 different cancer types on mutation features.

One of the major findings of this study is that some mutation features associated with alcohol consumption accumulate in genome regions that are replicated early during cell division. This connection is particularly pronounced in esophageal cancer, head and neck cancer, and liver cancer.

Researchers note that this discovery is unexpected, as mutations often occur in regions replicated late in cell division since these are the areas with higher error rates. Early DNA replication during cell division is more precise, and genome segments replicated early are less susceptible to mutations. However, researchers found the opposite to be true for mutation features associated with alcohol consumption.

Researchers also observed mutation features related to the antiviral activity of a group of enzymes called APOBEC3. They found that these mutation features accumulate in both early and late replication regions of the genome.

“These findings are significant because many important genes reside in early replicating regions of the genome. Our research suggests that certain mutational processes do not follow the usual rules, making them likely to hit crucial genes and pathways that are typically protected,” says Alexandrov.

The research team has compiled the results of this study as an online resource. Researchers can utilize it to determine which topographic features are associated with which mutation features, and vice versa. It also shows which cancer types exhibit these associations.

Such a resource will be invaluable for future research focused on understanding the role of topographic features in the development, evolution, and treatment of cancer.