Unanticipated Discovery: The Correlation Between Human Genome Landscapes and Cancer-Related Mutations Identified

Attribution: Laura Rodríguez Porras

A team of researchers from the University of California, San Diego has unearthed a significant correlation between the topological features of the human genome and mutations commonly found in various types of cancer. These researchers identified specific zones within the genome that act as hubs where mutations are more likely to accumulate.

Recently divulged in the scientific journal Cell Reports, the findings underscore the consequential impact that the three-dimensional structure of the human genome could have on the genesis of different cancer types.

The human genome is typically portrayed as a double helix of DNA, constituted by a sequence of nucleotides represented by the alphabets A, C, G, and T. “Nonetheless, the genome embodies much more complexity,” elaborated Ludmil Alexandrov, the principal investigator of the study and a professor of bioengineering and cellular and molecular medicine at the University of California, San Diego. “Analogous to Earth, replete with its variegated landscapes, the genome also exhibits a multifaceted topography composed of assorted structures and characteristics.”

To illustrate, the human genome consists of segments where the DNA is tightly or loosely coiled, sections that are looped, and others marked by unique attributes like replication timing. During this process, some genome sections are duplicated early in the cell division cycle, while others are replicated later.

The extensive study spearheaded by Alexandrov’s team scrutinized how these topological features affect the occurrence of mutations in various types of cancer. Comparable to how distinct terrains on Earth host unique ecosystems, specialized features within the genome appear to create favorable conditions for certain mutations.

“It’s a common assumption that mutations in cancer are randomly distributed across the genome. However, our observations indicate otherwise due to the distinctive features of different genomic regions,” stated Alexandrov.

“Through our topological analysis, we’ve demonstrated that certain mutations preferentially cluster within specific genome areas,” said Burçak Otlu, the study’s lead author and former postdoctoral researcher under Alexandrov.

The researchers conducted a thorough analysis of known genomic topological attributes and sought associations with distinct patterns of mutations, termed as ‘mutational signatures,’ across a comprehensive set of 5,120 whole-genome sequenced tumors from 40 cancer categories.

A pivotal observation of the study is that several mutational signatures associated with alcohol consumption tend to gather in genome regions that are duplicated early during cell division. This was particularly noted in esophageal, head and neck, and liver cancers. Such an observation is contrary to expectations, as mutations generally occur more frequently in regions that are replicated later in the cell cycle.

Additionally, mutational signatures related to the antiviral action of the enzyme family APOBEC3 deaminases were found to be present in both early- and late-replicating regions of the genome.

“This is a significant discovery because critical genes predominantly reside in the early-replicated regions of the genome,” Alexandrov explained. “Our study reveals that certain mutagenic processes do not adhere to common rules and might affect essential genes usually safeguarded from mutations.”

The findings of this study have been consolidated into an online resource, aiding other researchers in cross-referencing topological features with mutational signatures, and vice versa. The resource also indicates which types of cancer demonstrate these relationships.

“The utility of this resource is immense for forthcoming studies aimed at understanding the role of genomic topography in cancer etiology, evolution, and therapeutic strategies,” said Otlu.

Citation: “Topography of mutational signatures in human cancer” by Burçak Otlu, Marcos Díaz-Gay, Ian Vermes, Erik N. Bergstrom, Maria Zhivagui, Mark Barnes, and Ludmil B. Alexandrov, published on 4 August 2023 in Cell Reports. DOI: 10.1016/j.celrep.2023.112930

Financial Support: The study was partially funded by a Cancer Research UK Grand Challenge Award (C98/A24032) and grants from the National Institutes of Health (R01ES030993, R01ES032547, and R01CA269919).

Disclosures: Ludmil Alexandrov has financial involvement as a paid consultant and holds equity in io9, LLC and Genome Insight. His spouse is employed by Biotheranostics, Inc. He also holds U.S. Patent 10,776,718 for source identification by non-negative matrix factorization and has declared U.S. provisional patent applications with serial numbers 63/366,392, 63/412,835, and 63/492,348. Additionally, Alexandrov and Erik Bergstrom have declared U.S. provisional patent applications with serial numbers 63/289,601, 63/269,033, and 63/438,237.

Frequently Asked Questions (FAQs) about Human Genome and Cancer Mutations Link

More about Human Genome and Cancer Mutations Link

• Cell Reports Journal
• University of California, San Diego – Bioengineering Department
• National Institutes of Health
• Cancer Research UK Grand Challenge Award
• Information on Mutational Signatures in Cancer
• Understanding the Human Genome
• About DNA Replication Timing
• APOBEC3 Deaminases and Cancer