Genetic fingerprints could help identify cancer-causing culprits

Causes of cancer are being cataloged through an international study revealing the genetic fingerprints of DNA-damaging processes that drive cancer development. Researchers from University of California San Diego School of Medicine, Wellcome Sanger Institute, Duke-NUS Medical School Singapore, the Broad Institute of MIT and Harvard, with collaborators around the world, have created the most detailed list yet of these genetic fingerprints, providing clues to how each cancer develops.

These fingerprints will allow scientists to search for previously unknown chemicals, biological pathways and environmental agents responsible for causing cancer.

We identified almost every publically available cancer genome at the start of this project and analyzed their whole genome sequences. The data from these thousands of cancers allowed us to describe mutational signatures in much more detail, and we are confident that we now know most of the signatures that exist."

Ludmil B. Alexandrov, PhD, first author, assistant professor of in the departments of Cellular and Molecular Medicine and Bioengineering at UC San Diego

The research, published on February 5, 2020 in Nature as part of the global Pan-Cancer Project, will help delineate the causes of cancer, inform prevention strategies and define new directions for cancer diagnoses and treatments.

In the United States, the National Cancer Institute estimates 1.7 million new cases of cancer were diagnosed in 2018 and more than 600,000 people died from the disease. Approximately 38 percent of men and women in this country will be diagnosed with cancer in their lifetime.

Cancer is caused by genetic changes -- mutations -- in the DNA of a cell, prompting the cell to divide uncontrollably. Many known causes of cancer, such as ultraviolet light and tobacco use, leave a specific fingerprint of damage in the DNA, known as a mutational signature. These fingerprints can help understand how cancers develop, and potentially how they might be prevented. However, past studies have not been large enough to identify all potential mutational signatures.

"Using our detailed catalogue of the range of mutational signatures in cancer DNA, researchers worldwide will now be able to investigate which chemicals or processes are linked to these signatures," said co-senior author Mike Stratton, PhD, director of the Wellcome Sanger Institute. "This will increase our understanding of how cancer develops, and discover new causes of cancer, helping to inform public health strategies to prevent cancer."

This study identified new mutational signatures that had not been seen before, from single letter typo mutations, to slightly larger insertions and deletions of genetic code. The result is the largest database of reference mutational signatures. Only about half of all mutational signatures have known causes.

"Some types of these DNA fingerprints, or mutational signatures, reflect how the cancer could respond to drugs," said co-senior author Steven Rozen, PhD, director of the Center for Computational Biology and professor of Cancer and Stem Cell Biology at Duke-NUS Medical School. "Further research into this could help to diagnose some cancers and what drugs they might respond to."

The global Pan-Cancer Project is the largest and most comprehensive study of whole cancer genomes. The collaboration has created a huge resource of primary cancer genomes, available to researchers worldwide to advance cancer research.

"The availability of a large number of whole genomes enabled us to apply more advanced analytical methods to discover and refine mutational signatures and expand our study into additional types of mutations," said co-senior author Gad Getz, PhD, institute member of the Broad Institute of MIT and Harvard, professor of pathology at Harvard Medical School, and faculty member and director of bioinformatics at the Massachusetts General Hospital Cancer Center.

"Our new collection of signatures provides a more complete picture of biological and chemical processes that damage or repair DNA and will enable researchers to decipher the mutational processes that affect the genomes of newly sequenced cancers."

Source:
Journal reference:

Alexandrov, L.B., et al. (2020) The repertoire of mutational signatures in human cancer. Nature. doi.org/10.1038/s41586-020-1943-3.

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