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Sanger-led Team Catalogs Mutational Signatures in 30 Cancer Types

NEW YORK (GenomeWeb News) – A large international team led by investigators at the Wellcome Trust Sanger Institute has published a new study outlining a mutational catalog reflecting the processes at play in dozens of the most common cancer culprits.

As they reported online today in Nature, the researchers brought together data for more than 7,000 cancer genomes as part of an effort to unravel characteristic mutation profiles — and the mutation processes behind them — for 30 top cancer types. The search led to at least 20 mutational signatures, which tend to be found in distinct combinations in tumors depending on an individual's age, cancer type, past exposures to DNA mutating agents, and so on.

More research is needed to understand the various DNA replication glitches, repair problems, modifications, and mutagens that can produce this suite of mutational signatures and prompt the onset of various cancers, the study authors noted. But by documenting these patterns, they hope to spur future studies into the nature of those mutational processes as well.

"We have uncovered the archaeological traces within cancer genomes of the diverse mutational processes that lead to the development of most cancers," corresponding author Michael Stratton, a researcher with the Sanger Institute's Cancer Genome Project, said in a statement.

"This compendium of mutational signatures and the consequent insights into the mutational processes underlying them has profound implications for the understanding of cancer development," he added, "with potential applications in disease prevention and treatment."

The analysis hinged on an algorithm that members of the same team used to find and profile mutational signatures in breast cancers in previous studies.

By applying a similar computational method to exome sequence data for 6,535 cancer cases as well as 507 whole cancer genomes, Stratton and his colleagues identified almost 5 million somatic substitutions, small insertions, and small deletions in tumors from 30 common cancer types.

With that information, the team tracked down and verified 21 mutational signatures. The combinations of these signatures tended to vary in ways that coincided with factors such as a patient's past exposure to mutagenic compounds, his or her age at the time of cancer diagnosis, and the type of cancer involved.

Based on their findings so far, researchers suspect that at least two types of mutational signature are at play in most cancer types. Even so, they noted that some of the signatures seem to be specific to a narrow swath of cancers, while others are far more common.

For instance, the study's authors noted that the activation of genes coding for cytidine deaminase enzymes in the APOBEC family — detected in more than half of the cancer types considered — appears to be linked to two mutational signatures and to kataegis, a form of hyper-mutation marked by a flurry of alterations affecting small, isolated portions of the genome.

In the whole-genome sequence data, the group unearthed multiple kataegic sites in a subset of the breast, lung, and haematological cancer genomes, along with more modest signs of kataegis across these and other cancer types. On the other hand, that mutational phenomenon was not detected in acute myeloid leukemia or pilocytic astrocytoma genomes.

Some of the mutational signatures documented in the study could be at least partially explained by processes proposed in the past. For example, several of the breast, ovarian, or pancreatic cancer genomes carried the type of mutational patterns that occur in the presence of inactivating changes to BRCA1 or BRCA2 genes.

And not unexpectedly, cancer types associated with smoking tended to carry tobacco-related mutational signatures, while mutational signatures linked to ultraviolet light exposure often marked the genomes of malignant melanomas and squamous head and neck carcinomas.

The source of other mutational signatures was less clear, the study's authors explained, leaving the door open for future studies to delineate the range of processes that may contribute to their development.

"Elucidating the underlying mutational processes will depend upon two major streams of investigation," they noted. "First, compilation of mutational signatures from model systems exposed to known mutagens or perturbations of the DNA maintenance machinery and comparison with those found in human cancers. Second, correlation of the contributions of mutational signatures with other biological characteristics of each cancer through diverse approaches ranging from molecular profiling to epidemiology."