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Mutational Signatures Begin to Reveal Processes Underpinning Mutation Development

SAN DIEGO (GenomeWeb News) — Researchers are beginning to trace mutations present in tumors back to the processes that formed them.

Cancer-causing processes leave signs of their effects in the resulting tumors that researchers are starting to tease out, work that was described during a session at the American Association for Cancer Research annual meeting here.

How somatic mutations develop into cancer isn't always clear, though some processes are known to have certain effects. For instance, UV light commonly leads to C to T mutations in skin cancer while tobacco exposure leads to a preponderance of C to A mutations.

"There can be many mutational processes," said Mike Stratton, the director of the Wellcome Trust Sanger Institute, in a session at AACR. A given tumor can be the result of various processes, he noted, leading to a certain mutational signature that's seen in the mature tumor.

Drawing on a large catalog of cancer samples, Stratton and his colleagues have uncovered some 30 mutational signatures, two of which they've linked to deamination by APOBEC family enzymes. His team relied on a non-negative matrix factorization (NMF) approach to extract mutational signatures from their catalog of mutations.

By drawing on a set of more than 7,000 primary cancers comprising 30 cancer types, Stratton and his team compiled more than 4.9 million somatic substitutions and small indels.

For this, Stratton and his colleagues focused on substitutions. Though rather than concentrating on the six classes of substitutions, like C to T substitutions and C to A substitutions, they incorporated the bases to the 5' and 3' sides of the substituted loci, making them TCG to TTG substitutions or ACG to ATG substitutions. This way, there are 96 substitution subtypes, which allows for greater resolution, Stratton said.

Some signatures are marked by one or two of the 96 possible substitutions, while others include nearly all possible substitutions. For example, signature 2 includes mostly C to G substitutions and C to T substitutions, while signature 3 includes low levels of all kinds of substitutions.

Additionally, some signatures are found across cancer types and others are found in just one or two types of cancer. Signatures 1A and 1B, for instance, were present in nearly every cancer type the researchers looked at, while signature 2 was in about half.

"There is considerable diversity of patterns," Stratton said.

Signature 2 and signature 13, which include mostly C to G substitutions and C to T substitutions, have been linked to the APOBEC cytidine deaminases, Stratton said.

APOBEC, he noted, is also a part of innate immunity, and he hypothesized that signature 2 is the result of collateral damage inflicted by the response to viral entry, retrotransposons, or inflammation.

Stratton further said that people with certain partial APOBEC deletions have a small, but consistent, increased risk of developing breast cancer.

This deletion as well as signature 2 is associated with hypermutations, which are also associated with increased breast cancer risk.

The APOBEC family, he added, is linked to katageis, regions of localized hypermutations associated with clusters of C to T mutations and C to G mutations. In yeast, APOBEC seems to be partially responsible for katageis, though double-stranded breaks also appear to be a necessary part of the equation.

Drawing on Stratton's NMF work, the National Cancer Centre of Singapore's Bin Teh searched for a specific mutational signature in upper urinary tract urothelial cell carcinomas linked to exposure to aristolochic acid, a component of a plant used as a traditional remedy. He argued that such a signature could possibly be used as a screening tool.

Through whole-exome and whole-genome analysis of AA-associated UTUCs, Teh and his colleagues found that such tumors included a high number of mutations —— some 150 mutations per megabase, more than what is associated with either UV or tobacco exposure.

They also teased out a mutational signature linked to AA exposure marked by an A:T to T:A transversion at the A[C|T]AGG motif that tends to occur on the non-transcribed strand. AA-induced mutations also commonly take place at splice sites.

Through RNA-sequencing, Teh and his colleagues found that CAG to CTC mutations at 3' splice sites also demonstrated atypical splicing, such as exon skipping.

In cell lines and in vitro, Teh said that he and his team found that AA alone was enough to create the mutational signature and renal pathology.

They also suspected that AA might have effects beyond the kidneys, as the enzyme that metabolizes the compound is also active in the liver. According to Teh, some 10 percent of hepatocellular carcinoma cases they examined had the AA-associated mutation signature, suggesting that it is a sort of "molecular fingerprint" for previous carcinogen exposure. Other cancers like bladder cancer may also harbor the signature.

Teh noted that his group is currently examining an independent HCC cohort in Taiwan in addition to pursuing in vivo studies.

This signature also underscores, Teh said, the need to examine cancer genomes from people living in varied parts of the world to capture differences due to ethnicity and dietary habits as well as to differences in carcinogen, environmental, and pollution exposure.

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